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1. Psychiatric Disorders and Genotoxicity Following Primary Metal on Polyethylene Total Hip Arthroplasty and Their Correlation to Cobalt/Chromium Levels

Author

Abdel Hamid OI, Attia ME, Hirshon JM, El-Shinawi M, El-Hussaini M, and El-Setouhy M

Subjects
metal on polyethylene hip arthroplasty, cobalt, chromium, major depressive inventory, mini-mental state examination, genotoxicity, Medicine (General), R5-920
Abstract

Omaima I Abdel Hamid,1 Mohamed E Attia,2 Jon M Hirshon,3,4 Mohamed El-Shinawi,5,6 Moustafa El-Hussaini,7 Maged El-Setouhy7,8 1Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 2Orthopedics Departments, Faculty of Medicine, Zagazig University, Zagazig, Egypt; 3Department of Emergency Medicine, University of Maryland, School of Medicine, Baltimore, MD, USA; 4Department of Epidemiology and Public Health, University of Maryland, School of Medicine, Baltimore, MD, USA; 5Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 6Galala University, Galala City, Suez, Egypt; 7Department of Community, Environmental and Occupational Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 8Department of Family and Community Medicine, Faculty of Medince, Jazan University, Jazan, Kingdom of Saudi ArabiaCorrespondence: Omaima I Abdel Hamid, Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt, Tel +201001664310, Email dr_omaima2006@yahoo.comIntroduction: Hip arthroplasty (HA) using implantable metal components is among the commonest orthopedic interventions. However, it can be followed by several complications following corrosion and the release of metal ions. Several studies proved that damaged genomic DNA may contribute to the pathophysiology of mental disorders.Aim: The current work aims to evaluate the psychiatric disorders in metal on polyethylene hip arthroplasty (MOP-HA) patients and its correlation to cobalt/chromium (Co/Cr) levels and genotoxicity.Methods: The work was a longitudinal follow-up study including 34 adults with unilateral primary MOP-HA meeting the inclusion and exclusion criteria. Preoperatively, 6, 12-months-postoperatively, patients were examined for cognitive impairment using mini-mental-state-examination (MMSE), depression using major-depressive-inventory (MDI), and blood samples were collected for estimation of Co/Cr, detection of genotoxicity by single-cell-gel-electrophoresis (comet assay) and serum 8-hydroxy-2’–deoxyguanosine (8-OHdG).Results: Cognitive impairment was reported in 18.5% and 14.8% at 6-months, and 12-months postoperative, respectively. Depressive disorder was recorded in 22.2% at 6-months and 14.8% at 12-months postoperative. The marginal homogeneity tests proved a non-significant difference. There was a non-significant difference in preoperative, 6-months, 12-months postoperative MMSE, and MDI scores. There were significantly increased Co/Cr levels at 6-months postoperative. The levels decreased at 12-months postoperative, however, still significantly higher than preoperative values. There was a significant increase in serum 8-OHdG and the levels were positively correlated to cobalt levels at both 6 and 12-months-postoperative. There was a non-significant difference among preoperative, 6-months, and 12-months postoperative comet assay measurements.Conclusion: From previous findings, we can conclude that will-functioning MOP hip arthroplasty can induce increased ion levels and positively correlated increase in biochemical markers of genotoxicity (8-OHdG).Keywords: metal on polyethylene hip arthroplasty, cobalt, chromium, major depressive inventory, mini-mental state examination, genotoxicity

Published
2022

2. Epidemiology of Knife Injuries at Ain Shams University Hospital Emergency Department from 2018 to 2019: A Cross-Sectional Study

Author

Ellaban MM, Afifi E, El Houssinie M, Hirshon JM, El-Shinawi M, and El-Setouhy M

Subjects
epidemiology, knife injuries, accidental, emergency department, asuh, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Manar M Ellaban,1 Eman Afifi,2 Moustafa El Houssinie,1 Jon Mark Hirshon,3,4 Mohamed El-Shinawi,3,5,6 Maged El-Setouhy1,3,7 1Department of Community, Environmental and Occupational Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 2Department of Geriatrics and Gerontology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 3Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; 4Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA; 5General Surgery Department, Ain Shams University, Cairo, Egypt; 6Galala University, Cairo, Egypt; 7Department of Family and Community Medicine, Faculty of Medicine, Jazan University, Jazan, Saudi ArabiaCorrespondence: Manar M EllabanCommunity, Environmental and Occupational Medicine, Faculty of Medicine, Ain Shams University, Abbasia, Cairo, EgyptTel +201550690740Fax +2024346041Email manarellaban@med.asu.edu.egPurpose: For knife-related injuries (KRI), a comprehensive understanding of the incidence, mechanism, and pattern of injury is required for the development of prevention strategies. Unfortunately, reliable data on knife-related injuries are difficult to obtain. In Egypt, there is no national routine surveillance system for all knife injuries. The aim was to examine the epidemiologic characteristics of knife-related injuries at the Ain Shams University Hospital (ASUH) emergency department (ED).Patients and Methods: A cross-sectional study was conducted on 140 patients who presented with knife injuries at the ASUH ED. Data collection was done during a randomly selected period of seven days each month from October 2018 to September 2019. The sociodemographic characteristics, injury-related variables, and outcomes of the injury were recorded on a structured worksheet.Results: Knife-related injuries represented 22.9% of all injury cases that presented to the ED. Majority of the knife-related injuries (87.86%) were accidental, 7.9% were assault, and 4.3% were self-inflicted. Home was the most reported place of injury. Most of the victims were discharged from the ED (87.1%), and 84.3% recovered completely. The mean hospital stay was 3.6 ± 1.3 days.Conclusion: Majority of the knife-related injuries were accidental, and the most common pattern was isolated chest injury with contusions. Cases that were not severe and had favorable prognosis (ie, complete recovery) comprised the largest proportion. Recommendations include development of a surveillance system may result in the effective control and prevention of this growing problem of knife-related injuries.Keywords: epidemiology, knife injuries, accidental, emergency department, ASUH

Published
2021

3. Patient Satisfaction with a Tertiary Hospital in Egypt using a HCAHPS-Derived Survey

Author

Farghaly M, Kamal A, El-Setouhy M, Hirshon JM, and El-Shinawi M

Subjects
hcahps, quality, patients' satisfaction, community, Medicine (General), R5-920
Abstract

