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1. Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement

Author

Christy W. LaFlamme, Cassandra Rastin, Soham Sengupta, Helen E. Pennington, Sophie J. Russ-Hall, Amy L. Schneider, Emily S. Bonkowski, Edith P. Almanza Fuerte, Talia J. Allan, Miranda Perez-Galey Zalusky, Joy Goffena, Sophia B. Gibson, Denis M. Nyaga, Nico Lieffering, Malavika Hebbar, Emily V. Walker, Daniel Darnell, Scott R. Olsen, Pandurang Kolekar, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Haley McConkey, Jennifer Kerkhof, Michael A. Levy, Raissa Relator, Dorit Lev, Tally Lerman-Sagie, Kristen L. Park, Marielle Alders, Gerarda Cappuccio, Nicolas Chatron, Leigh Demain, David Genevieve, Gaetan Lesca, Tony Roscioli, Damien Sanlaville, Matthew L. Tedder, Sachin Gupta, Elizabeth A. Jones, Monika Weisz-Hubshman, Shamika Ketkar, Hongzheng Dai, Kim C. Worley, Jill A. Rosenfeld, Hsiao-Tuan Chao, Undiagnosed Diseases Network, Geoffrey Neale, Gemma L. Carvill, University of Washington Center for Rare Disease Research, Zhaoming Wang, Samuel F. Berkovic, Lynette G. Sadleir, Danny E. Miller, Ingrid E. Scheffer, Bekim Sadikovic, and Heather C. Mefford

Subjects
Science
Abstract

Abstract Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.

Published
2024
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2. Generation of five induced pluripotent stem cell lines from patients with MECP2 Duplication Syndrome

Author

Danielle Mendonca, Gerarda Cappuccio, Jennifer Sheppard, Magdalena Delacruz, Jesse Bengtsson, Claudia M.B. Carvalho, Aleksandar Bajic, Hyekyung Park, Jean J. Kim, Paymaan Jafar-Nejad, Christine Coquery, Davut Pehlivan, Bernhard Suter, and Mirjana Maletic-Savatic

Subjects
Biology (General), QH301-705.5
Abstract

MECP2 Duplication Syndrome (MDS) is a rare, severe neurodevelopmental disorder arising from duplications in the Xq28 region containing the MECP2 gene that predominantly affects males. We generated five human induced pluripotent stem cell (iPSC) lines from the fibroblasts of individuals carrying between 0.355 and 11.2 Mb size duplications in the chromosomal locus containing MECP2. All lines underwent extensive testing to confirm MECP2 duplication and iPSC-related features such as morphology, pluripotency markers, and trilineage differentiation potential. These lines are a valuable resource for molecular and functional studies of MDS as well as screening for a variety of therapeutic approaches.

Published
2024
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3. TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease

Author

Lindsey Van Haute, Emily O’Connor, Héctor Díaz-Maldonado, Benjamin Munro, Kiran Polavarapu, Daniella H. Hock, Gautham Arunachal, Alkyoni Athanasiou-Fragkouli, Mainak Bardhan, Magalie Barth, Dominique Bonneau, Nicola Brunetti-Pierri, Gerarda Cappuccio, Nikeisha J. Caruana, Natalia Dominik, Himanshu Goel, Guy Helman, Henry Houlden, Guy Lenaers, Karine Mention, David Murphy, Bevinahalli Nandeesh, Catarina Olimpio, Christopher A. Powell, Veeramani Preethish-Kumar, Vincent Procaccio, Rocio Rius, Pedro Rebelo-Guiomar, Cas Simons, Seena Vengalil, Maha S. Zaki, Alban Ziegler, David R. Thorburn, David A. Stroud, Reza Maroofian, John Christodoulou, Claes Gustafsson, Atchayaram Nalini, Hanns Lochmüller, Michal Minczuk, and Rita Horvath

Subjects
Science
Abstract

Van Haute et al describe autosomal recessive TEFM variants that impair mitochondrial transcription elongation and reduce the levels of promoter distal mitochondrial RNA transcripts, leading to heterogeneous mitochondrial diseases with a treatable neuromuscular transmission defect.

Published
2023
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4. Mass spectrometry imaging as an emerging tool for studying metabolism in human brain organoids

Author

Gerarda Cappuccio, Saleh M. Khalil, Sivan Osenberg, Feng Li, and Mirjana Maletic-Savatic

Subjects
metabolome, neurons, neuroprogenitors, brain organoids, mass spectrometry imaging method, Biology (General), QH301-705.5
Abstract

Human brain organoids are emerging models to study human brain development and pathology as they recapitulate the development and characteristics of major neural cell types, and enable manipulation through an in vitro system. Over the past decade, with the advent of spatial technologies, mass spectrometry imaging (MSI) has become a prominent tool for metabolic microscopy, providing label-free, non-targeted molecular and spatial distribution information of the metabolites within tissue, including lipids. This technology has never been used for studies of brain organoids and here, we set out to develop a standardized protocol for preparation and mass spectrometry imaging of human brain organoids. We present an optimized and validated sample preparation protocol, including sample fixation, optimal embedding solution, homogenous deposition of matrices, data acquisition and processing to maximize the molecular information derived from mass spectrometry imaging. We focus on lipids in organoids, as they play critical roles during cellular and brain development. Using high spatial and mass resolution in positive- and negative-ion modes, we detected 260 lipids in the organoids. Seven of them were uniquely localized within the neurogenic niches or rosettes as confirmed by histology, suggesting their importance for neuroprogenitor proliferation. We observed a particularly striking distribution of ceramide-phosphoethanolamine CerPE 36:1; O2 which was restricted within rosettes and of phosphatidyl-ethanolamine PE 38:3, which was distributed throughout the organoid tissue but not in rosettes. This suggests that ceramide in this particular lipid species might be important for neuroprogenitor biology, while its removal may be important for terminal differentiation of their progeny. Overall, our study establishes the first optimized experimental pipeline and data processing strategy for mass spectrometry imaging of human brain organoids, allowing direct comparison of lipid signal intensities and distributions in these tissues. Further, our data shed new light on the complex processes that govern brain development by identifying specific lipid signatures that may play a role in cell fate trajectories. Mass spectrometry imaging thus has great potential in advancing our understanding of early brain development as well as disease modeling and drug discovery.

Published
2023
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5. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Tianyun Wang, Kendra Hoekzema, Davide Vecchio, Huidan Wu, Arvis Sulovari, Bradley P. Coe, Madelyn A. Gillentine, Amy B. Wilfert, Luis A. Perez-Jurado, Malin Kvarnung, Yoeri Sleyp, Rachel K. Earl, Jill A. Rosenfeld, Madeleine R. Geisheker, Lin Han, Bing Du, Chris Barnett, Elizabeth Thompson, Marie Shaw, Renee Carroll, Kathryn Friend, Rachael Catford, Elizabeth E. Palmer, Xiaobing Zou, Jianjun Ou, Honghui Li, Hui Guo, Jennifer Gerdts, Emanuela Avola, Giuseppe Calabrese, Maurizio Elia, Donatella Greco, Anna Lindstrand, Ann Nordgren, Britt-Marie Anderlid, Geert Vandeweyer, Anke Van Dijck, Nathalie Van der Aa, Brooke McKenna, Miroslava Hancarova, Sarka Bendova, Marketa Havlovicova, Giovanni Malerba, Bernardo Dalla Bernardina, Pierandrea Muglia, Arie van Haeringen, Mariette J. V. Hoffer, Barbara Franke, Gerarda Cappuccio, Martin Delatycki, Paul J. Lockhart, Melanie A. Manning, Pengfei Liu, Ingrid E. Scheffer, Nicola Brunetti-Pierri, Nanda Rommelse, David G. Amaral, Gijs W. E. Santen, Elisabetta Trabetti, Zdeněk Sedláček, Jacob J. Michaelson, Karen Pierce, Eric Courchesne, R. Frank Kooy, The SPARK Consortium, Magnus Nordenskjöld, Corrado Romano, Hilde Peeters, Raphael A. Bernier, Jozef Gecz, Kun Xia, and Evan E. Eichler

Subjects
Science
Abstract

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

Published
2020
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6. Cavitating and tigroid‐like leukoencephalopathy in a case of NDUFA2‐related disorder

Author

Marianna Alagia, Gerarda Cappuccio, Annalaura Torella, Alessandra D'Amico, Federica Mazio, Alfonso Romano, Simona Fecarotta, Giorgio Casari, Vincenzo Nigro, TUDP, and Nicola Brunetti‐Pierri

Subjects
leukodystrophy, mitochondrial, NDUFA2, Diseases of the endocrine glands. Clinical endocrinology, RC648-665, Genetics, QH426-470
Abstract

Abstract Biallelic variants in nuclear gene NDUFA2 have been reported so far in only three children with variable presentations including Leigh syndrome or leukoencephalopathy. Herein, we report a further female child affected by NDUFA2‐related disorder presenting with cavitating and tigroid‐like pattern of leukodystrophy and without systemic biochemical abnormalities of mitochondrial disorders.

Published
2020
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7. RARS1‐related hypomyelinating leukodystrophy: Expanding the spectrum

Author

Marisa I. Mendes, Lydia M. C. Green, Enrico Bertini, Davide Tonduti, Chiara Aiello, Desiree Smith, Ettore Salsano, Shanice Beerepoot, Jozef Hertecant, Sarah vonSpiczak, John H. Livingston, Lisa Emrick, Jamie Fraser, Laura Russell, Genevieve Bernard, Stefania Magri, Daniela Di Bella, Franco Taroni, Mary K. Koenig, Isabella Moroni, Gerarda Cappuccio, Nicola Brunetti‐Pierri, Jullie Rhee, Bryce A. Mendelsohn, Ingo Helbig, Katherine Helbig, Hiltrud Muhle, Omar Ismayl, Adeline L. Vanderver, Gajja S. Salomons, Marjo S. van derKnaap, and Nicole I. Wolf

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Objective Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1‐related disease, and to identify possible genotype‐phenotype relationships. Methods We performed a multinational cross‐sectional survey among 20 patients with biallelic RARS1 variants identified by next‐generation sequencing techniques. Clinical data, brain MRI findings and genetic results were analyzed. Additionally, ArgRS activity was measured in fibroblasts of four patients, and translation of long and short ArgRS isoforms was quantified by western blot. Results Clinical presentation ranged from severe (onset in the first 3 months, usually with refractory epilepsy and early brain atrophy), to intermediate (onset in the first year with nystagmus and spasticity), and mild (onset around or after 12 months with minimal cognitive impairment and preserved independent walking). The most frequent RARS1 variant, c.5A>G, led to mild or intermediate phenotypes, whereas truncating variants and variants affecting amino acids close to the ArgRS active centre led to severe phenotypes. ArgRS activity was significantly reduced in three patients with intermediate and severe phenotypes; in a fourth patient with intermediate to severe presentation, we measured normal ArgRS activity, but found translation mainly of the short instead of the long ArgRS isoform. Interpretation Variants in RARS1 impair ArgRS activity and do not only lead to a classic hypomyelination presentation with nystagmus and spasticity, but to a wide spectrum, ranging from severe, early‐onset epileptic encephalopathy with brain atrophy to mild disease with relatively preserved myelination.

Published
2020
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8. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Author

Michael A. Levy, Haley McConkey, Jennifer Kerkhof, Mouna Barat-Houari, Sara Bargiacchi, Elisa Biamino, María Palomares Bralo, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, Barbara R. DuPont, Mariet W. Elting, Laurence Faivre, Timothy Fee, Robin S. Fletcher, Florian Cherik, Aidin Foroutan, Michael J. Friez, Cristina Gervasini, Sadegheh Haghshenas, Benjamin A. Hilton, Zandra Jenkins, Simranpreet Kaur, Suzanne Lewis, Raymond J. Louie, Silvia Maitz, Donatella Milani, Angela T. Morgan, Renske Oegema, Elsebet Østergaard, Nathalie Ruiz Pallares, Maria Piccione, Simone Pizzi, Astrid S. Plomp, Cathryn Poulton, Jack Reilly, Raissa Relator, Rocio Rius, Stephen Robertson, Kathleen Rooney, Justine Rousseau, Gijs W.E. Santen, Fernando Santos-Simarro, Josephine Schijns, Gabriella Maria Squeo, Miya St John, Christel Thauvin-Robinet, Giovanna Traficante, Pleuntje J. van der Sluijs, Samantha A. Vergano, Niels Vos, Kellie K. Walden, Dimitar Azmanov, Tugce Balci, Siddharth Banka, Jozef Gecz, Peter Henneman, Jennifer A. Lee, Marcel M.A.M. Mannens, Tony Roscioli, Victoria Siu, David J. Amor, Gareth Baynam, Eric G. Bend, Kym Boycott, Nicola Brunetti-Pierri, Philippe M. Campeau, John Christodoulou, David Dyment, Natacha Esber, Jill A. Fahrner, Mark D. Fleming, David Genevieve, Kristin D. Kerrnohan, Alisdair McNeill, Leonie A. Menke, Giuseppe Merla, Paolo Prontera, Cheryl Rockman-Greenberg, Charles Schwartz, Steven A. Skinner, Roger E. Stevenson, Antonio Vitobello, Marco Tartaglia, Marielle Alders, Matthew L. Tedder, and Bekim Sadikovic

Subjects
Episignatures, Neurodevelopmental disorders, DNA methylation, Epigenetics, Clinical diagnostics, Genetics, QH426-470
Abstract

Summary: Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Published
2022
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9. The Treatment of Hypersalivation in Rett Syndrome with Botulinum Toxin: Efficacy and Clinical Implications

Author

Pia Bernardo, Enza Raiano, Gerarda Cappuccio, Raffaele Dubbioso, Carmela Bravaccio, Emilia Vergara, Silvio Peluso, Fiore Manganelli, and Marcello Esposito

Subjects
Botulinum toxin, Bruxism, Drooling, Rett syndrome, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Introduction Subjects with Rett syndrome (RS) develop invariably severe motor deterioration resulting in swallowing difficulties that may produce excessive drooling. Hypersalivation can cause discomfort due to hygienic problems and may complicate with oral and respiratory dysfunctions. The aim of this study is to evaluate the response to treatment with botulinum toxin (BTX) for hypersalivation and to identify possible benefits of saliva reduction on oral motor and respiratory disorders of patients with RS. Methods Five consecutive patients with RS and hypersalivation were treated with incobotulinumtoxin A injected in salivary glands with ultrasound guidance. Severity of excessive drooling was assessed with the Thomas-Stonell and Greenberg Scale (TGSC) and the clinical impact of the treatment was evaluated using three selected items of RS Assessment Rating Scale (R.A.R.S.): eating habits, dyspnoea and bruxism. Scale rating was performed before BTX injection (T0), 4 (T1) and 12 (T2) weeks after. Results Scores of TGSC and R.A.R.S. (for eating and bruxism) were reduced significantly after therapy at T1. Conclusions BTX treatment for sialorrhea in RS is effective in reducing saliva production and may also improve oral motor functions.