Mahmoud Farghaly,1 Abdallah Kamal,1,2 Maged El-Setouhy,3,4 Jon Mark Hirshon,5,6 Mohamed El-Shinawi1,7 1Department of General Surgery, Ain Shams University, Cairo, Egypt; 2Department of Radiology, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; 3Department of Community, Environmental and Occupational Medicine, Ain Shams University, Cairo, Egypt; 4Department of Family and Community Medicine, Jazan University, Jazan, Saudi Arabia; 5Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; 6Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA; 7Department of Medical Education, Galala University, Cairo, EgyptCorrespondence: Mahmoud FarghalyDepartment of General Surgery, Ain Shams University, Cairo, EgyptTel +20 1001775378Email Mahmoudfarghali@med.asu.edu.egStudy Design: Retrograde cross-sectional study.Objective: To assess patient satisfaction and outcomes in polytraumatized patients in EL-Demerdash hospital.Background: This is the first study that assessed patient satisfaction with a tertiary hospital in Egypt. Ain Shams University Surgery Hospital, which is one of the largest hospitals in Egypt and serves millions of patients each year, was the site of the study.Methods: A version of the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey was used to query 361 patients from November 2015 until July 2018 Survey questions were divided into the following categories: communication with doctors, responsiveness of hospital staff, cleanliness of the hospital environment, quietness of the hospital environment, pain management, communication about medicines, discharge information, overall rating of the hospital, and willingness to recommend the hospital.Results: A total of 361 patients were interviewed. The results showed both positive and negative levels of satisfaction. The positive results included no delay in admission, friendly staff including nurses and doctors, better patient outcomes regarding pain management and adverse side effects, and the overall rating of the hospital was good, which reflected patient satisfaction. The negative findings were lack of proper communication between the medical staff and patients. Patients indicated they did not get a satisfactory explanation of their prescribed drug doses and drug adverse effects. In addition, they did not get enough instruction on what to do after being released from the hospital.Conclusion: The medical staff at Ain Shams University Surgery Hospital should focus more on the patient’s own preferences and communicate better with patients. We recommended that the hospital organize regular communication skills courses for medical students, physicians, and nurses. Patients should understand the discharge report and indications and side effects of the medications before leaving the hospital.Keywords: HCAHPS, quality, patients’ satisfaction, community

Published
2021

4. TBX6 null variants and a common hypomorphic allele in congenital scoliosis.

Author

Shen, J, Chen, Y, Zhang, T, Zhang, J, Choy, K, Wang, J, Wang, Q, Li, S, Zhou, W, Guo, J, Wang, Y, Zhang, C, Zhao, Hong, An, Yu, Zhao, Yu, Liu, Z, Zuo, Y, Tian, Y, Weng, X, Sutton, V, Wang, H, Ming, Y, Kulkarni, S, Zhong, T, Giampietro, P, Dunwoodie, S, Cheung, S, Zhang, X, Jin, L, Lupski, J, Qiu, G, Zhang, F, Wu, N, Ming, X, Xiao, J, Wu, Z, Chen, X, Shinawi, M, Shen, Y, Yu, G, Liu, J, Xie, H, Gucev, Z, Liu, S, Yang, N, Al-Kateb, H, Chen, J, Hauser, N, Tasic, V, Liu, P, Su, X, Pan, X, Liu, C, Wang, L, and Shen, Joseph

Subjects
Adolescent, Asian People, Child, Child, Preschool, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genotype, Humans, Male, Mutation, Pedigree, Phenotype, Radiography, Scoliosis, Sequence Deletion, Spine, T-Box Domain Proteins
Abstract

BACKGROUND: Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. METHODS: We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions. RESULTS: We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P

Published
2015

5. The Cognitive and Behavioral Phenotypes of Individuals with 'CHRNA7' Duplications

Author

Gillentine, M. A., Berry, L. N., Goin-Kochel, R. P., Ali, M. A., Ge, J., Guffey, D., Rosenfeld, J. A., Hannig, V., Bader, P., Proud, M., Shinawi, M., Graham, B. H., Lin, A., Lalani, S. R., Reynolds, J., Chen, M., Grebe, T., Minard, C. G., Stankiewicz, P., Beaudet, A. L., and Schaaf, C. P.

Abstract

Chromosome 15q11q13 is among the least stable regions in the genome due to its highly complex genomic architecture. Low copy repeat elements at 15q13.3 facilitate recurrent copy number variants (CNVs), with deletions established as pathogenic and "CHRNA7" implicated as a candidate gene. However, the pathogenicity of duplications of "CHRNA7" is unclear, as they are found in affected probands as well as in reportedly healthy parents and unaffected control individuals. We evaluated 18 children with microduplications involving "CHRNA7," identified by clinical chromosome microarray analysis (CMA). Comprehensive phenotyping revealed high prevalence of developmental delay/intellectual disability, autism spectrum disorder, and attention deficit/hyperactivity disorder. As "CHRNA7" duplications are the most common CNVs identified by clinical CMA, this study provides anticipatory guidance for those involved with care of affected individuals.

Published
2017
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7. De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus

Author

Galosi, S., Edani, B.H., Martinelli, S., Hansikova, H., Eklund, E.A., Caputi, C., Masuelli, L., Corsten-Janssen, N., Srour, M., Oegema, R., Bosch, D.G.M., Ellis, C.A., Amlie-Wolf, L., Accogli, A., Atallah, I., Averdunk, L., Barañano, K.W., Bei, R., Bagnasco, I., Brusco, A., Demarest, S., Alaix, A.S., Bonaventura, C. Di, Distelmaier, F., Elmslie, F., Gan-Or, Z., Good, J.M., Gripp, K., Kamsteeg, E.J., Macnamara, E., Marcelis, C.L.M., Mercier, N., Peeden, J., Pizzi, S., Pannone, L., Shinawi, M., Toro, C., Verbeek, N.E., Venkateswaran, S., Wheeler, P.G., Zdrazilova, L., Zhang, R., Zorzi, G., Guerrini, R., Sessa, W.C., Lefeber, D.J., Tartaglia, M., Hamdan, F.F., Grabińska, K.A., Leuzzi, V., Galosi, S., Edani, B.H., Martinelli, S., Hansikova, H., Eklund, E.A., Caputi, C., Masuelli, L., Corsten-Janssen, N., Srour, M., Oegema, R., Bosch, D.G.M., Ellis, C.A., Amlie-Wolf, L., Accogli, A., Atallah, I., Averdunk, L., Barañano, K.W., Bei, R., Bagnasco, I., Brusco, A., Demarest, S., Alaix, A.S., Bonaventura, C. Di, Distelmaier, F., Elmslie, F., Gan-Or, Z., Good, J.M., Gripp, K., Kamsteeg, E.J., Macnamara, E., Marcelis, C.L.M., Mercier, N., Peeden, J., Pizzi, S., Pannone, L., Shinawi, M., Toro, C., Verbeek, N.E., Venkateswaran, S., Wheeler, P.G., Zdrazilova, L., Zhang, R., Zorzi, G., Guerrini, R., Sessa, W.C., Lefeber, D.J., Tartaglia, M., Hamdan, F.F., Grabińska, K.A., and Leuzzi, V.