Published
2019
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10. Mild form of Zellweger Spectrum Disorders (ZSD) due to variants in PEX1: Detailed clinical investigation in a 9-years-old female

Author

Maria Rosaria Barillari, Marianthi Karali, Valentina Di Iorio, Maria Contaldo, Vincenzo Piccolo, Maria Esposito, Giuseppe Costa, Giuseppe Argenziano, Rosario Serpico, Marco Carotenuto, Gerarda Cappuccio, Sandro Banfi, Paolo Melillo, and Francesca Simonelli

Subjects
Sensorineural hearing loss, Retinitis pigmentosa, Enamel defects, PEX genes, Peroxisomal biogenesis disorders, Mild Zellweger syndrome, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Peroxisomal biogenesis disorders (PBD) are rare autosomal recessive disorders with various degrees of severity caused by hypomorphic mutations in 13 different peroxin (PEX) genes. In this study, we report the clinical and molecular characterization of a 9-years-old female presenting an apparently isolated pre-lingual sensorineural hearing loss (SNHL) and early onset Retinitis Pigmentosa (RP) that may clinically overlap with Usher syndrome. Genetic testing by clinical exome sequencing identified two variants in PEX1: the missense variant c.274G > C; p.(Val92Leu) that was already reported in a PBD patient, and the variant c.2140_2145dup; p.(Ser714_Gln715dup) which is a novel, non-frameshift variant, absent in control databases. On the basis of the molecular analysis, a thorough clinical examination revealed nail and dental abnormalities, a mild cognitive impairment, learning disabilities and poor feeding, apart from the retinal and audiological features initially identified. The clinical and molecular findings led us to the diagnosis of a mild form of PBD. This study further emphasizes that mild forms of PBD can be a differential diagnosis of Usher syndrome and suggests that patients with mild cognitive impairment associated to visual and hearing loss should perform a comprehensive mutation screening that includes PEX genes.

Published
2020
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11. Mild Clinical Presentation of Joubert Syndrome in a Male Adult Carrying Biallelic MKS1 Truncating Variants

Author

Raffaella Brunetti-Pierri, Marianthi Karali, Francesco Testa, Gerarda Cappuccio, Maria Elena Onore, Francesca Romano, Giuseppe De Rosa, Enrico Tedeschi, Nicola Brunetti-Pierri, Sandro Banfi, and Francesca Simonelli

Subjects
MKS1, autosomal recessive Retinitis Pigmentosa, Joubert syndrome, phenotype extension, Medicine (General), R5-920
Abstract

Pathogenic variants in the MKS1 gene are responsible for a ciliopathy with a wide spectrum of clinical manifestations ranging from Meckel and Joubert syndrome (JBTS) to Bardet-Biedl syndrome, and involving the central nervous system, liver, kidney, skeleton, and retina. We report a 39-year-old male individual presenting with isolated Retinitis Pigmentosa (RP), as assessed by full ophthalmological evaluation including Best-Corrected Visual Acuity measurements, fundus examination, Goldmann Visual Field test, and full-field Electroretinography. A clinical exome identified biallelic nonsense variants in MKS1 that prompted post-genotyping investigations for systemic abnormalities of ciliopathy. Brain magnetic resonance imaging revealed malformations of the posterior cranial fossa with the ‘molar tooth sign’ and cerebellar folia dysplasia, which are both distinctive features of JBTS. No other organ or skeletal abnormalities were detected. This case illustrates the power of clinical exome for the identification of the mildest forms of a disease spectrum, such as a mild JBTS with RP in the presented case of an individual carrying biallelic truncating variants in MKS1.

Published
2021
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12. Retinal dystrophy in an individual carrying a de novo missense variant of SMARCA4

Author

Gerarda Cappuccio, Raffaella Brunetti‐Pierri, Annalaura Torella, Michele Pinelli, Raffaele Castello, Giorgio Casari, Vincenzo Nigro, Sandro Banfi, Francesca Simonelli, TUDP, and Nicola Brunetti‐Pierri

Subjects
Coffin–Siris syndrome, retinitis pigmentosa, SMARCA4, Genetics, QH426-470
Abstract

Abstract Background Coffin–Siris syndrome (CSS) is characterized by intellectual disability, dysmorphic facial features, growth deficiency, microcephaly, and abnormalities of the fifth fingers/toes. CSS is caused by mutations in several genes of the BRG1‐associated factor pathway including SMARCA4. Methods Whole‐exome sequencing was performed on a 14‐year‐old female individual who presented with mild intellectual disability and dysmorphic features, tooth abnormalities, and short stature. She had brachydactyly but no aplasia or hypoplasia of the distal phalanx or nail of the fifth digit. She was also found to have retinal dystrophy that has not been previously reported in CSS. Results The individual presented herein was found to harbor a previously unreported de novo variant in SMARCA4. Conclusion This case expands the phenotypic spectrum of CSS manifestations.

Published
2019
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13. Severe presentation and complex brain malformations in an individual carrying a CCND2 variant

Author

Gerarda Cappuccio, Lorenzo Ugga, Elena Parrini, Alessandra D’Amico, and Nicola Brunetti‐Pierri

Subjects
CCND2, Megalencephaly‐polymicrogyria‐polydactyly‐hydrocephalus, MPPH, Genetics, QH426-470
Abstract

Abstract Background Megalencephaly‐polymicrogyria‐polydactyly‐hydrocephalus (MPPH) is a developmental brain disorder characterized by megalencephaly and bilateral perisylvian polymicrogyria due to defects in genes of the PI3K‐AKT pathway. Only a few patients with CCND2 mutations have been reported to date. Methods We describe an individual harboring a de novo variant in CCND2 undergoing neuroradiological evaluation including diffusion tensor imaging (DTI). Results The individual presented with a severe brain malformation extending to both brainstem and cerebellum with hypomyelination not previously reported in CCND2‐related disorder. Severe hypoplasia and white matter disorganization were confirmed by DTI. Conclusion This report expands the phenotypic spectrum of the disorder due to CCND2 variants.

Published
2019
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14. Diagnosis of adenylosuccinate lyase deficiency by metabolomic profiling in plasma reveals a phenotypic spectrum

Author

Taraka R. Donti, Gerarda Cappuccio, Leroy Hubert, Juanita Neira, Paldeep S. Atwal, Marcus J. Miller, Aaron L. Cardon, V. Reid Sutton, Brenda E. Porter, Fiona M. Baumer, Michael F. Wangler, Qin Sun, Lisa T. Emrick, and Sarah H. Elsea

Subjects
Metabolomic profiling, ADSL deficiency, Intellectual disability, Succinyladenosine, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Adenylosuccinate lyase (ADSL) deficiency is a rare autosomal recessive neurometabolic disorder that presents with a broad-spectrum of neurological and physiological symptoms. The ADSL gene produces an enzyme with binary molecular roles in de novo purine synthesis and purine nucleotide recycling. The biochemical phenotype of ADSL deficiency, accumulation of SAICAr and succinyladenosine (S-Ado) in biofluids of affected individuals, serves as the traditional target for diagnosis with targeted quantitative urine purine analysis employed as the predominate method of detection. In this study, we report the diagnosis of ADSL deficiency using an alternative method, untargeted metabolomic profiling, an analytical scheme capable of generating semi-quantitative z-score values for over 1000 unique compounds in a single analysis of a specimen. Using this method to analyze plasma, we diagnosed ADSL deficiency in four patients and confirmed these findings with targeted quantitative biochemical analysis and molecular genetic testing. ADSL deficiency is part of a large a group of neurometabolic disorders, with a wide range of severity and sharing a broad differential diagnosis. This phenotypic similarity among these many inborn errors of metabolism (IEMs) has classically stood as a hurdle in their initial diagnosis and subsequent treatment. The findings presented here demonstrate the clinical utility of metabolomic profiling in the diagnosis of ADSL deficiency and highlights the potential of this technology in the diagnostic evaluation of individuals with neurologic phenotypes.

Published
2016
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15. Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Tianyun Wang, Kendra Hoekzema, Davide Vecchio, Huidan Wu, Arvis Sulovari, Bradley P. Coe, Madelyn A. Gillentine, Amy B. Wilfert, Luis A. Perez-Jurado, Malin Kvarnung, Yoeri Sleyp, Rachel K. Earl, Jill A. Rosenfeld, Madeleine R. Geisheker, Lin Han, Bing Du, Chris Barnett, Elizabeth Thompson, Marie Shaw, Renee Carroll, Kathryn Friend, Rachael Catford, Elizabeth E. Palmer, Xiaobing Zou, Jianjun Ou, Honghui Li, Hui Guo, Jennifer Gerdts, Emanuela Avola, Giuseppe Calabrese, Maurizio Elia, Donatella Greco, Anna Lindstrand, Ann Nordgren, Britt-Marie Anderlid, Geert Vandeweyer, Anke Van Dijck, Nathalie Van der Aa, Brooke McKenna, Miroslava Hancarova, Sarka Bendova, Marketa Havlovicova, Giovanni Malerba, Bernardo Dalla Bernardina, Pierandrea Muglia, Arie van Haeringen, Mariette J. V. Hoffer, Barbara Franke, Gerarda Cappuccio, Martin Delatycki, Paul J. Lockhart, Melanie A. Manning, Pengfei Liu, Ingrid E. Scheffer, Nicola Brunetti-Pierri, Nanda Rommelse, David G. Amaral, Gijs W. E. Santen, Elisabetta Trabetti, Zdeněk Sedláček, Jacob J. Michaelson, Karen Pierce, Eric Courchesne, R. Frank Kooy, The SPARK Consortium, Magnus Nordenskjöld, Corrado Romano, Hilde Peeters, Raphael A. Bernier, Jozef Gecz, Kun Xia, and Evan E. Eichler

Subjects
Science
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
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16. Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet.

Author

Gerarda Cappuccio, Michele Pinelli, Marianna Alagia, Taraka Donti, Debra-Lynn Day-Salvatore, Pierangelo Veggiotti, Valentina De Giorgis, Simona Lunghi, Maria Stella Vari, Pasquale Striano, Nicola Brunetti-Pierri, Adam D Kennedy, and Sarah H Elsea

Subjects
Medicine, Science
Abstract

Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.

Published
2017
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17. Sphingolipid Metabolism Perturbations in Rett Syndrome

Author

Gerarda Cappuccio, Taraka Donti, Michele Pinelli, Pia Bernardo, Carmela Bravaccio, Sarah H. Elsea, and Nicola Brunetti-Pierri

Subjects
rett syndrome, sphingolipid, sphinganine, sphingosine, mecp2, Microbiology, QR1-502
Abstract

Rett syndrome is a severe neurodevelopmental disorder affecting mostly females and is caused by loss-of-function mutations in the MECP2 gene that encoded the methyl-CpG-binding protein 2. The pathogenetic mechanisms of Rett syndrome are not completely understood and metabolic derangements are emerging as features of Rett syndrome. We performed a semi-quantitative tandem mass spectrometry-based analysis that measured over 900 metabolites on blood samples from 14 female subjects with Rett syndrome carrying MECP2 mutations. The metabolic profiling revealed alterations in lipids, mostly involved in sphingolipid metabolism, and sphinganine/sphingosine, that are known to have a neurotrophic role. Further investigations are required to understand the mechanisms underlying such perturbations and their significance in the disease pathogenesis. Nevertheless, these metabolites are attractive for studies on the disease pathogenesis and as potential disease biomarkers.

Published
2019
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18. Antibody Deficiency in Patients with Biallelic KARS1 Mutations

Author

Francesco, Saettini, primary, Fabiola, Guerra, additional, Grazia, Fazio, additional, Cristina, Bugarin, additional, J, McMillan Hugh, additional, Akira, Ohtake, additional, Anna, Ardissone, additional, Masayuki, Itoh, additional, Sabrina, Giglio, additional, Gerarda, Cappuccio, additional, Giuliana, Giardino, additional, Roberta, Romano, additional, Manuel, Quadri, additional, Serena, Gasperini, additional, Daniele, Moratto, additional, Marco, Chiarini, additional, Akira, Ishiguro, additional, Yasuyuki, Fukuhara, additional, Itaru, Hayakawa, additional, Yasushi, Okazaki, additional, Mario, Mauri, additional, Rocco, Piazza, additional, Gianni, Cazzaniga, additional, and Andrea, Biondi, additional

Published
2023
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19. <scp>POU3F3</scp> ‐related disorder: Defining the phenotype and expanding the molecular spectrum

Author

Alessandra Rossi, Lot Snijders Blok, Sonja Neuser, Chiara Klöckner, Konrad Platzer, Laurence Olivier Faivre, Heike Weigand, Maria L. Dentici, Marco Tartaglia, Marcello Niceta, Paolo Alfieri, Siddharth Srivastava, David Coulter, Lacey Smith, Kristin Vinorum, Gerarda Cappuccio, Nicola Brunetti‐Pierri, Deniz Torun, Mutluay Arslan, Mathilde F. Lauridsen, Oliver Murch, Rachel Irving, Sally A. Lynch, Sarju G. Mehta, Jenny Carmichael, Evelien Zonneveld‐Huijssoon, Bert de Vries, Tjitske Kleefstra, Katrine M. Johannesen, Ian T. Westphall, Susan S. Hughes, Sarah Smithson, Julie Evans, Tracy Dudding‐Byth, Marleen Simon, Ellen van Binsbergen, Johanna C. Herkert, Gea Beunders, Henry Oppermann, Mert Bakal, Rikke S. Møller, Guido Rubboli, and Allan Bayat

Subjects
Genetics, Genetics (clinical)
Published
2023

20. Functional effects of disease-associated variants reveal that the S1–M1 linker of the NMDA receptor critically controls channel opening

Author

Lingling Xie, Miranda J. McDaniel, Riley E. Perszyk, Sukhan Kim, Gerarda Cappuccio, Kevin A. Shapiro, Beatriz Muñoz-Cabello, Pedro A. Sanchez-Lara, Katheryn Grand, Jing Zhang, Kelsey A. Nocilla, Rehan Sheikh, Lluis Armengol, Roberta Romano, Tyler Mark Pierson, Hongjie Yuan, Scott J. Myers, and Stephen F. Traynelis

Subjects
Pharmacology, Cellular and Molecular Neuroscience, Molecular Medicine, Cell Biology, Molecular Biology
Published
2023

21. Expanding the phenotype of <scp> HNRNPU </scp> ‐related neurodevelopmental disorder with emphasis on seizure phenotype and review of literature

Author

James Taylor, Michael Spiller, Kara Ranguin, Antonio Vitobello, Christophe Philippe, Ange‐Line Bruel, Gerarda Cappuccio, Nicola Brunetti‐Pierri, Marjolaine Willems, Bertrand Isidor, Kristen Park, Meena Balasubramanian, Taylor, Jame, Spiller, Michael, Ranguin, Kara, Vitobello, Antonio, Philippe, Christophe, Bruel, Ange-Line, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Willems, Marjolaine, Isidor, Bertrand, Park, Kristen, and Balasubramanian, Meena

Subjects
seizure, Developmental Disabilitie, Developmental Disabilities, global developmental delay, Heterogeneous-Nuclear Ribonucleoprotein U, Phenotype, Neurodevelopmental Disorders, Seizures, HNRNPU, Child, Preschool, Intellectual Disability, Genetics, Humans, Agenesis of Corpus Callosum, Child, Genetics (clinical), Human
Abstract

Pathogenic variants in heterogeneous nuclear ribonucleoprotein U (HNRNPU) results in a novel neurodevelopmental disorder recently delineated. Here, we report on 17 previously unpublished patients carrying HNRNPU pathogenic variants. All patients were found to harbor de novo loss-of-function variants except for one individual where the inheritance could not be determined, as a parent was unavailable for testing. All patients had seizures which started in early childhood, global developmental delay, intellectual disability, and dysmorphic features. In addition, hypotonia, behavioral abnormalities (such as autistic features, aggression, anxiety, and obsessive-compulsive behaviors), and cardiac (septal defects) and/or brain abnormalities (ventriculomegaly and corpus callosum thinning/agenesis) were frequently observed. We have noted four recurrent variants in the literature (c.1089G>A p.(Trp363*), c.706_707del p.(Glu236Thrfs*6), c.847_857del p.(Phe283Serfs*5), and c.1681dels p.(Gln561Serfs*45)).

Published
2022

22. De Novo ATP1A1 Variants in an Early-Onset Complex Neurodevelopmental Syndrome

Author

Maike F. Dohrn, Adriana P. Rebelo, Siddharth Srivastava, Gerarda Cappuccio, Robert Smigiel, Alka Malhotra, Donald Basel, Ingrid van de Laar, Rinze Frederik Neuteboom, Coranne Aarts-Tesselaar, Sonal Mahida, Nicola Brunetti-Pierri, Ryan J. Taft, Stephan Züchner, Dohrn, Maike F, Rebelo, Adriana P, Srivastava, Siddharth, Cappuccio, Gerarda, Smigiel, Robert, Malhotra, Alka, Basel, Donald, van de Laar, Ingrid, Neuteboom, Rinze Frederik, Aarts-Tesselaar, Coranne, Mahida, Sonal, Brunetti-Pierri, Nicola, Taft, Ryan J, Züchner, Stephan, Clinical Genetics, and Neurology

Subjects
Phenotype, Intellectual Disability, Mutation, Migraine with Aura, Syndrome, Neurology (clinical), Sodium-Potassium-Exchanging ATPase, Human
Abstract

ATP1A1 encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic ATP1A1 variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous ATP1A1 variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity in silico prediction scores. In HEK cells transfected with ouabain-insensitive ATP1A1 constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of ATP1A1.

Published
2022

23. Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for <scp> SMAD4 </scp> in human neural crest defects

Author

Gerarda Cappuccio, Nicola Brunetti‐Pierri, Paul Clift, Christopher Learn, John C. Dykes, Catherine L. Mercer, Bert Callewaert, Ilse Meerschaut, Alessandro Mauro Spinelli, Irene Bruno, Matthew J. Gillespie, Aaron T. Dorfman, Adda Grimberg, Mark E. Lindsay, Angela E. Lin, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Clift, Paul, Learn, Christopher, Dykes, John C, Mercer, Catherine L, Callewaert, Bert, Meerschaut, Ilse, Spinelli, Alessandro Mauro, Bruno, Irene, Gillespie, Matthew J, Dorfman, Aaron T, Grimberg, Adda, Lindsay, Mark E, and Lin, Angela E

Subjects
Heart Defects, Congenital, Male, conotruncal heart defect, restrictive cardiomyopathy, Facies, SMAD4, Myhre syndrome, Phenotype, Intellectual Disability, Cryptorchidism, Genetics, Humans, tetralogy of Fallot, Hand Deformities, Congenital, neural crest, Growth Disorders, Genetics (clinical), Smad4 Protein
Abstract

Tetralogy of Fallot (ToF) can be associated with a wide range of extracardiac anomalies, with an underlying etiology identified in approximately 10% of cases. Individuals affected with Myhre syndrome due to recurrent SMAD4 mutations frequently have cardiovascular anomalies, including congenital heart defects. In addition to two patients in the literature with ToF, we describe five additional individuals with Myhre syndrome and classic ToF, ToF with pulmonary atresia and multiple aorto-pulmonary collaterals, and ToF with absent pulmonary valve. Aorta hypoplasia was documented in one patient and suspected in another two. In half of these individuals, postoperative cardiac dysfunction was thought to be more severe than classic postoperative ToF repair. There may be an increase in right ventricular pressure, and right ventricular dysfunction due to free pulmonic regurgitation. Noncardiac developmental abnormalities in our series and the literature, including corectopia, heterochromia iridis, and congenital miosis suggest an underlying defect of neural crest cell migration in Myhre syndrome. We advise clinicians that Myhre syndrome should be considered in the genetic evaluation of a child with ToF, short stature, unusual facial features, and developmental delay, as these children may be at risk for increased postoperative morbidity. Additional research is needed to investigate the hypothesis that postoperative hemodynamics in these patients may be consistent with restrictive myocardial physiology.

Published
2022

24. Contributors

Author

Irene Antony, Elizabeth D. Buttermore, Gerarda Cappuccio, Juan Cruz Casabona, Gareth Chapman, Ivy Pin-Fang Chen, Harue Chou, Laurence Daheron, Alfred K. Dei-Ampeh, Thomas M. Durcan, Sandra J. Engle, Patrick Faloon, Kevin T. FitzGerald, Deborah L. French, James Giordano, Madison R. Glass, Komal Kaushik, Robin J. Kleiman, Teun Klein Gunnewiek, Kristen L. Kroll, Felix A. Kyere, Herbert M. Lachman, Brooke Latour, Mirjana Maletic-Savatic, Xiaobo Mao, Abigail Mariga, Gilles Maussion, Kesavan Meganathan, Swati Mishra, Nael Nadif Kasri, Andrew Petersen, Luisa Pimentel, Ramachandran Prakasam, Aiko Robert, Cecilia Rocha, Manuj Shah, Jason L. Stein, Maria Sundberg, Rik Van Der Kant, Coen Van Deursen, Elisa A. Waxman, Samantha Wu, Mingyao Ying, Damian W. Young, and Jessica E. Young

Published
2023

26. Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders

Author

Michael A. Levy, Raissa Relator, Haley McConkey, Erinija Pranckeviciene, Jennifer Kerkhof, Mouna Barat‐Houari, Sara Bargiacchi, Elisa Biamino, María Palomares Bralo, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, Barbara R. DuPont, Mariet W. Elting, Laurence Faivre, Timothy Fee, Marco Ferilli, Robin S. Fletcher, Florian Cherick, Aidin Foroutan, Michael J. Friez, Cristina Gervasini, Sadegheh Haghshenas, Benjamin A. Hilton, Zandra Jenkins, Simranpreet Kaur, Suzanne Lewis, Raymond J. Louie, Silvia Maitz, Donatella Milani, Angela T. Morgan, Renske Oegema, Elsebet Østergaard, Nathalie R. Pallares, Maria Piccione, Astrid S. Plomp, Cathryn Poulton, Jack Reilly, Rocio Rius, Stephen Robertson, Kathleen Rooney, Justine Rousseau, Gijs W. E. Santen, Fernando Santos‐Simarro, Josephine Schijns, Gabriella M. Squeo, Miya St John, Christel Thauvin‐Robinet, Giovanna Traficante, Pleuntje J. van der Sluijs, Samantha A. Vergano, Niels Vos, Kellie K. Walden, Dimitar Azmanov, Tugce B. Balci, Siddharth Banka, Jozef Gecz, Peter Henneman, Jennifer A. Lee, Marcel M. A. M. Mannens, Tony Roscioli, Victoria Siu, David J. Amor, Gareth Baynam, Eric G. Bend, Kym Boycott, Nicola Brunetti‐Pierri, Philippe M. Campeau, Dominique Campion, John Christodoulou, David Dyment, Natacha Esber, Jill A. Fahrner, Mark D. Fleming, David Genevieve, Delphine Heron, Thomas Husson, Kristin D. Kernohan, Alisdair McNeill, Leonie A. Menke, Giuseppe Merla, Paolo Prontera, Cheryl Rockman‐Greenberg, Charles Schwartz, Steven A. Skinner, Roger E. Stevenson, Marie Vincent, Antonio Vitobello, Marco Tartaglia, Marielle Alders, Matthew L. Tedder, Bekim Sadikovic, Human genetics, Amsterdam Reproduction & Development (AR&D), Pediatrics, Levy M.A., Relator R., McConkey H., Pranckeviciene E., Kerkhof J., Barat-Houari M., Bargiacchi S., Biamino E., Palomares Bralo M., Cappuccio G., Ciolfi A., Clarke A., DuPont B.R., Elting M.W., Faivre L., Fee T., Ferilli M., Fletcher R.S., Cherick F., Foroutan A., Friez M.J., Gervasini C., Haghshenas S., Hilton B.A., Jenkins Z., Kaur S., Lewis S., Louie R.J., Maitz S., Milani D., Morgan A.T., Oegema R., Ostergaard E., Pallares N.R., Piccione M., Plomp A.S., Poulton C., Reilly J., Rius R., Robertson S., Rooney K., Rousseau J., Santen G.W.E., Santos-Simarro F., Schijns J., Squeo G.M., John M.S., Thauvin-Robinet C., Traficante G., van der Sluijs P.J., Vergano S.A., Vos N., Walden K.K., Azmanov D., Balci T.B., Banka S., Gecz J., Henneman P., Lee J.A., Mannens M.M.A.M., Roscioli T., Siu V., Amor D.J., Baynam G., Bend E.G., Boycott K., Brunetti-Pierri N., Campeau P.M., Campion D., Christodoulou J., Dyment D., Esber N., Fahrner J.A., Fleming M.D., Genevieve D., Heron D., Husson T., Kernohan K.D., McNeill A., Menke L.A., Merla G., Prontera P., Rockman-Greenberg C., Schwartz C., Skinner S.A., Stevenson R.E., Vincent M., Vitobello A., Tartaglia M., Alders M., Tedder M.L., Sadikovic B., Levy, Michael A, Relator, Raissa, Mcconkey, Haley, Pranckeviciene, Erinija, Kerkhof, Jennifer, Barat-Houari, Mouna, Bargiacchi, Sara, Biamino, Elisa, Bralo, María Palomare, Cappuccio, Gerarda, Ciolfi, Andrea, Clarke, Angu, Dupont, Barbara R, Elting, Mariet W, Faivre, Laurence, Fee, Timothy, Ferilli, Marco, Fletcher, Robin S, Cherick, Florian, Foroutan, Aidin, Friez, Michael J, Gervasini, Cristina, Haghshenas, Sadegheh, Hilton, Benjamin A, Jenkins, Zandra, Kaur, Simranpreet, Lewis, Suzanne, Louie, Raymond J, Maitz, Silvia, Milani, Donatella, Morgan, Angela T, Oegema, Renske, Østergaard, Elsebet, Pallares, Nathalie Ruiz, Piccione, Maria, Plomp, Astrid S, Poulton, Cathryn, Reilly, Jack, Rius, Rocio, Robertson, Stephen, Rooney, Kathleen, Rousseau, Justine, Santen, Gijs W E, Santos-Simarro, Fernando, Schijns, Josephine, Squeo, Gabriella Maria, John, Miya St, Thauvin-Robinet, Christel, Traficante, Giovanna, van der Sluijs, Pleuntje J, Vergano, Samantha A, Vos, Niel, Walden, Kellie K, Azmanov, Dimitar, Balci, Tugce B, Banka, Siddharth, Gecz, Jozef, Henneman, Peter, Lee, Jennifer A, Mannens, Marcel M A M, Roscioli, Tony, Siu, Victoria, Amor, David J, Baynam, Gareth, Bend, Eric G, Boycott, Kym, Brunetti-Pierri, Nicola, Campeau, Philippe M, Campion, Dominique, Christodoulou, John, Dyment, David, Esber, Natacha, Fahrner, Jill A, Fleming, Mark D, Genevieve, David, Heron, Delphine, Husson, Thoma, Kernohan, Kristin D, Mcneill, Alisdair, Menke, Leonie A, Merla, Giuseppe, Prontera, Paolo, Rockman-Greenberg, Cheryl, Schwartz, Charle, Skinner, Steven A, Stevenson, Roger E, Vincent, Marie, Vitobello, Antonio, Tartaglia, Marco, Alders, Marielle, Tedder, Matthew L, Sadikovic, Bekim, Human Genetics, General Paediatrics, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, and ACS - Pulmonary hypertension & thrombosis