Abstract

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Published
2022

8. De novo missense variants in FBXO11 alter its protein expression and subcellular localization

Author

Gregor, A, Meerbrei, T, Gerstner, T, Toutain, A, Lynch, SA, Stals, K, Maxton, C, Lemke, JR, Bernat, JA, Bombei, HM, Foulds, N, Hunt, D, Kuechler, A, Beygo, J, Stobe, P, Bouman, A, Palomares-Bralo, M, Santos-Simarro, F, Garcia-Minaur, S, Pacio-Miguez, M, Popp, B, Vasileiou, G, Hebebrand, M, Reis, A, Schuhmann, S, Krumbiegel, M, Brown, NJ, Sparber, P, Melikyan, L, Bessonova, L, Cherevatova, T, Sharkov, A, Shcherbakova, N, Dabir, T, Kini, U, Schwaibold, EMC, Haack, TB, Bertoli, M, Hoffjan, S, Falb, R, Shinawi, M, Sticht, H, Zweier, C, Gregor, A, Meerbrei, T, Gerstner, T, Toutain, A, Lynch, SA, Stals, K, Maxton, C, Lemke, JR, Bernat, JA, Bombei, HM, Foulds, N, Hunt, D, Kuechler, A, Beygo, J, Stobe, P, Bouman, A, Palomares-Bralo, M, Santos-Simarro, F, Garcia-Minaur, S, Pacio-Miguez, M, Popp, B, Vasileiou, G, Hebebrand, M, Reis, A, Schuhmann, S, Krumbiegel, M, Brown, NJ, Sparber, P, Melikyan, L, Bessonova, L, Cherevatova, T, Sharkov, A, Shcherbakova, N, Dabir, T, Kini, U, Schwaibold, EMC, Haack, TB, Bertoli, M, Hoffjan, S, Falb, R, Shinawi, M, Sticht, H, and Zweier, C

Abstract

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data, our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.

Published
2022

12. Loss-of-function truncating and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct neurodevelopmental phenotype

Author

Zanoni, P., Steindl, K., Sengupta, D., Sticht, H., Joset, P., Baar, A., van Ravenswaaij-Arts, C. M. A., Shinawi, M., Maystadt, I., Belnap, N., Benoit, V., de Vries, B. B. A., Lacombe, D., Larson, A., Pfundt, R., Ramsey, K., Blok, L. Snijders, Wheeler, P. G., Wevers, M. R., Gozani, O., Rauch, A., and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Published
2020

13. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Author

Manole, A, Efthymiou, S, O'Connor, E, Mendes, MI, Jennings, M, Maroofian, R, Davagnanam, I, Mankad, K, Lopez, MR, Salpietro, V, Harripaul, R, Badalato, L, Walia, J, Francklyn, CS, Athanasiou-Fragkouli, A, Sullivan, R, Desai, S, Baranano, K, Zafar, F, Rana, N, Ilyas, M, Horga, A, Kara, M, Mattioli, F, Goldenberg, A, Griffin, H, Piton, A, Henderson, LB, Kara, B, Aslanger, AD, Raaphorst, J, Pfundt, R, Portier, R, Shinawi, M, Kirby, A, Christensen, KM, Wang, L, Rosti, RO, Paracha, SA, Sarwar, MT, Jenkins, D, SYNAPS Study Group, Ahmed, J, Santoni, FA, Ranza, E, Iwaszkiewicz, J, Cytrynbaum, C, Weksberg, R, Wentzensen, IM, Guillen Sacoto, MJ, Si, Y, Telegrafi, A, Andrews, MV, Baldridge, D, Gabriel, H, Mohr, J, Oehl-Jaschkowitz, B, Debard, S, Senger, B, Fischer, F, van Ravenwaaij, C, Fock, AJM, Stevens, SJC, Bähler, J, Nasar, A, Mantovani, JF, Manzur, A, Sarkozy, A, Smith, DEC, Salomons, GS, Ahmed, ZM, Riazuddin, S, Usmani, MA, Seibt, A, Ansar, M, Antonarakis, SE, Vincent, JB, Ayub, M, Grimmel, M, Jelsig, AM, Hjortshøj, TD, Karstensen, HG, Hummel, M, Haack, TB, Jamshidi, Y, Distelmaier, F, Horvath, R, Gleeson, JG, Becker, H, Mandel, J-L, Koolen, DA, and Houlden, H

Abstract

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.

Published
2020

14. Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

Author

Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., Ravenswaaij-Arts, C.M.A. van, Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., Belnap, N., Benoit, V., Delplancq, G., Vries, B.B.A. de, Grotto, S., Lacombe, D., Larson, A., Mourmans, J., Õunap, K., Petrilli, G., Pfundt, R.P., Ramsey, K., Snijders Blok, L., Tsatsaris, V., Vitobello, A., Faivre, L., Wheeler, P.G., Wevers, M.R., Wojcik, M., Zweier, M., Gozani, O., Rauch, A., Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., Ravenswaaij-Arts, C.M.A. van, Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., Belnap, N., Benoit, V., Delplancq, G., Vries, B.B.A. de, Grotto, S., Lacombe, D., Larson, A., Mourmans, J., Õunap, K., Petrilli, G., Pfundt, R.P., Ramsey, K., Snijders Blok, L., Tsatsaris, V., Vitobello, A., Faivre, L., Wheeler, P.G., Wevers, M.R., Wojcik, M., Zweier, M., Gozani, O., and Rauch, A.

Abstract

Contains fulltext : 237837.pdf (Publisher’s version ) (Open Access), PURPOSE: Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf-Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. METHODS: We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. RESULTS: The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2's folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. CONCLUSION: NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch-Steindl syndrome after the delineators of this phenotype.

Published
2021

15. Wilms tumor in patients with osteopathia striata with cranial sclerosis.

Author

Bach A., Mi J., Hunter M., Halliday B.J., Garcia-Minaur S., Sperotto F., Trevisson E., Markie D., Morison I.M., Shinawi M., Willis D.N., Robertson S.P., Bach A., Mi J., Hunter M., Halliday B.J., Garcia-Minaur S., Sperotto F., Trevisson E., Markie D., Morison I.M., Shinawi M., Willis D.N., and Robertson S.P.

Abstract

Germline pathogenic variants in AMER1 cause osteopathia striata with cranial sclerosis (OSCS: OMIM 300373), an X-linked sclerosing bone disorder. Female heterozygotes exhibit metaphyseal striations in long bones, macrocephaly, cleft palate, and, occasionally, learning disability. Male hemizygotes typically manifest the condition as fetal or neonatal death. Somatically acquired variants in AMER1 are found in neoplastic tissue in 15-30% of patients with Wilms tumor; however, to date, only one individual with OSCS has been reported with a Wilms tumor. Here we present four cases of Wilms tumor in unrelated individuals with OSCS, including the single previously published case. We also report the first case of bilateral Wilms tumor in a patient with OSCS. Tumor tissue analysis showed no clear pattern of histological subtypes. In Beckwith-Wiedemann syndrome, which has a known predisposition to Wilms tumor development, clinical protocols have been developed for tumor surveillance. In the absence of further evidence, we propose a similar protocol for patients with OSCS to be instituted as an initial precautionary approach to tumor surveillance. Further evidence is needed to refine this protocol and to evaluate the possibility of development of other neoplasms later in life, in patients with OSCS.Copyright © 2020, The Author(s), under exclusive licence to European Society of Human Genetics.

Published
2021

18. Microdeletions including YWHAE in the Miller–Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment

Author

Sreenath Nagamani, S C, Zhang, F, Shchelochkov, O A, Bi, W, Ou, Z, Scaglia, F, Probst, F J, Shinawi, M, Eng, C, Hunter, J V, Sparagana, S, Lagoe, E, Fong, C-T, Pearson, M, Doco-Fenzy, M, Landais, E, Mozelle, M, Chinault, A C, Patel, A, Bacino, C A, Sahoo, T, Kang, S H, Cheung, S W, Lupski, J R, and Stankiewicz, P

Published
2009
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20. Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

Author

Castilla-Vallmanya L, Selmer KK, Dimartino C, Raquel Rabionet Janssen, Blanco-Sánchez B, Yang S, Reijnders MRF, van Essen AJ, Oufadem M, Vigeland MD, Stadheim B, Houge G, Cox H, Kingston H, Clayton-Smith J, Innis JW, Iascone M, Cereda A, Gabbiadini S, Chung WK, Sanders V, Charrow J, Bryant E, Millichap J, Vitobello A, Thauvin C, Mau-Them FT, Faivre L, Lesca G, Labalme A, Rougeot C, Chatron N, Sanlaville D, Christensen KM, Kirby A, Lewandowski R, Gannaway R, Aly M, Lehman A, Clarke L, Graul-Neumann L, Zweier C, Lessel D, Lozic B, Aukrust I, Peretz R, Stratton R, Smol T, Dieux-Coëslier A, Meira J, Wohler E, Sobreira N, Beaver EM, Heeley J, Briere LC, High FA, Sweetser DA, Walker MA, Keegan CE, Jayakar P, Shinawi M, Kerstjens-Frederikse WS, Earl DL, Siu VM, Reesor E, Yao T, Hegele RA, Vaske OM, Rego S, Undiagnosed Diseases Network, Care4Rare Canada Consortium, Shapiro KA, Wong B, Gambello MJ, McDonald M, Karlowicz D, Colombo R, Serretti A, Pais L, O'Donnell-Luria A, Wray A, Sadedin S, Chong B, Tan TY, Christodoulou J, White SM, Slavotinek A, Barbouth D, Morel Swols D, Parisot M, Bole-Feysot C, Nitschké P, Pingault V, Munnich A, Cho MT, Cormier-Daire V, Balcells S, Lyonnet S, Grinberg-Vaisman DR, Amiel J, Urreizti R, and Gordon CT

Subjects
craniofacial development, patent ductus arteriosus, TRAF7, intellectual disability, blepharophimosis
Abstract

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

Published
2020

21. Microdeletions including YWHAE in the Miller-Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment

Author

Nagamani, S.C. Sreenath, Zhang, F., Shchelochkov, O.A., Bi, W., Ou, Z., Scaglia, F., Probst, F.J., Shinawi, M., Eng, C., Hunter, J.V., Sparagana, S., Lagoe, E., Fong, C.-T., Pearson, M., Doco-Fenzy, M., Landais, E., Mozelle, M., Chinault, A.C., Patel, A., Bacino, C.A., Sahoo, T., Kang, S.H., Cheung, S.W., Lupski, J.R., and Stankiewicz, P.

Subjects
Miller-Dieker syndrome -- Research, Miller-Dieker syndrome -- Genetic aspects, Chromosomes -- Research, Cognition disorders -- Research, Cognition disorders -- Genetic aspects, Health
Published
2009

22. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, E. D. (Enrico D. H.), Nardini, N. (Niels), Caliebe, A. (Almuth), Nagel, I. (Inga), Young, D. (Dana), Horvath, G. (Gabriella), Santoro, S. L. (Stephanie L.), Shuss, C. (Christine), Ziegler, A. (Alban), Bonneau, D. (Dominique), Kempers, M. (Marlies), Pfundt, R. (Rolph), Legius, E. (Eric), Bouman, A. (Arjan), Stuurman, K. E. (Kyra E.), Õunap, K. (Katrin), Pajusalu, S. (Sander), Wojcik, M. H. (Monica H.), Vasileiou, G. (Georgia), Le Guyader, G. (Gwenaël), Schnelle, H. M. (Hege M.), Berland, S. (Siren), Zonneveld-Huijssoon, E. (Evelien), Kersten, S. (Simone), Gupta, A. (Aditi), Blackburn, P. R. (Patrick R.), Ellingson, M. S. (Marissa S.), Ferber, M. J. (Matthew J.), Dhamija, R. (Radhika), Klee, E. W. (Eric W.), McEntagart, M. (Meriel), Lichtenbelt, K. D. (Klaske D.), Kenney, A. (Amy), Vergano, S. A. (Samantha A.), Jamra, R. A. (Rami Abou), Platzer, K. (Konrad), Pierpont, M. E. (Mary Ella), Khattar, D. (Divya), Hopkin, R. J. (Robert J.), Martin, R. J. (Richard J.), Jongmans, M. C. (Marjolijn C. J.), Chang, V. Y. (Vivian Y.), Martinez-Agosto, J. A. (Julian A.), Kuismin, O. (Outi), Kurki, M. I. (Mitja I.), Pietiläinen, O. (Olli), Palotie, A. (Aarno), Maarup, T. J. (Timothy J.), Johnson, D. S. (Diana S.), Venborg Pedersen, K. (Katja), Laulund, L. W. (Lone W.), Lynch, S. A. (Sally A.), Blyth, M. (Moira), Prescott, K. (Katrina), Canham, N. (Natalie), Ibitoye, R. (Rita), Brilstra, E. H. (Eva H.), Shinawi, M. (Marwan), Fassi, E. (Emily), Study, D. (DDD), Sticht, H. (Heinrich), Gregor, A. (Anne), Van Esch, H. (Hilde), and Zweier, C. (Christiane)

Subjects
Drosophila melanogaster, intellectual disability, neurodevelopmental disorders, CTCF, chromatin organization
Abstract

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Published
2019

23. Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD

Author

Granadillo, Jorge Luis, P.A. Stegmann, Alexander, Guo, Hui, Xia, K., Angle, Brad, Bontempo, Kelly, Pfundt, R.P., Rosenfeld, J.A., Shinawi, M., Granadillo, Jorge Luis, P.A. Stegmann, Alexander, Guo, Hui, Xia, K., Angle, Brad, Bontempo, Kelly, Pfundt, R.P., Rosenfeld, J.A., and Shinawi, M.