Subjects
DNA methylation, clinical diagnostics, Syndrome, DNA methylation, clinical diagnostics, episignatures, neurodevelopmental syndromes, neurodevelopmental syndromes, Epigenesis, Genetic, Neurodevelopmental Disorders, Genetics, Humans, CpG Islands, DNA, Intergenic, episignatures, Episignature, Genetics (clinical)
Abstract

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes which can share significant overlap amongst different conditions. In this study we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders. This article is protected by copyright. All rights reserved.

Published
2022

27. Long-Term Efficacy of T3 Analogue Triac in Children and Adults With MCT8 Deficiency: A Real-Life Retrospective Cohort Study

Author

Monique de Waart, Anina Enderli, Ferdy S van Geest, Adri van der Walt, Krishna Chatterjee, Sjoerd A A van den Berg, Laura Paone, Patricia Crock, Anne-Marie van Wermeskerken, Lilla Szeifert, Francesco Porta, D Barca, Carla Moran, Katalin E Müller, Alice Dica, Athanasia Stoupa, Felipe Monti Lora, Dana Craiu, Hans van Toor, Peter Christian, Amnon Zung, Stefan Groeneweg, W. Edward Visser, Ronald van der Wal, Régis Coutant, Luigi Garibaldi, Marco Spada, Joel Vanderniet, Jolanta Wierzba, Tony Huynh, Greta Lyons, Annette Hackenberg, Gerarda Cappuccio, Serap Turan, Michaela Linder-Lucht, Jan Fairchild, Peter J Simm, Yolanda B. de Rijke, Enrico Bertini, Amy Lawson-Yuen, Erica L T van den Akker, Bianka Heinrich, Nicola Brunetti-Pierri, Michel Polak, Cheyenne Dewey, Rachana Dubey, Christina Reinauer, Praveen G. Paul, Belinda George, Doris Brunner, Robin P. Peeters, Paul Dimitri, Marco Cappa, Anna Simon, Federica Zibordi, Tuba Seven Menevse, Jonathan Gallichan, Anna Kłosowska, Rowen Seckold, Iuliu Bacos, Davide Tonduti, Alexander D Chesover, Internal Medicine, Pediatrics, Clinical Chemistry, van Geest, Ferdy S, Groeneweg, Stefan, van den Akker, Erica L T, Bacos, Iuliu, Barca, Diana, van den Berg, Sjoerd A A, Bertini, Enrico, Brunner, Dori, Brunetti-Pierri, Nicola, Cappa, Marco, Cappuccio, Gerarda, Chatterjee, Krishna, Chesover, Alexander D, Christian, Peter, Coutant, Régi, Craiu, Dana, Crock, Patricia, Dewey, Cheyenne, Dica, Alice, Dimitri, Paul, Dubey, Rachana, Enderli, Anina, Fairchild, Jan, Gallichan, Jonathan, Garibaldi, Luigi R, George, Belinda, Hackenberg, Annette, Heinrich, Bianka, Huynh, Tony, Kłosowska, Anna, Lawson-Yuen, Amy, Linder-Lucht, Michaela, Lyons, Greta, Lora, Felipe Monti, Moran, Carla, Müller, Katalin E, Paone, Laura, Paul, Praveen G, Polak, Michel, Porta, Francesco, Reinauer, Christina, de Rijke, Yolanda B, Seckold, Rowen, Menevşe, Tuba Seven, Simm, Peter, Simon, Anna, Spada, Marco, Stoupa, Athanasia, Szeifert, Lilla, Tonduti, Davide, van Toor, Han, Turan, Serap, Vanderniet, Joel, de Waart, Monique, van der Wal, Ronald, van der Walt, Adri, van Wermeskerken, Anne-Marie, Wierzba, Jolanta, Zibordi, Federica, Zung, Amnon, Peeters, Robin P, and Visser, W Edward

Subjects
Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Biochemistry, chemistry.chemical_compound, Endocrinology, Clinical endpoint, MCT8 Deficiency, Child, Symporters, Thyroid, Middle Aged, Muscular Atrophy, Treatment Outcome, medicine.anatomical_structure, Child, Preschool, Muscle Hypotonia, Triiodothyronine, Female, Adult, Monocarboxylic Acid Transporters, medicine.medical_specialty, Adolescent, Context (language use), AHDS, Young Adult, SDG 3 - Good Health and Well-being, Internal medicine, Heart rate, medicine, Humans, Allan-Herndon-Dudley syndrome, Aged, Retrospective Studies, Creatinine, Allan–Herndon–Dudley syndrome, T3 analogue, business.industry, Biochemistry (medical), Infant, Retrospective cohort study, medicine.disease, chemistry, Mutation, Mental Retardation, X-Linked, business, thyromimetic drug, Follow-Up Studies, Hormone
Abstract

Context Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. Objective Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. Methods In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. Results From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. Conclusions Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.

Published
2021

28. De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders

Author

Xiangbin Jia, Shujie Zhang, Senwei Tan, Bing Du, Mei He, Haisong Qin, Jia Chen, Xinyu Duan, Jingsi Luo, Fei Chen, Luping Ouyang, Jian Wang, Guodong Chen, Bin Yu, Ge Zhang, Zimin Zhang, Yongqing Lyu, Yi Huang, Jian Jiao, Jin Yun (Helen) Chen, Kathryn J. Swoboda, Emanuele Agolini, Antonio Novelli, Chiara Leoni, Giuseppe Zampino, Gerarda Cappuccio, Nicola Brunetti-Pierri, Benedicte Gerard, Emmanuelle Ginglinger, Julie Richer, Hugh McMillan, Alexandre White-Brown, Kendra Hoekzema, Raphael A. Bernier, Evangeline C. Kurtz-Nelson, Rachel K. Earl, Claartje Meddens, Marielle Alders, Meredith Fuchs, Roseline Caumes, Perrine Brunelle, Thomas Smol, Ryan Kuehl, Debra-Lynn Day-Salvatore, Kristin G. Monaghan, Michelle M. Morrow, Evan E. Eichler, Zhengmao Hu, Ling Yuan, Jieqiong Tan, Kun Xia, Yiping Shen, Hui Guo, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Jia, Xiangbin, Zhang, Shujie, Tan, Senwei, Du, Bing, He, Mei, Qin, Haisong, Chen, Jia, Duan, Xinyu, Luo, Jingsi, Chen, Fei, Ouyang, Luping, Wang, Jian, Chen, Guodong, Yu, Bin, Zhang, Ge, Zhang, Zimin, Lyu, Yongqing, Huang, Yi, Jiao, Jian, Chen, Jin Yun Helen, Swoboda, Kathryn J, Agolini, Emanuele, Novelli, Antonio, Leoni, Chiara, Zampino, Giuseppe, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Gerard, Benedicte, Ginglinger, Emmanuelle, Richer, Julie, Mcmillan, Hugh, White-Brown, Alexandre, Hoekzema, Kendra, Bernier, Raphael A, Kurtz-Nelson, Evangeline C, Earl, Rachel K, Meddens, Claartje, Alders, Marielle, Fuchs, Meredith, Caumes, Roseline, Brunelle, Perrine, Smol, Thoma, Kuehl, Ryan, Day-Salvatore, Debra-Lynn, Monaghan, Kristin G, Morrow, Michelle M, Eichler, Evan E, Hu, Zhengmao, Yuan, Ling, Tan, Jieqiong, Xia, Kun, Shen, Yiping, and Guo, Hui

Subjects
Multidisciplinary, Animal, DNA Helicases, RNA Helicase, DNA Helicase, Stress Granule, Stress Granules, Mice, RNA Recognition Motif Proteins, Neurodevelopmental Disorders, RNA Recognition Motif Protein, Animals, Poly-ADP-Ribose Binding Proteins, RNA Helicases, Poly-ADP-Ribose Binding Protein
Abstract

Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in UBAP2L , which encodes an essential regulator of SG assembly. Ubap2l haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes ( G3BP1 , G3BP2 , and UBAP2L ) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRIN1 , disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.

Published
2022

30. Clinical heterogeneity of Kabuki syndrome in a cohort of Italian patients and review of the literature

Author

Mariateresa Falco, Pietro Strisciuglio, Ilaria De Maggio, Fortunato Lonardo, Daniela Melis, Gabriella Maria Squeo, Giuseppe Merla, Gerarda Cappuccio, Gioacchino Scarano, Carmen Rosano, Maria Siano, Claudia Mandato, Carmelo Piscopo, Paolo Fontana, Francesca Di Candia, P. Paglia, Daniele De Brasi, Matteo Della Monica, Di Candia, Francesca, Fontana, Paolo, Paglia, Pamela, Falco, Mariateresa, Rosano, Carmen, Piscopo, Carmelo, Cappuccio, Gerarda, Siano, Maria Anna, De Brasi, Daniele, Mandato, Claudia, De Maggio, Ilaria, Squeo, Gabriella Maria, Monica, Matteo Della, Scarano, Gioacchino, Lonardo, Fortunato, Strisciuglio, Pietro, Merla, Giuseppe, and Melis, Daniela

Subjects
0301 basic medicine, Adult, Male, Microcephaly, Pediatrics, medicine.medical_specialty, Adolescent, Neurological features, Autoimmunity, Vitiligo, 030105 genetics & heredity, Brain anomalie, 03 medical and health sciences, Young Adult, Intellectual disability, Medicine, Humans, Brain anomalies, Kabuki syndrome, Child, Face, Female, Retrospective Studies, Abnormalities, Multiple, Hematologic Diseases, Vestibular Diseases, Hypertelorism, Strabismus, Immunodeficiency, business.industry, medicine.disease, 030104 developmental biology, Pediatrics, Perinatology and Child Health, Cohort, Original Article, medicine.symptom, Abnormalities, business, Multiple
Abstract

Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10–26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG’s abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient.Conclusions: These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known• Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability• Immune dysfunction is a common finding but autoimmune diseases are rarely seen• Neurological features are common What is New• Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus)• Higher prevalence of autoimmune disorders than previously reported• Particular neurological features are present in this cohort (EEG and MRI brain abnormalities)

Published
2021

31. Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability

Author

Stephen J. Guter, Laurie A. Demmer, Jasmine Lf Fung, Gerarda Cappuccio, Naomichi Matsumoto, Nicola Brunetti-Pierri, Catherine Sarret, Hamish S. Scott, Lynn Pais, Alison Yeung, Ken Saida, Christopher P. Barnett, Felix Boschann, Andre Heinen, Noriko Miyake, Jenny C. Taylor, Jonathan Gadian, Cyril Mignot, Boris Keren, Sandra Whalen, Hagar Mor-Shaked, Matteo P. Ferla, John Christodoulou, Raffaele Iorio, Alistair T. Pagnamenta, Tiong Yang Tan, Brian Hy Chung, Marcus Cy Chan, Susan M. White, Ruth Sheffer, Dana Mittag, Edwin H. Cook, Jens Schallner, Alicia B. Byrne, Rachel Stapleton, Natalie B Tan, Alison Kraus, Fabiola Di Dato, Tan, Natalie B, Pagnamenta, Alistair T, Ferla, Matteo P, Gadian, Jonathan, Byrne, Alicia B, White, Sue, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Tan, N. B., Pagnamenta, A. T., Ferla, M. P., Gadian, J., Chung, B. H. Y., Chan, M. C. Y., Fung, J. L. F., Cook, E., Guter, S., Boschann, F., Heinen, A., Schallner, J., Mignot, C., Keren, B., Whalen, S., Sarret, C., Mittag, D., Demmer, L., Stapleton, R., Saida, K., Matsumoto, N., Miyake, N., Sheffer, R., Mor-Shaked, H., Barnett, C. P., Byrne, A. B., Scott, H. S., Kraus, A., Cappuccio, G., Brunetti Pierri, N., Iorio, R., Di Dato, F., Pais, L. S., Yeung, A., Tan, T. Y., Taylor, J. C., Christodoulou, J., and White, S.

Subjects
medicine.medical_specialty, Genomics, Biology, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, GNB2, Intellectual disability, Genetics, medicine, Missense mutation, Gene, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Exome sequencing, 030304 developmental biology, 0303 health sciences, G-beta protein, medicine.disease, developmental delay, intellectual disability, Medical genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human genome, 030217 neurology & neurosurgery
Abstract

PurposeBinding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.MethodsWe discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.ResultsWe identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.ConclusionMissense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

Published
2021

32. A pilot clinical trial with losartan in Myhre syndrome

Author

Giuseppe Limongelli, Gerarda Cappuccio, Daniela Melis, Martina Caiazza, Marta Rubino, Nicola Brunetti-Pierri, Gabor Matyas, Antonella Iuliano, Alessandro Roca, Cappuccio, Gerarda, Caiazza, Martina, Roca, Alessandro, Melis, Daniela, Iuliano, Antonella, Matyas, Gabor, Rubino, Marta, Limongelli, Giuseppe, and Brunetti-Pierri, Nicola

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, losartan, systemic sclerosis, Heart malformation, Pilot Projects, SMAD4, Myhre syndrome, Congenital, Young Adult, Intellectual Disability, Internal medicine, Cryptorchidism, TGF‐beta, Genetics, medicine, Humans, TGF-beta, Preschool, Child, Growth Disorders, Genetics (clinical), Angiotensin II Type 1 Receptor Blockers, Child, Preschool, Facies, Female, Follow-Up Studies, Hand Deformities, Congenital, Losartan, Prognosis, business.industry, Mean age, Original Articles, Hand Deformities, SMAD4 gene, medicine.disease, Clinical trial, Joint stiffness, Cardiology, Original Article, medicine.symptom, business, Range of motion, medicine.drug
Abstract

Introduction Myhre syndrome (MS) is an ultra‐rare disorder due to pathogenic variants in the SMAD4 gene that encodes a protein regulating the TGF‐β pathway and extra‐cellular matrix (ECM) homeostasis. Main clinical features of MS include thickening of skin and joint stiffness. Previous studies showed that losartan improved ECM deposition in MS fibroblasts. Materials and methods Four molecularly confirmed MS subjects (mean age 23.8 ± 17 years) were evaluated for: (a) skin thickness by Rodnan score, (b) joint range of motion (ROM) by goniometry, and (c) speckle‐tracking echocardiogram. Following baseline evaluations, three MS individuals received losartan for 12 months and pre‐defined endpoints were monitored after 6 and 12 months of treatment. Results At baseline, Rodnan scores were increased, joint ROM was reduced, and speckle‐tracking echocardiogram revealed reduced myocardial strain. In three MS subjects, improvements in skin thickness, joint ROM and to a lesser extent of myocardial strain, were observed after 6 and 12 months of losartan treatment. Conclusions Although further long‐term controlled clinical trials with a larger number of affected individuals are needed, the present study suggests that losartan might improve skin, joint and heart abnormalities of MS.

Published
2020

33. Biallelic variants in CENPF causing a phenotype distinct from Stromme syndrome

Author

Gerarda Cappuccio, Simona Brillante, Roberta Tammaro, Michele Pinelli, Margherita Lucia De Bernardi, Maria Grazia Gensini, Emilia K. Bijlsma, Tamara T. Koopmann, Mariette J. V. Hoffer, Kimberly McDonald, Laura G. Hendon, Sofia Douzgou, Charulata Deshpande, Stefano D'Arrigo, Annalaura Torella, Vincenzo Nigro, Brunella Franco, Nicola Brunetti‐Pierri, Cappuccio, Gerarda, Brillante, Simona, Tammaro, Roberta, Pinelli, Michele, De Bernardi, Margherita Lucia, Gensini, Maria Grazia, Bijlsma, Emilia K, Koopmann, Tamara T, Hoffer, Mariette J V, Mcdonald, Kimberly, Hendon, Laura G, Douzgou, Sofia, Deshpande, Charulata, D'Arrigo, Stefano, Torella, Annalaura, Nigro, Vincenzo, Franco, Brunella, and Brunetti-Pierri, Nicola

Subjects
Male, duodenal atresia, Stromme syndrome, Chromosomal Proteins, Non-Histone, Microfilament Proteins, Intestinal Atresia, CENPF, cilia, Eye Abnormalitie, Phenotype, Strømme syndrome, Intellectual Disability, Mutation, Microcephaly, Genetics, Humans, Female, anterior chamber defect, Eye Abnormalities, Genetics (clinical), Human
Abstract

Biallelic loss-of-function (LoF) variants in CENPF gene are responsible for Stromme syndrome, a condition presenting with intestinal atresia, anterior ocular chamber anomalies, and microcephaly. Through an international collaboration, four individuals (three males and one female) carrying CENPF biallelic variants, including two missense variants in homozygous state and four LoF variants, were identified by exome sequencing. All individuals had variable degree of developmental delay/intellectual disability and microcephaly (ranging from -2.9 SDS to -5.6 SDS) and a recognizable pattern of dysmorphic facial features including inverted-V shaped interrupted eyebrows, epicanthal fold, depressed nasal bridge, and pointed chin. Although one of the cases had duodenal atresia, all four individuals did not have the combination of internal organ malformations of Stromme syndrome (intestinal atresia and anterior eye segment abnormalities). Immunofluorescence analysis on skin fibroblasts on one of the four cases with the antibody for ARL13B that decorates primary cilia revealed shorter primary cilia that are consistent with a ciliary defect. This case-series of individuals with biallelic CENPF variants suggests the spectrum of clinical manifestations of the disorder that may be related to CENPF variants is broad and can include phenotypes lacking the cardinal features of Stromme syndrome.

Published
2022

34. Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

Author

Kristen J. Verhey, Simranpreet Kaur, Matthew D. Burton, Wendy K. Chung, Zeynep Tümer, Breane G. Budaitis, Nicole J Van Bergen, Bitten Schönewolf-Greulich, Rhea Sonawane, Cameron J. Nowell, Annalaura Torella, Yang Yue, Nicola Brunetti-Pierri, Gerarda Cappuccio, Lia Boyle, John Christodoulou, Tony Roscioli, Mark J. Cowley, Carolyn Ellaway, Wendy A. Gold, Irene Bruno, Sean Massey, Vincenzo Nigro, Kaur, Simranpreet, Van Bergen, Nicole J, Verhey, Kristen J, Nowell, Cameron J, Budaitis, Breane, Yue, Yang, Ellaway, Carolyn, Brunetti-Pierri, Nicola, Cappuccio, Gerarda, Bruno, Irene, Boyle, Lia, Nigro, Vincenzo, Torella, Annalaura, Roscioli, Tony, Cowley, Mark J, Massey, Sean, Sonawane, Rhea, Burton, Matthew D, Schonewolf-Greulich, Bitten, Tümer, Zeynep, Chung, Wendy K, Gold, Wendy A, Christodoulou, John, Kaur, S., Van Bergen, N. J., Verhey, K. J., Nowell, C. J., Budaitis, B., Yue, Y., Ellaway, C., Cappuccio, G., Bruno, I., Boyle, L., Nigro, V., Torella, A., Roscioli, T., Cowley, M. J., Massey, S., Sonawane, R., Burton, M. D., Schonewolf-Greulich, B., Tumer, Z., Chung, W. K., Gold, W. A., and Christodoulou, J.

Subjects
Heterozygote, Neurite, Mutation, Missense, Kinesins, Rett syndrome, Biology, kinesin, Article, MECP2, 03 medical and health sciences, Microtubule, Genetics, medicine, Humans, Missense mutation, Family, KIF1A, Genetics (clinical), 030304 developmental biology, KAND, 0303 health sciences, 030305 genetics & heredity, medicine.disease, Phenotype, neurite tip accumulation, Neurodevelopmental Disorders, Mutation, Kinesin, Female, microtubule
Abstract

Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron-specific ATP-dependent anterograde axonal transporter of synaptic cargo, are well-recognized to cause a spectrum of neurological conditions, commonly known as KIF1A-associated neurological disorders (KAND). Here we report one mutation-negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant [NP_001230937.1:p.(Asp248Glu)] in the highly-conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel [NP_001230937.1:p.(Cys92Arg) & p.(Pro305Leu)] or previously reported [NP_001230937.1:p.(Thr99Met)] variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modelling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along neurite lengths of differentiated SH-SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in KIF1A motor domain to include clinical features commonly seen in RTT individuals. This article is protected by copyright. All rights reserved.

Published
2020

35. Expansion of the phenotype of lateral meningocele syndrome

Author

Michele Pinelli, Annalaura Torella, Nicola Brunetti-Pierri, Marianna Alagia, Bruno Corrado, Brunella Franco, Vincenzo Nigro, Ennio Del Giudice, Gerarda Cappuccio, Tudp, Alessandra D'Amico, Diletta Apuzzo, Cappuccio, Gerarda, Apuzzo, Diletta, Alagia, Marianna, Torella, Annalaura, Pinelli, Michele, Franco, Brunella, Corrado, Bruno, Del Giudice, Ennio, D'Amico, Alessandra, Nigro, Vincenzo, Brunetti-Pierri, Nicola, Cappuccio, G., Apuzzo, D., Alagia, M., Torella, A., Pinelli, M., Franco, B., Corrado, B., del Giudice, E., D'Amico, A., Nigro, V., and Brunetti-Pierri, N.

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Hearing loss, Kyphosis, Scoliosis, 030105 genetics & heredity, lateral meningocele syndrome, Short stature, Clinical Reports, Encephalocele, 03 medical and health sciences, NOTCH3, Genetics, medicine, encephalocele, Genetics (clinical), Exome sequencing, Clinical Report, business.industry, medicine.disease, 030104 developmental biology, Lateral meningocele syndrome, medicine.symptom, business, Multiple renal cysts
Abstract

Lateral meningocele syndrome (LMS) is due to specific pathogenic variants in the last exon of NOTCH3 gene. Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties. Here, we report a girl with neurosensorial hearing loss, severe gastroesophageal reflux disease, congenital heart defects, multiple renal cysts, kyphosis and left‐convex scoliosis, dysmorphic features, and mild developmental delay. Exome sequencing detected the previously unreported de novo loss‐of‐function variant in exon 33 of NOTCH3 p.(Lys2137fs). Following the identification of the gene defect, MRI of the brain and spine revealed temporal encephaloceles, inner ears anomalies, multiple spinal lateral meningoceles, and intra‐ and extra‐dural arachnoid spinal cysts. This case illustrates the power of reverse phenotyping to establish clinical diagnosis and expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi‐cystic kidney disease.

Published
2020

36. Cavitating and tigroid‐like leukoencephalopathy in a case of NDUFA2‐related disorder

Author

Nicola Brunetti-Pierri, Gerarda Cappuccio, Vincenzo Nigro, Alfonso Romano, Alessandra D'Amico, Simona Fecarotta, Marianna Alagia, Giorgio Casari, Annalaura Torella, Tudp, Federica Mazio, Alagia, Marianna, Cappuccio, Gerarda, Torella, Annalaura, D'Amico, Alessandra, Mazio, Federica, Romano, Alfonso, Fecarotta, Simona, Casari, Giorgio, Nigro, Vincenzo, Brunetti-Pierri, Nicola, Alagia, M., Cappuccio, G., Torella, A., D'Amico, A., Mazio, F., Romano, A., Fecarotta, S., Casari, G., Nigro, V., and Brunetti-Pierri, N.

Subjects
Pathology, medicine.medical_specialty, leukodystrophy, lcsh:RC648-665, lcsh:QH426-470, business.industry, Endocrinology, Diabetes and Metabolism, Mitochondrial disease, Leukodystrophy, Case Report, Case Reports, medicine.disease, mitochondrial, Biochemistry, Genetics and Molecular Biology (miscellaneous), lcsh:Diseases of the endocrine glands. Clinical endocrinology, Leukoencephalopathy, lcsh:Genetics, NDUFA2, Internal Medicine, medicine, Related disorder, business
Abstract

Biallelic variants in nuclear gene NDUFA2 have been reported so far in only three children with variable presentations including Leigh syndrome or leukoencephalopathy. Herein, we report a further female child affected by NDUFA2‐related disorder presenting with cavitating and tigroid‐like pattern of leukodystrophy and without systemic biochemical abnormalities of mitochondrial disorders.