Abstract

Contains fulltext : 226271.pdf (Publisher’s version ) (Closed access)

Published
2020

24. De novo pathogenic variants in CSNK2B cause a new intellectual disability-craniodigital syndrome distinguished from Poirier-Bienvenu neurodevelopmental syndrome

Author

Asif, M., Kaygusuz, E., Shinawi, M., Nickelsen, A., Hochscherf, J., Lindenblatt, D., Noegel, A. A., Tinschert, S., Niefind, K., Fortugno, P., Jose, J., Brancati, F., Nuernberg, P., Hussain, M. S., Asif, M., Kaygusuz, E., Shinawi, M., Nickelsen, A., Hochscherf, J., Lindenblatt, D., Noegel, A. A., Tinschert, S., Niefind, K., Fortugno, P., Jose, J., Brancati, F., Nuernberg, P., and Hussain, M. S.

Published
2020

26. Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability

Author

Marom, R., Jain, M., Burrage, L.C., Song, I.W., Graham, B.H., Brown, C.W., Stevens, S.J.C., Stegmann, A.P.A., Gunter, A.T., Kaplan, J.D., Gavrilova, R.H., Shinawi, M., Rosenfeld, J.A., Bae, Y., Tran, A.A., Chen, Y, Lu, J.T., Gibbs, R.A., Eng, C., Yang, Y, Rousseau, J., Vries, B.B.A. de, Campeau, P.M., Lee, B., MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output

Subjects
Male, Heterozygote, speech delay, Adolescent, Chromosomal Proteins, Non-Histone, Micrognathism, Mutation, Missense, Article, CHROMATIN-REMODELING COMPLEX, Humans, Exome, BAF complex, Child, HAPLOINSUFFICIENCY CAUSES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COFFIN-SIRIS SYNDROME, DNA Helicases, Nuclear Proteins, SWI/SNF COMPLEX, Chromatin Assembly and Disassembly, BARAITSER-WINTER SYNDROME, GENE, Actins, NUCLEAR ACTIN, DNA-Binding Proteins, ACTIN-RELATED PROTEINS, intellectual disability, DE-NOVO MUTATIONS, Face, Multiprotein Complexes, ACTL6A, Female, Hand Deformities, Congenital, MENTAL-RETARDATION, Protein Binding, Transcription Factors
Abstract

Item does not contain fulltext Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to beta-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

Published
2017
Full Text
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27. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro, V. Dixon, C.L. Guo, H. Bello, O.D. Vandrovcova, J. Efthymiou, S. Maroofian, R. Heimer, G. Burglen, L. Valence, S. Torti, E. Hacke, M. Rankin, J. Tariq, H. Colin, E. Procaccio, V. Striano, P. Mankad, K. Lieb, A. Chen, S. Pisani, L. Bettencourt, C. Männikkö, R. Manole, A. Brusco, A. Grosso, E. Ferrero, G.B. Armstrong-Moron, J. Gueden, S. Bar-Yosef, O. Tzadok, M. Monaghan, K.G. Santiago-Sim, T. Person, R.E. Cho, M.T. Willaert, R. Yoo, Y. Chae, J.-H. Quan, Y. Wu, H. Wang, T. Bernier, R.A. Xia, K. Blesson, A. Jain, M. Motazacker, M.M. Jaeger, B. Schneider, A.L. Boysen, K. Muir, A.M. Myers, C.T. Gavrilova, R.H. Gunderson, L. Schultz-Rogers, L. Klee, E.W. Dyment, D. Osmond, M. Parellada, M. Llorente, C. Gonzalez-Peñas, J. Carracedo, A. Van Haeringen, A. Ruivenkamp, C. Nava, C. Heron, D. Nardello, R. Iacomino, M. Minetti, C. Skabar, A. Fabretto, A. Hanna, M.G. Bugiardini, E. Hostettler, I. O’Callaghan, B. Khan, A. Cortese, A. O’Connor, E. Yau, W.Y. Bourinaris, T. Kaiyrzhanov, R. Chelban, V. Madej, M. Diana, M.C. Vari, M.S. Pedemonte, M. Bruno, C. Balagura, G. Scala, M. Fiorillo, C. Nobili, L. Malintan, N.T. Zanetti, M.N. Krishnakumar, S.S. Lignani, G. Jepson, J.E.C. Broda, P. Baldassari, S. Rossi, P. Fruscione, F. Madia, F. Traverso, M. De-Marco, P. Pérez-Dueñas, B. Munell, F. Kriouile, Y. El-Khorassani, M. Karashova, B. Avdjieva, D. Kathom, H. Tincheva, R. Van-Maldergem, L. Nachbauer, W. Boesch, S. Gagliano, A. Amadori, E. Goraya, J.S. Sultan, T. Kirmani, S. Ibrahim, S. Jan, F. Mine, J. Banu, S. Veggiotti, P. Zuccotti, G.V. Ferrari, M.D. Van Den Maagdenberg, A.M.J. Verrotti, A. Marseglia, G.L. Savasta, S. Soler, M.A. Scuderi, C. Borgione, E. Chimenz, R. Gitto, E. Dipasquale, V. Sallemi, A. Fusco, M. Cuppari, C. Cutrupi, M.C. Ruggieri, M. Cama, A. Capra, V. Mencacci, N.E. Boles, R. Gupta, N. Kabra, M. Papacostas, S. Zamba-Papanicolaou, E. Dardiotis, E. Maqbool, S. Rana, N. Atawneh, O. Lim, S.Y. Shaikh, F. Koutsis, G. Breza, M. Coviello, D.A. Dauvilliers, Y.A. AlKhawaja, I. AlKhawaja, M. Al-Mutairi, F. Stojkovic, T. Ferrucci, V. Zollo, M. Alkuraya, F.S. Kinali, M. Sherifa, H. Benrhouma, H. Turki, I.B.Y. Tazir, M. Obeid, M. Bakhtadze, S. Saadi, N.W. Zaki, M.S. Triki, C.C. Benfenati, F. Gustincich, S. Kara, M. Belcastro, V. Specchio, N. Capovilla, G. Karimiani, E.G. Salih, A.M. Okubadejo, N.U. Ojo, O.O. Oshinaike, O.O. Oguntunde, O. Wahab, K. Bello, A.H. Abubakar, S. Obiabo, Y. Nwazor, E. Ekenze, O. Williams, U. Iyagba, A. Taiwo, L. Komolafe, M. Senkevich, K. Shashkin, C. Zharkynbekova, N. Koneyev, K. Manizha, G. Isrofilov, M. Guliyeva, U. Salayev, K. Khachatryan, S. Rossi, S. Silvestri, G. Haridy, N. Ramenghi, L.A. Xiromerisiou, G. David, E. Aguennouz, M. Fidani, L. Spanaki, C. Tucci, A. Raspall-Chaure, M. Chez, M. Tsai, A. Fassi, E. Shinawi, M. Constantino, J.N. De Zorzi, R. Fortuna, S. Kok, F. Keren, B. Bonneau, D. Choi, M. Benzeev, B. Zara, F. Mefford, H.C. Scheffer, I.E. Clayton-Smith, J. Macaya, A. Rothman, J.E. Eichler, E.E. Kullmann, D.M. Houlden, H. SYNAPS Study Group

Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. © 2019, The Author(s).

Published
2019

28. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, E.D.H., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G., Santoro, S.L., Shuss, C., Ziegler, A., Bonneau, D., Kempers, M.J.E., Pfundt, R.P., Legius, E., Bouman, A., Stuurman, K.E., Ounap, K., Pajusalu, S., Wojcik, M.H., Vasileiou, G., Guyader, G. Le, Schnelle, H.M., Berland, S., Zonneveld-Huijssoon, E., Kersten, S., Gupta, A., Blackburn, P.R., Ellingson, M.S., Ferber, M.J., Dhamija, R., Klee, E.W., McEntagart, M., Lichtenbelt, K.D., Kenney, A., Vergano, Samantha A., Jamra, R. Abou, Platzer, K., Pierpont, M. Ella, Khattar, D., Hopkin, R.J., Martin, R.J., Jongmans, M.C.J., Chang, V.Y., Martinez-Agosto, J.A., Kuismin, O., Kurki, M.I., Pietilainen, O., Palotie, A., Maarup, T.J., Johnson, D.S., Pedersen, K., Laulund, L.W., Lynch, S.A., Blyth, M., Prescott, K., Canham, N., Ibitoye, R., Brilstra, E.H., Shinawi, M., Fassi, E., Sticht, H., Gregor, A., Esch, H. Van, Zweier, C., Konrad, E.D.H., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G., Santoro, S.L., Shuss, C., Ziegler, A., Bonneau, D., Kempers, M.J.E., Pfundt, R.P., Legius, E., Bouman, A., Stuurman, K.E., Ounap, K., Pajusalu, S., Wojcik, M.H., Vasileiou, G., Guyader, G. Le, Schnelle, H.M., Berland, S., Zonneveld-Huijssoon, E., Kersten, S., Gupta, A., Blackburn, P.R., Ellingson, M.S., Ferber, M.J., Dhamija, R., Klee, E.W., McEntagart, M., Lichtenbelt, K.D., Kenney, A., Vergano, Samantha A., Jamra, R. Abou, Platzer, K., Pierpont, M. Ella, Khattar, D., Hopkin, R.J., Martin, R.J., Jongmans, M.C.J., Chang, V.Y., Martinez-Agosto, J.A., Kuismin, O., Kurki, M.I., Pietilainen, O., Palotie, A., Maarup, T.J., Johnson, D.S., Pedersen, K., Laulund, L.W., Lynch, S.A., Blyth, M., Prescott, K., Canham, N., Ibitoye, R., Brilstra, E.H., Shinawi, M., Fassi, E., Sticht, H., Gregor, A., Esch, H. Van, and Zweier, C.

Abstract

Contains fulltext : 215582.pdf (publisher's version ) (Open Access), PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Published
2019

29. De novo variants disruting the HX repeat motif of ATN1 cause a non-progressive neurocognitive disorder with recognisable facial features and congenital malformations

Author

Palmer, EE ; https://orcid.org/0000-0003-1844-215X, Hong, S, Al Zahrani, F, Hashem, M Omar, Aleisa, FA, Ahmed, HM Jalal, Kandula, T, Macintosh, R ; https://orcid.org/0000-0001-5036-0264, Minoche, A, Puttick, C, Gayevskiy, V, Drew, AP, Cowley, MJ ; https://orcid.org/0000-0002-9519-5714, Dinger, ME ; https://orcid.org/0000-0003-4423-934X, Rosenfeld, JA, Xiao, R, Cho, MT, Henderson, LB, Sacoto, MJ Guillen, Begtrup, A, Hamad, M, Shinawi, M, Andrews, M, Jones, MC, Lindstrom, K, Kayani, S, Snyder, M, Villanueva, M, Schteinschnaider, A, Roscioli, T, Kirk, EP ; https://orcid.org/0000-0002-4662-0024, Bye, A, Merzaban, J, Jaremko, L, Jaremko, M, Sachdev, RK, Alkuraya, FS, Arold, ST, Palmer, EE ; https://orcid.org/0000-0003-1844-215X, Hong, S, Al Zahrani, F, Hashem, M Omar, Aleisa, FA, Ahmed, HM Jalal, Kandula, T, Macintosh, R ; https://orcid.org/0000-0001-5036-0264, Minoche, A, Puttick, C, Gayevskiy, V, Drew, AP, Cowley, MJ ; https://orcid.org/0000-0002-9519-5714, Dinger, ME ; https://orcid.org/0000-0003-4423-934X, Rosenfeld, JA, Xiao, R, Cho, MT, Henderson, LB, Sacoto, MJ Guillen, Begtrup, A, Hamad, M, Shinawi, M, Andrews, M, Jones, MC, Lindstrom, K, Kayani, S, Snyder, M, Villanueva, M, Schteinschnaider, A, Roscioli, T, Kirk, EP ; https://orcid.org/0000-0002-4662-0024, Bye, A, Merzaban, J, Jaremko, L, Jaremko, M, Sachdev, RK, Alkuraya, FS, and Arold, ST

Published
2019

30. Erratum: De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-progressive Neurocognitive Syndrome (The American Journal of Human Genetics (2019) 104(3) (542–552), (S0002929719300138), (10.1016/j.ajhg.2019.01.013))

Author

Palmer, EE, Hong, S, Al Zahrani, F, Hashem, MO, Aleisa, FA, Jalal Ahmed, HM, Kandula, T, Macintosh, R, Minoche, AE, Puttick, C, Gayevskiy, V, Drew, AP, Cowley, MJ, Dinger, M, Rosenfeld, JA, Xiao, R, Cho, MT, Yakubu, SF, Henderson, LB, Guillen Sacoto, MJ, Begtrup, A, Hamad, M, Shinawi, M, Andrews, MV, Jones, MC, Lindstrom, K, Bristol, RE, Kayani, S, Snyder, M, Villanueva, MM, Schteinschnaider, A, Faivre, L, Thauvin, C, Vitobello, A, Roscioli, T, Kirk, EP, Bye, A, Merzaban, J, Jaremko, Ł, Jaremko, M, Sachdev, RK, Alkuraya, FS, Arold, ST, Palmer, Elizabeth, Palmer, EE, Hong, S, Al Zahrani, F, Hashem, MO, Aleisa, FA, Jalal Ahmed, HM, Kandula, T, Macintosh, R, Minoche, AE, Puttick, C, Gayevskiy, V, Drew, AP, Cowley, MJ, Dinger, M, Rosenfeld, JA, Xiao, R, Cho, MT, Yakubu, SF, Henderson, LB, Guillen Sacoto, MJ, Begtrup, A, Hamad, M, Shinawi, M, Andrews, MV, Jones, MC, Lindstrom, K, Bristol, RE, Kayani, S, Snyder, M, Villanueva, MM, Schteinschnaider, A, Faivre, L, Thauvin, C, Vitobello, A, Roscioli, T, Kirk, EP, Bye, A, Merzaban, J, Jaremko, Ł, Jaremko, M, Sachdev, RK, Alkuraya, FS, Arold, ST, and Palmer, Elizabeth

Abstract

(The American Journal of Human Genetics 104, 542–552; March 7, 2019) In the original version of this article published on March 7, 2019, Łukasz Jaremko's name was unfortunately misspelled as Łukas Jaremko. It appears correctly here and online. The Journal and the authors apologize for this error.

Published
2019

31. Pathogenic variants in GPC4 cause Keipert syndrome

Author

Amor, D.J., Stephenson, S.E.M., Mustapha, M., Mensah, M.A., Ockeloen, C.W., Lee, W.S., Tankard, R.M., Phelan, D.G., Shinawi, M., de Brouwer, A.P.M., Pfundt, R., Dowling, C., Toler, T.L., Sutton, V.R., Agolini, E., Rinelli, M., Capolino, R., Martinelli, D., Zampino, G., Dumić, M., Reardon, W., Shaw-Smith, C., Leventer, R.J., Delatycki, M.B., Kleefstra, T., Mundlos, S., Mortier, G., Bahlo, M., Allen, N.J., Lockhart, P.J., Amor, D.J., Stephenson, S.E.M., Mustapha, M., Mensah, M.A., Ockeloen, C.W., Lee, W.S., Tankard, R.M., Phelan, D.G., Shinawi, M., de Brouwer, A.P.M., Pfundt, R., Dowling, C., Toler, T.L., Sutton, V.R., Agolini, E., Rinelli, M., Capolino, R., Martinelli, D., Zampino, G., Dumić, M., Reardon, W., Shaw-Smith, C., Leventer, R.J., Delatycki, M.B., Kleefstra, T., Mundlos, S., Mortier, G., Bahlo, M., Allen, N.J., and Lockhart, P.J.

Abstract

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

Published
2019

32. De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome

Author

Palmer, EE ; https://orcid.org/0000-0003-1844-215X, Hong, S, Al Zahrani, F, Hashem, MO, Aleisa, FA, Ahmed, HMJ, Kandula, T ; https://orcid.org/0000-0002-4355-4965, Macintosh, R ; https://orcid.org/0000-0001-5036-0264, Minoche, AE, Puttick, C, Gayevskiy, V, Drew, AP, Cowley, MJ ; https://orcid.org/0000-0002-9519-5714, Dinger, M ; https://orcid.org/0000-0003-4423-934X, Rosenfeld, JA, Xiao, R, Cho, MT, Yakubu, SF, Henderson, LB, Guillen Sacoto, MJ, Begtrup, A, Hamad, M, Shinawi, M, Andrews, MV, Jones, MC, Lindstrom, K, Bristol, RE, Kayani, S, Snyder, M, Villanueva, MM, Schteinschnaider, A, Faivre, L, Thauvin, C, Vitobello, A, Roscioli, T ; https://orcid.org/0000-0003-1502-5000, Kirk, EP ; https://orcid.org/0000-0002-4662-0024, Bye, A, Merzaban, J, Jaremko, Ł, Jaremko, M, Sachdev, RK, Alkuraya, FS, Arold, ST, Palmer, Elizabeth ; https://orcid.org/0000-0003-1844-215X, Palmer, EE ; https://orcid.org/0000-0003-1844-215X, Hong, S, Al Zahrani, F, Hashem, MO, Aleisa, FA, Ahmed, HMJ, Kandula, T ; https://orcid.org/0000-0002-4355-4965, Macintosh, R ; https://orcid.org/0000-0001-5036-0264, Minoche, AE, Puttick, C, Gayevskiy, V, Drew, AP, Cowley, MJ ; https://orcid.org/0000-0002-9519-5714, Dinger, M ; https://orcid.org/0000-0003-4423-934X, Rosenfeld, JA, Xiao, R, Cho, MT, Yakubu, SF, Henderson, LB, Guillen Sacoto, MJ, Begtrup, A, Hamad, M, Shinawi, M, Andrews, MV, Jones, MC, Lindstrom, K, Bristol, RE, Kayani, S, Snyder, M, Villanueva, MM, Schteinschnaider, A, Faivre, L, Thauvin, C, Vitobello, A, Roscioli, T ; https://orcid.org/0000-0003-1502-5000, Kirk, EP ; https://orcid.org/0000-0002-4662-0024, Bye, A, Merzaban, J, Jaremko, Ł, Jaremko, M, Sachdev, RK, Alkuraya, FS, Arold, ST, and Palmer, Elizabeth ; https://orcid.org/0000-0003-1844-215X

Abstract

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid “HX repeat” motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.