Published
2020

37. Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study

Author

Anina Enderli, Krishna Chatterjee, David A. Koolen, Jana Malikova, Paul Dimitri, Roelineke J. Lunsing, Patricia Crock, Charles Marques Lourenço, Corstiaan A. den Uil, Ferdy S van Geest, Jan Lebl, Christine M. Armour, Michaela Linder-Lucht, Tony Huynh, Annette Hackenberg, Zita Halász, Jan Fairchild, Francesco Porta, Adri van der Walt, Verónica Mericq, Gautem P. Ambegaonkar, Nitash Zwaveling-Soonawala, Daniel Konrad, D Barca, Barbara Castellotti, Cláudia Fernandes Lorea, Anna Dolcetta-Capuzzo, Peter J Simm, Heiko Krude, Evelien F. Gevers, Ayhan Abaci, Claudia Castiglioni, Jet van der Spek, Jolante Wierzba, Carla Moran, Serap Turan, Isabelle Oliver-Petit, Felipe Monti Lora, Amnon Zung, Klara Rozenkova, Nicola Brunetti-Pierri, Fabiano de Oliveira Poswar, W. Edward Visser, Gopinath M. Subramanian, Bianka Heinrich, Irenaeus F.M. de Coo, Milou A.M. Stals, Belinda George, Michael Wurm, Alice Dica, Amy Lawson-Yuen, Rachana Dubey, Christina Reinauer, Athanasia Stoupa, Stefan Groeneweg, Joel Vanderniet, Marjolein H G Dremmen, Marie Claire Y. de Wit, Marjo S. van der Knaap, Edna E. Mancilla, Dana Craiu, Korcan Demir, Greta Lyons, Gerarda Cappuccio, Jean Louis Wémeau, Yogen Singh, Anne McGowan, Alberto Alcantud, Praveen G. Paul, Enrico Bertini, Laura Paone, Marco Spada, Régis Coutant, Marco Cappa, Ingrid M. van Beynum, Jonathan Gallichan, Nicole I. Wolf, Michel Polak, Marieke M. van der Knoop, Christian DeGoede, Davide Tonduti, Federica Zibordi, Tuba Seven Menevse, Katalin Eszter Müller, Anna Simon, Marianna Bugiani, Priyanka Bakhtiani, Anna Kłosowska, Internal Medicine, Pediatrics, Neurology, Radiology & Nuclear Medicine, Cardiology, Intensive Care, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Pathology, Pediatric surgery, Paediatric Endocrinology, ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Functional Genomics, Groeneweg, S., van Geest, F. S., Abaci, A., Alcantud, A., Ambegaonkar, G. P., Armour, C. M., Bakhtiani, P., Barca, D., Bertini, E. S., van Beynum, I. M., Brunetti-Pierri, Nicola, Bugiani, M., Cappa, M., Cappuccio, G., Castellotti, B., Castiglioni, C., Chatterjee, K., de Coo, I. F. M., Coutant, R., Craiu, D., Crock, P., Degoede, C., Demir, K., Dica, A., Dimitri, P., Dolcetta-Capuzzo, A., Dremmen, M. H. G., Dubey, R., Enderli, A., Fairchild, J., Gallichan, J., George, B., Gevers, E. F., Hackenberg, A., Halasz, Z., Heinrich, B., Huynh, T., Klosowska, A., van der Knaap, M. S., van der Knoop, M. M., Konrad, D., Koolen, D. A., Krude, H., Lawson-Yuen, A., Lebl, J., Linder-Lucht, M., Lorea, C. F., Lourenco, C. M., Lunsing, R. J., Lyons, G., Malikova, J., Mancilla, E. E., Mcgowan, A., Mericq, V., Lora, F. M., Moran, C., Muller, K. E., Oliver-Petit, I., Paone, L., Paul, P. G., Polak, M., Porta, F., Poswar, F. O., Reinauer, C., Rozenkova, K., Menevse, T. S., Simm, P., Simon, A., Singh, Y., Spada, M., van der Spek, J., Stals, M. A. M., Stoupa, A., Subramanian, G. M., Tonduti, D., Turan, S., den Uil, C. A., Vanderniet, J., van der Walt, A., Wemeau, J. -L., Wierzba, J., de Wit, M. -C. Y., Wolf, N. I., Wurm, M., Zibordi, F., Zung, A., Zwaveling-Soonawala, N., and Visser, W. E.

Subjects
Male, Pediatrics, Endocrinology, Diabetes and Metabolism, Bayley Scales of Infant Development, Monocarboxylic Acid Transporter, 0302 clinical medicine, Endocrinology, Retrospective Studie, Neurodevelopmental Disorder, Medicine, 030212 general & internal medicine, Child, Thyroid hormone transport, Symporters, Mental Disorders, Hazard ratio, SDG 10 - Reduced Inequalities, Middle Aged, Prognosis, Survival Rate, International Agencie, Child, Preschool, Cohort, Mental Disorder, Female, Disease characteristics, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Human, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Cohort study, Adult, Monocarboxylic Acid Transporters, medicine.medical_specialty, Adolescent, Prognosi, HEART-RATE, 030209 endocrinology & metabolism, Sudden death, Follow-Up Studie, MONOCARBOXYLATE TRANSPORTER-8, Young Adult, 03 medical and health sciences, HORMONE, Muscular Diseases, Internal Medicine, Humans, PSYCHOMOTOR RETARDATION, Survival rate, Aged, Retrospective Studies, Muscular Disease, business.industry, MUTATIONS, Symporter, Other Research Radboud Institute for Health Sciences [Radboudumc 0], Infant, International Agencies, Retrospective cohort study, Biomarker, Neurodevelopmental Disorders, Mutation, business, Biomarkers, Follow-Up Studies
Abstract

Contains fulltext : 220431.pdf (Publisher’s version ) (Closed access) BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1.5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score

Published
2020

38. Epilepsy in KAT6A syndrome: Description of two individuals and revision of the literature

Author

Nicola Brunetti-Pierri, Serena Troisi, Leonilda Bilo, Alice Spano, Tudp, Silvia Maitz, Annalaura Torella, Mariasavina Severino, Vincenzo Nigro, Antonietta Coppola, Gerarda Cappuccio, Troisi, S., Maitz, S., Severino, M., Spano, A., Cappuccio, G., Brunetti-Pierri, N., Torella, A., Nigro, V., Santoro, Claudia, Bilo, L., Coppola, A., and Tudp

Subjects
Microcephaly, Pediatrics, medicine.medical_specialty, Adolescent, KAT6A, Spasms, Epilepsy, Seizures, Intellectual disability, Genetics, Medicine, Humans, Dysmorphic facial features, Child, Genetics (clinical), Histone Acetyltransferases, business.industry, General Medicine, medicine.disease, Seizure, Developmental disorder, Phenotype, Speech delay, Female, medicine.symptom, business
Abstract

Pathogenic variants in KAT6A, encoding a histone acetyltransferase, have been identified as a cause of a developmental disorder with a definite clinical spectrum including intellectual disability, speech delay, dysmorphic facial features, microcephaly, cardiac and gastrointestinal defects. Seizures have been described in a minority of patients without a detailed characterization. In this work we focus on epilepsy in KAT6A syndrome, reporting two affected girls with history of seizures, bearing a KAT6A de novo heterozygous variant, of which one is novel. We describe the different epilepsy phenotypes of these two patients and compare them to the other individuals in literature presenting with epilepsy.

Published
2022

39. Postnatal microcephaly and retinal involvement expand the phenotype of RPL10-related disorder

Author

Gerarda Cappuccio, Margherita Lucia De Bernardi, Alessia Morlando, Cristina Peduto, Iris Scala, Michele Pinelli, Emanuele Bellacchio, Flavio Gioele Gallo, Adriano Magli, Carmen Plaitano, Mercedes Serrano, Leticia Pías, Jaume Català, Mercè Bolasell, Annalaura Torella, Vincenzo Nigro, Ginevra Zanni, Nicola Brunetti‐Pierri, Cappuccio, Gerarda, De Bernardi, Margherita Lucia, Morlando, Alessia, Peduto, Cristina, Scala, Iri, Pinelli, Michele, Bellacchio, Emanuele, Gallo, Flavio Gioele, Magli, Adriano, Plaitano, Carmen, Serrano, Mercede, Pías, Leticia, Català, Jaume, Bolasell, Mercè, Torella, Annalaura, Nigro, Vincenzo, Zanni, Ginevra, and Brunetti-Pierri, Nicola

Subjects
Male, Phenotype, RPL10, Autism Spectrum Disorder, intellectual disability, Genetics, Humans, microcephaly, retinal dystrophy, Nervous System Malformations, Genetics (clinical), ocular
Abstract

Hemizygous missense variants in the RPL10 gene encoding a ribosomal unit are responsible for an X-linked syndrome presenting with intellectual disability (ID), autism spectrum disorder, epilepsy, dysmorphic features, and multiple congenital anomalies. Among 15 individuals with RPL10-related disorder reported so far, only one patient had retinitis pigmentosa and microcephaly was observed in approximately half of the cases. By exome sequencing, three Italian and one Spanish male children, from three independent families, were found to carry the same hemizygous novel missense variant p.(Arg32Leu) in RPL10, inherited by their unaffected mother in all cases. The variant, not reported in gnomAD, is located in the 28S rRNA binding region, affecting an evolutionary conserved residue and predicted to disrupt the salt-bridge between Arg32 and Asp28. In addition to features consistent with RPL10-related disorder, all four boys had retinal degeneration and postnatal microcephaly. Pathogenic variants in genes responsible for inherited retinal degenerations were ruled out in all the probands. A novel missense RPL10 variant was detected in four probands with a recurrent phenotype including ID, dysmorphic features, progressive postnatal microcephaly, and retinal anomalies. The presented individuals suggest that retinopathy and postnatal microcephaly are clinical clues of RPL10-related disorder, and at least the retinal defect might be more specific for the p.(Arg32Leu) RPL10 variant, suggesting a specific genotype/phenotype correlation.

Published
2022

40. Mild neurological phenotype in a family carrying a novel N-terminal null GRIN2A variant

Author

Margherita Lucia De Bernardi, Agnese Di Stazio, Alfonso Romano, Raffaella Minardi, Francesca Bisulli, Laura Licchetta, Salvatore Aiello, Valerio Carelli, Nicola Brunetti-Pierri, Gerarda Cappuccio, Gaetano Terrone, DE BERNARDI, MARGHERITA LUCIA, DI STAZIO, Agnese, Romano, Alfonso, Minardi, Raffaella, Bisulli, Francesca, Licchetta, Laura, Aiello, Salvatore, Carelli, Valerio, BRUNETTI PIERRI, Nicola, Cappuccio, Gerarda, and Terrone, Gaetano

Subjects
GRIN2AHaploinsufficiencyAtypical childhood epilepsy with centrotemporal spikes, Landau-Kleffner Syndrome, Epilepsy, Phenotype, Mutation, Genetics, Humans, Electroencephalography, General Medicine, Child, Receptors, N-Methyl-D-Aspartate, Genetics (clinical)
Abstract

GRIN2A encodes for the 2A subunit of N-methyl-D-aspartate receptors. Pathogenic variants in GRIN2A have been associated with a wide spectrum of neurodevelopmental disorders ranging from speech disorders and/or self-limiting epilepsy (childhood epilepsy with centrotemporal spikes) to severe and disabling phenotypes (atypical childhood epilepsy with centrotemporal spikes, epileptic encephalopathy with continuous spike-wave during sleep, Landau-Kleffner syndrome and infantile-onset epileptic encephalopathy). Here we describe a family with two affected sisters with atypical childhood epilepsy with centrotemporal spikes and their mildly affected mother carrying a novel N-terminal null variant in GRIN2A gene. These familial cases corroborate previous studies showing that loss-of-function GRIN2A variants are associated with milder phenotypes, possibly due to haploinsufficiency.

Published
2021

41. De Novo

Author

Maike F, Dohrn, Adriana P, Rebelo, Siddharth, Srivastava, Gerarda, Cappuccio, Robert, Smigiel, Alka, Malhotra, Donald, Basel, Ingrid, van de Laar, Rinze Frederik, Neuteboom, Coranne, Aarts-Tesselaar, Sonal, Mahida, Nicola, Brunetti-Pierri, Ryan J, Taft, and Stephan, Züchner

Subjects
Phenotype, Intellectual Disability, Migraine with Aura, Mutation, Clinical/Scientific Note, Humans, Syndrome, Sodium-Potassium-Exchanging ATPase
Abstract

ATP1A1 encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic ATP1A1 variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous ATP1A1 variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity in silico prediction scores. In HEK cells transfected with ouabain-insensitive ATP1A1 constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of ATP1A1.

Published
2021

42. Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants

Author

Alessandro Mussa, Chiara Leoni, Matteo Iacoviello, Diana Carli, Carlotta Ranieri, Antonino Pantaleo, Paola Sabrina Buonuomo, Rosanna Bagnulo, Giovanni Battista Ferrero, Andrea Bartuli, Daniela Melis, Silvia Maitz, Daria Carmela Loconte, Antonella Turchiano, Marilidia Piglionica, Annunziata De Luisi, Francesco Claudio Susca, Nenad Bukvic, Cinzia Forleo, Angelo Selicorni, Giuseppe Zampino, Roberta Onesimo, Gerarda Cappuccio, Livia Garavelli, Chiara Novelli, Luigi Memo, Carla Morando, Matteo Della Monica, Maria Accadia, Martina Capurso, Carmelo Piscopo, Anna Cereda, Marilena Carmela Di Giacomo, Veronica Saletti, Alessandro Mauro Spinelli, Patrizia Lastella, Romano Tenconi, Veronika Dvorakova, Alan D Irvine, Nicoletta Resta, Mussa, Alessandro, Leoni, Chiara, Iacoviello, Matteo, Carli, Diana, Ranieri, Carlotta, Pantaleo, Antonino, Buonuomo, Paola Sabrina, Bagnulo, Rosanna, Ferrero, Giovanni Battista, Bartuli, Andrea, Melis, Daniela, Maitz, Silvia, Loconte, Daria Carmela, Turchiano, Antonella, Piglionica, Marilidia, De Luisi, Annunziata, Susca, Francesco Claudio, Bukvic, Nenad, Forleo, Cinzia, Selicorni, Angelo, Zampino, Giuseppe, Onesimo, Roberta, Cappuccio, Gerarda, Garavelli, Livia, Novelli, Chiara, Memo, Luigi, Morando, Carla, Della Monica, Matteo, Accadia, Maria, Capurso, Martina, Piscopo, Carmelo, Cereda, Anna, Di Giacomo, Marilena Carmela, Saletti, Veronica, Spinelli, Alessandro Mauro, Lastella, Patrizia, Tenconi, Romano, Dvorakova, Veronika, Irvine, Alan D, and Resta, Nicoletta

Subjects
sequence analysis, DNA, sequence analysis, phenotype, genetic testing, genotype, molecular medicine, Genetics, DNA, Genetics (clinical)
Abstract

BackgroundPostzygotic activatingPIK3CAvariants cause several phenotypes within thePIK3CA-related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007PIK3CA-mutated patients, analysing our new data with previous literature to give a comprehensive picture.MethodsWe performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes andGNAQ,GNA11,RASA1andTEK. Additionally, 914 patients previously reported were systematically reviewed.Results93 of our 150 patients hadPIK3CApathogenetic variants. The merged PROS cohort showed thatPIK3CAvariants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-typePIK3CAallele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants inGNAQ,GNA11,RASA1orTEK.ConclusionWe confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping ‘vascular’ phenotypes; (2) strongly activatingPIK3CAvariants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other thanPIK3CA.

Published
2021

43. Bi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease

Author

Paola Goffrini, Felice D'Arco, Enrico Baruffini, Adeline Vanderver, Tamison Jewett, Enrico Bertini, Anya Revah-Politi, Eirik Bratland, Vandana Shashi, Alessandra D'Amico, Camilla Ceccatelli Berti, Vimla Aggarwal, Silvia Maitz, Kwame Anyane-Yeboa, Tara H. Stamper, Francesco Canonico, Gabriel S Kupchik, Andreas Benneche, César Augusto Pinheiro Ferreira Alves, Daniela Longo, Gerarda Cappuccio, Annalaura Torella, Vincenzo Nigro, Nicola Brunetti-Pierri, Marjo S van der Knaap, Siren Berland, Jennifer A. Sullivan, Pediatrics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Functional Genomics, Cappuccio, G., Ceccatelli Berti, C., Baruffini, E., Sullivan, J., Shashi, V., Jewett, T., Stamper, T., Maitz, S., Canonico, F., Revah-Politi, A., Kupchik, G. S., Anyane-Yeboa, K., Aggarwal, V., Benneche, A., Bratland, E., Berland, S., D'Arco, F., Alves, C. A., Vanderver, A., Longo, D., Bertini, E., Torella, A., Nigro, V., D'Amico, A., van der Knaap, M. S., Goffrini, P., Brunetti Pierri, N., and Brunetti-Pierri, N.

Subjects
Lysine-tRNA Ligase, Male, Mitochondrion, lysyl-transfer RNA synthetase, Cohort Studies, Cytosol, KARS, lysyl‐transfer RNA synthetase, Child, Research Articles, Muscular Dystrophie, Genetics (clinical), Allele, Genetics, 0303 health sciences, Progressive microcephaly, Homozygote, 030305 genetics & heredity, Phenotype, Mitochondria, Pedigree, Isoenzymes, mitochondrial disease, Child, Preschool, Transfer RNA, Disease Progression, Microcephaly, Female, KARS1, Research Article, Human, Gene isoform, Adolescent, Mitochondrial disease, Saccharomyces cerevisiae, Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Abnormalities, Multiple, Alleles, 030304 developmental biology, Organisms, Genetically Modified, Leukodystrophy, Brain Diseases, Metabolic, Inborn, Infant, LysRS, medicine.disease, Isoenzyme, Cohort Studie
Abstract

KARS1 encodes a lysyl-transfer RNA synthetase (LysRS) that links lysine to its cognate tRNA. Two different KARS1 isoforms exert functional effects in cytosol and mitochondria. Bi-allelic pathogenic variants in KARS1 have been associated to sensorineural hearing and visual loss, neuropathy, seizures, and leukodystrophy. We report the clinical, biochemical and neuroradiological features of nine individuals with KARS1-related disorder carrying 12 different variants with nine of them being novel. The consequences of these variants on the cytosol and/or mitochondrial LysRS were functionally validated in yeast mutants. Most cases presented with severe neurological features including congenital and progressive microcephaly, seizures, developmental delay/intellectual disability, and cerebral atrophy. Oculo-motor dysfunction and immuno-hematological problems were present in six and three cases, respectively. A yeast growth defect of variable severity was detected for most variants on both cytosolic and mitochondrial isoforms. The detrimental effects of two variants on yeast growth were partially rescued by lysine supplementation. Congenital progressive microcephaly, oculo-motor dysfunction and immuno-hematological problems are emerging phenotypes in KARS1-related disorders. The data in yeast emphasize the role of both mitochondrial and cytosolic isoforms in the pathogenesis of KARS1-related disorder and supports the therapeutic potential of lysine supplementation at least in a subset of patients. This article is protected by copyright. All rights reserved.

Published
2021

44. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Author

Ian R. Berry, Martin R. Larsen, Ann M. Neumeyer, Lilian Bomme Ousager, Leah J. Rowe, Richard E. Person, Chanika Phornphutkul, David A. Koolen, Constance T. R. M. Stumpel, Konrad Platzer, Elizabeth J. Bhoj, Eric Chater-Diehl, Jason Bunn, Erika Leenders, Koen L.I. van Gassen, Joshua Charkow, Rosanna Weksberg, Ny Hoang, Roos Cuperus, Davor Lessel, Rolph Pfundt, Oana Caluseriu, Sarah J. Goodman, Leandra Folk, Fanggeng Zou, Michelle T. Siu, David Chitayat, Dmitrijs Rots, Jeroen R. Vermeulen, Shuxi Liu, Cheryl Cytrynbaum, Elin Tønne, Hein Brackel, Mareike Mertens, Jennifer Campbell, Jonathan B. Strober, Maja Hempel, Tjitske Kleefstra, Małgorzata J.M. Nowaczyk, Amy Crunk, Marta Pacio-Míguez, Fernando Santos-Simarro, Nicola Brunetti-Pierri, Christa de Geus, María Palomares-Bralo, Lisenka E.L.M. Vissers, Sander Pajusalu, Peter Kannu, Sanaa Choufani, Kristin Lindstrom, Margarita Saenz, Berkley Schmidt, Daniëlle G.M. Bosch, Han G. Brunner, Arie van Haeringen, Ellen van Binsbergen, Brianna Pruniski, Claudia A. L. Ruivenkamp, William G. Wilson, Servi J. C. Stevens, Susan Walker, Kristian Tveten, Zain Awamleh, Gerarda Cappuccio, Alexander J. M. Dingemans, Michael Kwint, Ebba Alkhunaizi, Jonas Denecke, Alyssa Ritter, Eric W. Klee, Bert B.A. de Vries, Jeske V.T. van Harssel, Stephen Meyn, A. Chantal Deden, Francisca Millan, Eva Morava, Ingrid M. Wentzensen, Anne Slavotinek, Stephen W. Scherer, Katrin Õunap, Tuula Rinne, Jessica A. Radley, Yili Xie, Thatjana Gardeitchik, Laura Schultz-Rogers, Karit Reinson, Ronald D. Cohn, Hui Yang, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, MUMC+: DA KG Lab Centraal Lab (9), Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: DA Klinische Genetica (5), Rots, Dmitrij, Chater-Diehl, Eric, Dingemans, Alexander J M, Goodman, Sarah J, Siu, Michelle T, Cytrynbaum, Cheryl, Choufani, Sanaa, Hoang, Ny, Walker, Susan, Awamleh, Zain, Charkow, Joshua, Meyn, Stephen, Pfundt, Rolph, Rinne, Tuula, Gardeitchik, Thatjana, de Vries, Bert B A, Deden, A Chantal, Leenders, Erika, Kwint, Michael, Stumpel, Constance T R M, Stevens, Servi J C, Vermeulen, Jeroen R, van Harssel, Jeske V T, Bosch, Danielle G M, van Gassen, Koen L I, van Binsbergen, Ellen, de Geus, Christa M, Brackel, Hein, Hempel, Maja, Lessel, Davor, Denecke, Jona, Slavotinek, Anne, Strober, Jonathan, Crunk, Amy, Folk, Leandra, Wentzensen, Ingrid M, Yang, Hui, Zou, Fanggeng, Millan, Francisca, Person, Richard, Xie, Yili, Liu, Shuxi, Ousager, Lilian B, Larsen, Martin, Schultz-Rogers, Laura, Morava, Eva, Klee, Eric W, Berry, Ian R, Campbell, Jennifer, Lindstrom, Kristin, Pruniski, Brianna, Neumeyer, Ann M, Radley, Jessica A, Phornphutkul, Chanika, Schmidt, Berkley, Wilson, William G, Õunap, Katrin, Reinson, Karit, Pajusalu, Sander, van Haeringen, Arie, Ruivenkamp, Claudia, Cuperus, Roo, Santos-Simarro, Fernando, Palomares-Bralo, María, Pacio-Míguez, Marta, Ritter, Alyssa, Bhoj, Elizabeth, Tønne, Elin, Tveten, Kristian, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Rowe, Leah, Bunn, Jason, Saenz, Margarita, Platzer, Konrad, Mertens, Mareike, Caluseriu, Oana, Nowaczyk, Małgorzata J M, Cohn, Ronald D, Kannu, Peter, Alkhunaizi, Ebba, Chitayat, David, Scherer, Stephen W, Brunner, Han G, Vissers, Lisenka E L M, Kleefstra, Tjitske, Koolen, David A, and Weksberg, Rosanna

Subjects
0301 basic medicine, Heart Septal Defects, Ventricular, Male, DNA methylation signature, nonsense-mediated decay, speech delay, PROTEIN, 030105 genetics & heredity, PHENOTYPE, epigenomic, Medical and Health Sciences, Epigenesis, Genetic, Craniofacial Abnormalities, Cohort Studies, Neurodevelopmental disorder, 2.1 Biological and endogenous factors, Aetiology, Genetics (clinical), Growth Disorders, Epigenomics, non-FLHS SRCAP-related NDD, Genetics, Adenosine Triphosphatases, Genetics & Heredity, neurodevelopmental disorders, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], SOTOS-LIKE, Biological Sciences, SRCAP, Hypotonia, AT-HOOK, 3. Good health, Phenotype, Mental Health, intellectual disability, Speech delay, DNA methylation, Female, medicine.symptom, Abnormalities, Multiple, EXON 34, Intellectual and Developmental Disabilities (IDD), Locus (genetics), Biology, genotype-phenotype correlation, DIAGNOSIS, Article, 03 medical and health sciences, Genetic, Clinical Research, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Floating-Harbor syndrome, SPECTRUM, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MUTATIONS, Heart Septal Defects, Infant, Newborn, Ventricular, dNaM, Infant, DNA Methylation, medicine.disease, Newborn, neurodevelopmental disorder, GENE, Brain Disorders, 030104 developmental biology, Floating–Harbor syndrome, Case-Control Studies, Mutation, epigenomics, EPISIGNATURES, Epigenesis
Abstract

Contains fulltext : 234078.pdf (Publisher’s version ) (Open Access) Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

Published
2021

45. A small 7q11.23 microduplication involving <scp> GTF2I </scp> in a family with intellectual disability

Author

Nicola Brunetti-Pierri, Michele Pinelli, Floriana Imperati, Flavia Troglio, Rita Genesio, Gerarda Cappuccio, Gabriella Maria Squeo, Ennio Del Giudice, Giuseppe Merla, Gaetano Terrone, Giuseppe Testa, Piero Pignataro, Lucio Nitch, Pinelli, M., Terrone, G., Troglio, F., Squeo, G. M., Cappuccio, G., Imperati, F., Pignataro, P., Genesio, R., Nitch, L., Del Giudice, E., Merla, G., Testa, G., and Brunetti-Pierri, N.

Subjects
medicine.medical_specialty, Intellectual impairment, Chromosome 7q, GTF2I gene, medicine.disease, Abdominal Radiography, Chronic kidney failure, Intellectual disability, Learning disability, Genetics, medicine, medicine.symptom, Letters to the Editor, Psychology, Psychiatry, Letter to the Editor, Genetics (clinical)
Published
2020

46. Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis

Author

Flavia Palombo, Maarten Fornerod, Grazia M.S. Mancini, Joseph G. Gleeson, Lily Bazak, Esmee Kasteleijn, Natalia Ordonez-Herrera, Milena Laure-Kamionowska, Fowzan S. Alkuraya, Pawel Gawlinski, William B. Dobyns, Mariasavina Severino, Marjolein H G Dremmen, Marco Seri, Marie Claire Y. de Wit, Robert B. Hufnagel, Ghayda Mirzaa, Laura Vandervore, Rachel Schot, Maarten H. Lequin, Lina Basel-Salmon, Arndt Rolfs, Robert J. Hopkin, Ahmed Al Fares, Nicola Brunetti-Pierri, Bella Davidov, Gerarda Cappuccio, Maria Teresa Divizia, Rolf W. Stottmann, Daphne J. Smits, Aida M. Bertoli-Avella, Wojciech Wiszniewski, Damir Musaev, Valentina Stanley, Hanah Akleh, Peter Bauer, Amal Alhashem, Martina Wilke, Jeroen Demmers, Malak Al Ghamdi, Marjon van Slegtenhorst, Pasquale Striano, Mees van der Ent, Pamela Magini, Tommaso Pippucci, Marta Columbaro, Maha S. Zaki, Anna Jansen, Deema Aljeaid, Peter J. van der Spek, Noa Ruhrman Shahar, Frans W. Verheijen, Clinical Biology, Clinical sciences, Faculty of Medicine and Pharmacy, Physiotherapy, Human Physiology and Anatomy, Pediatrics, Public Health Sciences, Mental Health and Wellbeing research group, Neurogenetics, Magini, P., Smits, D. J., Vandervore, L., Schot, R., Columbaro, M., Kasteleijn, E., van der Ent, M., Palombo, Francesco, Lequin, M. H., Dremmen, M., de Wit, M. C. Y., Severino, M., Divizia, M. T., Striano, P., Ordonez-Herrera, N., Alhashem, A., Al Fares, A., Al Ghamdi, M., Rolfs, A., Bauer, P., Demmers, J., Verheijen, F. W., Wilke, M., van Slegtenhorst, M., van der Spek, P. J., Seri, M., Jansen, A. C., Stottmann, R. W., Hufnagel, R. B., Hopkin, R. J., Aljeaid, D., Wiszniewski, W., Gawlinski, P., Laure-Kamionowska, M., Alkuraya, F. S., Akleh, H., Stanley, V., Musaev, D., Gleeson, J. G., Zaki, M. S., Brunetti-Pierri, N., Cappuccio, G., Davidov, B., Basel-Salmon, L., Bazak, L., Shahar, N. R., Bertoli-Avella, A., Mirzaa, G. M., Dobyns, W. B., Pippucci, T., Fornerod, M., Mancini, G. M. S., Clinical Genetics, Clinical Chemistry, Cell biology, Radiology & Nuclear Medicine, Neurology, Biochemistry, Pathology, Magini P., Smits D.J., Vandervore L., Schot R., Columbaro M., Kasteleijn E., van der Ent M., Palombo F., Lequin M.H., Dremmen M., de Wit M.C.Y., Severino M., Divizia M.T., Striano P., Ordonez-Herrera N., Alhashem A., Al Fares A., Al Ghamdi M., Rolfs A., Bauer P., Demmers J., Verheijen F.W., Wilke M., van Slegtenhorst M., van der Spek P.J., Seri M., Jansen A.C., Stottmann R.W., Hufnagel R.B., Hopkin R.J., Aljeaid D., Wiszniewski W., Gawlinski P., Laure-Kamionowska M., Alkuraya F.S., Akleh H., Stanley V., Musaev D., Gleeson J.G., Zaki M.S., Brunetti-Pierri N., Cappuccio G., Davidov B., Basel-Salmon L., Bazak L., Shahar N.R., Bertoli-Avella A., Mirzaa G.M., Dobyns W.B., Pippucci T., Fornerod M., and Mancini G.M.S.

Subjects
Male, 0301 basic medicine, Microcephaly, Ceramide, RNA Splicing, Mitosis, Cell fate determination, Biology, Endoplasmic Reticulum, Article, arthrogryposis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Genetics, medicine, Humans, Cell Lineage, microcephaly, Nuclear pore, Child, SMPD4, Genetics (clinical), Arthrogryposis, arthrogryposi, neutral-sphingomyelinase, Gene Expression Profiling, Autophagy, medicine.disease, Sphingolipid, Pedigree, NET13, Cell biology, HEK293 Cells, Sphingomyelin Phosphodiesterase, 030104 developmental biology, chemistry, Neurodevelopmental Disorders, Female, medicine.symptom, Sphingomyelin, 030217 neurology & neurosurgery
Abstract

Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.

Published
2019

47. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy

Author

Rhonda E. Schnur, Fabio Sirchia, Olga Levchenko, Caroline Nava, Jane Juusola, Sarah Verheyen, Marketa Vlckova, Lindsay Rhodes, Gregory M. Cooper, Darina Prchalova, Thomas Courtin, Øystein L. Holla, David Kronn, Akemi J. Tanaka, E. Martina Bebin, Tara Funari, Miroslava Hancarova, Ennio Del Giudice, Nicolas Guex, Astrid Eisenkölbl, Dawn L. Earl, Toshiki Takenouchi, Ursula Gruber-Sedlmayr, Sedlácek Z, Sofia Douzgou, Heidelis A. Seebacher, Gerarda Cappuccio, Jasmin Blatterer, Anna Mikhaleva, Dian Donnai, Wendy K. Chung, Else Merckoll, Natasha J Brown, Elizabeth A. Sellars, Stefan Mundlos, Susan M. Hiatt, Giuliana Giannuzzi, Sinje Geuer, Giuseppina Vitiello, Séverine Lorrain, Alexandre Reymond, David J. Amor, Nicolas Chatron, Julien Delafontaine, Martine Doco, Kristian Tveten, Cecilie F. Rustad, Sylvain Pradervand, Delphine Héron, Alfredo Brusco, Elena L. Dadali, Nicola Brunetti-Pierri, Boris Keren, Yuri A. Zarate, Crystle Lee, Joel Charrow, Binnaz Yalcin, Heidi Taska-Tench, Elin Tønne, Tomoko Uehara, Alexander Lavrov, Jennifer Norman, Norine Voisin, Anna C.E. Hurst, Victoria R. Sanders, Ganka Douglas, Diana Johnson, Kenjiro Kosaki, Université de Lausanne = University of Lausanne (UNIL), Cooper Medical School of Rowan University [Camden] (CMSRU), Manchester University NHS Foundation Trust (MFT), University of Manchester [Manchester], HudsonAlpha Institute for Biotechnology [Huntsville, AL], Oslo University Hospital [Oslo], Victorian Clinical Genetics Services [Melbourne, VIC, Australia] (VCGS), Murdoch Children's Research Institute (MCRI), University of Melbourne, Seattle Children’s Hospital, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme [ CHU Pitié-Salpêtrière AP-HP] (GRC : DIA), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Research Centre for Medical Genetics [Moscow, Russia] (RCMG), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Medical University of Graz, Sheffield Children's NHS Foundation Trust, University of Arkansas at Little Rock, Charles University [Prague] (CU), University Hospital Motol [Prague], University of Alabama at Birmingham [ Birmingham] (UAB), Università degli studi di Torino = University of Turin (UNITO), Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino, University of Naples Federico II = Università degli studi di Napoli Federico II, Ann & Robert H. Lurie Children's Hospital of Chicago, Swiss Institute of Bioinformatics [Lausanne] (SIB), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), GeneDx [Gaithersburg, MD, USA], Johannes Kepler University Linz [Linz] (JKU), Telemark Hospital Trust [Skien, Norway], New York Medical College (NYMC), Integris Pediatric Neurology [Oklahoma City, OK, USA] (IPN), Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo' [Trieste], Keio University School of Medicine [Tokyo, Japan], Columbia University [New York], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Dupuis, Christine, Voisin, N., Schnur, R. E., Douzgou, S., Hiatt, S. M., Rustad, C. F., Brown, N. J., Earl, D. L., Keren, B., Levchenko, O., Geuer, S., Verheyen, S., Johnson, D., Zarate, Y. A., Hancarova, M., Amor, D. J., Bebin, E. M., Blatterer, J., Brusco, A., Cappuccio, G., Charrow, J., Chatron, N., Cooper, G. M., Courtin, T., Dadali, E., Delafontaine, J., Del Giudice, E., Doco, M., Douglas, G., Eisenkolbl, A., Funari, T., Giannuzzi, G., Gruber-Sedlmayr, U., Guex, N., Heron, D., Holla, O. L., Hurst, A. C. E., Juusola, J., Kronn, D., Lavrov, A., Lee, C., Lorrain, S., Merckoll, E., Mikhaleva, A., Norman, J., Pradervand, S., Prchalova, D., Rhodes, L., Sanders, V. R., Sedlacek, Z., Seebacher, H. A., Sellars, E. A., Sirchia, F., Takenouchi, T., Tanaka, A. J., Taska-Tench, H., Tonne, E., Tveten, K., Vitiello, G., Vlckova, M., Uehara, T., Nava, C., Yalcin, B., Kosaki, K., Donnai, D., Mundlos, S., Brunetti Pierri, N., Chung, W. K., and Reymond, A.

Subjects
Male, Models, Molecular, Hypertrichosis, [SDV]Life Sciences [q-bio], Mesomelic Dysplasia, Transcriptome, Mice, Gene Frequency, Missense mutation, Child, Zebrafish, Genetics (clinical), Genetics, Brain Diseases, 0303 health sciences, biology, Protein Stability, 030305 genetics & heredity, AFF3, AFF4, horseshoe kidney, intellectual disability, mesomelic dysplasia, Nuclear Proteins, Syndrome, Phenotype, Ubiquitin ligase, [SDV] Life Sciences [q-bio], Child, Preschool, Female, Transcriptional Elongation Factors, Adolescent, Mutation, Missense, Osteochondrodysplasias, Article, Evolution, Molecular, Young Adult, 03 medical and health sciences, medicine, Animals, Humans, Amino Acid Sequence, Fused Kidney, 030304 developmental biology, Epilepsy, Infant, Horseshoe kidney, biology.organism_classification, medicine.disease, biology.protein
Abstract

International audience; The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3-and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.

Published
2021

48. Milder presentation of TELO2-related syndrome in two sisters homozygous for the p.Arg609His pathogenic variant

Author

Francesco Musacchia, Valentina Duga, Antonietta Coppola, Valeria Capra, Corrado Romano, Diego Carrella, Annalaura Torella, Margherita Mutarelli, Stefano D'Arrigo, Martino Montomoli, Michele Pinelli, Nicola Brunetti-Pierri, Vincenzo Nigro, Gerarda Cappuccio, Chiara Pantaleoni, Raffaele Castello, Luisa Chiapparini, Claudia Ciaccio, Sandro Banfi, Albina Tummolo, Silvia Maitz, Daniele De Brasi, Isabella Moroni, Giuseppina Vitiello, Vincenzo Leuzzi, Silvia Esposito, Donatella Milani, Marcella Zollino, Giancarlo Parenti, Claudia Santoro, Angelo Selicorni, Ciaccio, C., Duga, V., Pantaleoni, C., Esposito, S., Moroni, I., Pinelli, M., Castello, R., Nigro, V., Chiapparini, L., D'Arrigo, S., Torella, A., Cappuccio, G., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Parenti, G., Capra, V., Leuzzi, V., Selicorni, A., Maitz, S., Brunetti-Pierri, N., Banfi, S., Zollino, M., Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., and Santoro, C.

Subjects
Microcephaly, Ataxia, Adolescent, Developmental Disabilitie, Developmental Disabilities, Mutation, Missense, Intellectual disability, Disease, Compound heterozygosity, Settore MED/03 - GENETICA MEDICA, Short stature, Young Adult, Genetics, Humans, Medicine, Abnormalities, Multiple, Global developmental delay, Genetics (clinical), Loss function, DNA-Repair, business.industry, Homozygote, Syndrome, General Medicine, medicine.disease, Pedigree, Phenotype, Female, medicine.symptom, TELO2, business, Human
Abstract

Biallelic loss of function of TELO2 gene cause a severe syndromic disease mainly characterized by global developmental delay with poor motor and language acquisitions, microcephaly, short stature, minor facial and limbs anomalies, sleep disorder, spasticity, and balance impairment up to ataxia. TELO2-related syndrome, also known as You-Hoover-Fong Syndrome, is extremely rare and since its first description in 2016 only 8 individuals have been reported, all showing a severe disability. The causative gene is member of the big molecular family of genes responsible for cells proliferation and DNA stability. We describe the case of two sisters, carrying the homozygous p. Arg609His variant of the gene, who present a milder phenotype of TELO2-related syndrome. Such variant has been reported once in a more severely affected patient, in compound heterozygous state associated with the p. Pro260Leu variant, suggesting a possible role of the p. Arg609His variant in determining milder phenotypes. Comparing the siblings with all previously reported cases, we offer an overview on the condition and discuss TELO2 genetic interactions, in order to further explore the molecular bases of this recently described disorder.

Published
2021

49. Peculiar footprints in a child with agenesis of corpus callosum

Author

Rita Genesio, Nicola Brunetti-Pierri, Piero Pignataro, Gerarda Cappuccio, Cappuccio, G., Genesio, R., Pignataro, P., and Brunetti Pierri, N.

Subjects
business.industry, Agenesis, Pediatrics, Perinatology and Child Health, medicine, Anatomy, Corpus callosum, medicine.disease, business
Abstract

no abstract available

Published
2021

50. Mild clinical presentation of joubert syndrome in a male adult carrying biallelic mks1 truncating variants

Author

Francesca Romano, Raffaella Brunetti-Pierri, Francesca Simonelli, Giuseppe De Rosa, Nicola Brunetti-Pierri, Maria Elena Onore, Marianthi Karali, Enrico Tedeschi, Gerarda Cappuccio, Sandro Banfi, Francesco Testa, Brunetti Pierri, R., Karali, M., Testa, F., Cappuccio, G., Onore, M. E., Romano, F., De Rosa, G., Tedeschi, E., Brunetti Pierri, N., Banfi, S., Simonelli, F., Brunetti-Pierri, R., and Brunetti-Pierri, N.

Subjects
Pathology, medicine.medical_specialty, Medicine (General), Visual acuity, Clinical Biochemistry, Autosomal recessive Retinitis Pigmentosa, Case Report, Joubert syndrome, 03 medical and health sciences, R5-920, MKS1, Retinitis pigmentosa, medicine, Exome, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, business.industry, 030305 genetics & heredity, medicine.disease, eye diseases, Ciliopathy, medicine.anatomical_structure, Posterior cranial fossa, Dysplasia, medicine.symptom, business, Phenotype extension, Electroretinography
Abstract

Pathogenic variants in the MKS1 gene are responsible for a ciliopathy with a wide spectrum of clinical manifestations ranging from Meckel and Joubert syndrome (JBTS) to Bardet-Biedl syndrome, and involving the central nervous system, liver, kidney, skeleton, and retina. We report a 39-year-old male individual presenting with isolated Retinitis Pigmentosa (RP), as assessed by full ophthalmological evaluation including Best-Corrected Visual Acuity measurements, fundus examination, Goldmann Visual Field test, and full-field Electroretinography. A clinical exome identified biallelic nonsense variants in MKS1 that prompted post-genotyping investigations for systemic abnormalities of ciliopathy. Brain magnetic resonance imaging revealed malformations of the posterior cranial fossa with the ‘molar tooth sign’ and cerebellar folia dysplasia, which are both distinctive features of JBTS. No other organ or skeletal abnormalities were detected. This case illustrates the power of clinical exome for the identification of the mildest forms of a disease spectrum, such as a mild JBTS with RP in the presented case of an individual carrying biallelic truncating variants in MKS1.

Published
2021

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