Published
2019

33. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, E.D.H. (Enrico D. H.), Nardini, N. (Niels), Caliebe, A. (Almuth), Nagel, I. (Inga), Young, D. (Dana), Horvath, G. (Gabriella), Santoro, S.L. (Stephanie L.), Shuss, C. (Christine), Ziegler, A. (Alban), Bonneau, D. (Dominique), Kempers, M.J.E. (Marlies), Pfundt, R. (Rolph), Legius, E. (Eric), Bouman, A. (Arjan), Stuurman, K.E. (Kyra E.), Õunap, K. (Katrin), Pajusalu, S. (Sander), Wojcik, M.H. (Monica H.), Vasileiou, G. (Georgia), Le Guyader, G. (Gwenaël), Schnelle, H.M. (Hege M.), Berland, S. (Siren), Zonneveld-Huijssoon, E. (Evelien), Kersten, S. (Simone), Gupta, A. (Aditi), Blackburn, P.R. (Patrick R.), Ellingson, M.S. (Marissa S.), Ferber, M.J. (Matthew J.), Dhamija, R. (Radhika), Klee, E.W. (Eric W.), McEntagart, M. (Meriel), Lichtenbelt, K.D. (Klaske), Kenney, A. (Amy), Vergano, S.A. (Samantha A.), Abou Jamra, R. (Rami), Platzer, K. (Konrad), Ella Pierpont, M. (Mary), Khattar, D. (Divya), Hopkin, R., Martin, R.J. (Richard J.), Jongmans, M.C.J. (Marjolijn), Chang, V.Y. (Vivian Y.), Martinez-Agosto, J.A. (Julian A.), Kuismin, O. (Outi), Kurki, M.I. (Mitja I.), Pietiläinen, O.P.H. (Olli), Palotie, A. (Aarno), Maarup, T.J. (Timothy J.), Johnson, D. (David), Venborg Pedersen, K. (Katja), Laulund, L.W. (Lone W.), Lynch, S.A. (Sally A.), Blyth, M. (Moira), Prescott, K. (Katrina), Canham, N. (Natalie), Ibitoye, R. (Rita), Brilstra, E.H. (Eva H.), Shinawi, M. (Marwan), Fassi, E. (Emily), Sticht, H. (Heinrich), Gregor, A. (Anne), Esch, H. (Hilde) van, Zweier, C. (Christiane), Konrad, E.D.H. (Enrico D. H.), Nardini, N. (Niels), Caliebe, A. (Almuth), Nagel, I. (Inga), Young, D. (Dana), Horvath, G. (Gabriella), Santoro, S.L. (Stephanie L.), Shuss, C. (Christine), Ziegler, A. (Alban), Bonneau, D. (Dominique), Kempers, M.J.E. (Marlies), Pfundt, R. (Rolph), Legius, E. (Eric), Bouman, A. (Arjan), Stuurman, K.E. (Kyra E.), Õunap, K. (Katrin), Pajusalu, S. (Sander), Wojcik, M.H. (Monica H.), Vasileiou, G. (Georgia), Le Guyader, G. (Gwenaël), Schnelle, H.M. (Hege M.), Berland, S. (Siren), Zonneveld-Huijssoon, E. (Evelien), Kersten, S. (Simone), Gupta, A. (Aditi), Blackburn, P.R. (Patrick R.), Ellingson, M.S. (Marissa S.), Ferber, M.J. (Matthew J.), Dhamija, R. (Radhika), Klee, E.W. (Eric W.), McEntagart, M. (Meriel), Lichtenbelt, K.D. (Klaske), Kenney, A. (Amy), Vergano, S.A. (Samantha A.), Abou Jamra, R. (Rami), Platzer, K. (Konrad), Ella Pierpont, M. (Mary), Khattar, D. (Divya), Hopkin, R., Martin, R.J. (Richard J.), Jongmans, M.C.J. (Marjolijn), Chang, V.Y. (Vivian Y.), Martinez-Agosto, J.A. (Julian A.), Kuismin, O. (Outi), Kurki, M.I. (Mitja I.), Pietiläinen, O.P.H. (Olli), Palotie, A. (Aarno), Maarup, T.J. (Timothy J.), Johnson, D. (David), Venborg Pedersen, K. (Katja), Laulund, L.W. (Lone W.), Lynch, S.A. (Sally A.), Blyth, M. (Moira), Prescott, K. (Katrina), Canham, N. (Natalie), Ibitoye, R. (Rita), Brilstra, E.H. (Eva H.), Shinawi, M. (Marwan), Fassi, E. (Emily), Sticht, H. (Heinrich), Gregor, A. (Anne), Esch, H. (Hilde) van, and Zweier, C. (Christiane)

Abstract

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Published
2019
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34. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro, V, Dixon, CL, Guo, H, Bello, OD, Vandrovcova, J, Efthymiou, S, Maroofian, R, Heimer, G, Burglen, L, Valence, S, Torti, E, Hacke, M, Rankin, J, Tariq, H, Colin, E, Procaccio, V, Striano, P, Mankad, K, Lieb, A, Chen, S, Pisani, L, Bettencourt, C, Mannikko, R, Manole, A, Brusco, A, Grosso, E, Ferrero, GB, Armstrong-Moron, J, Gueden, S, Bar-Yosef, O, Tzadok, M, Monaghan, KG, Santiago-Sim, T, Person, RE, Cho, MT, Willaert, R, Yoo, Y, Chae, J-H, Quan, Y, Wu, H, Wang, T, Bernier, RA, Xia, K, Blesson, A, Jain, M, Motazacker, MM, Jaeger, B, Schneider, AL, Boysen, K, Muir, AM, Myers, CT, Gavrilova, RH, Gunderson, L, Schultz-Rogers, L, Klee, EW, Dyment, D, Osmond, M, Parellada, M, Llorente, C, Gonzalez-Penas, J, Carracedo, A, Van Haeringen, A, Ruivenkamp, C, Nava, C, Heron, D, Nardello, R, Iacomino, M, Minetti, C, Skabar, A, Fabretto, A, Chez, M, Tsai, A, Fassi, E, Shinawi, M, Constantino, JN, De Zorzi, R, Fortuna, S, Kok, F, Keren, B, Bonneau, D, Choi, M, Benzeev, B, Zara, F, Mefford, HC, Scheffer, IE, Clayton-Smith, J, Macaya, A, Rothman, JE, Eichler, EE, Kullmann, DM, Houlden, H, Raspall-Chaure, M, Hanna, MG, Bugiardini, E, Hostettler, I, O'Callaghan, B, Khan, A, Cortese, A, O'Connor, E, Yau, WY, Bourinaris, T, Kaiyrzhanov, R, Chelban, V, Madej, M, Diana, MC, Vari, MS, Pedemonte, M, Bruno, C, Balagura, G, Scala, M, Fiorillo, C, Nobili, L, Malintan, NT, Zanetti, MN, Krishnakumar, SS, Lignani, G, Jepson, JEC, Broda, P, Baldassari, S, Rossi, P, Fruscione, F, Madia, F, Traverso, M, De-Marco, P, Perez-Duenas, B, Munell, F, Kriouile, Y, El-Khorassani, M, Karashova, B, Avdjieva, D, Kathom, H, Tincheva, R, Van-Maldergem, L, Nachbauer, W, Boesch, S, Gagliano, A, Amadori, E, Goraya, JS, Sultan, T, Kirmani, S, Ibrahim, S, Jan, F, Mine, J, Banu, S, Veggiotti, P, Zuccotti, G, Ferrari, MD, Van Den Maagdenberg, AMJ, Verrotti, A, Marseglia, GL, Savasta, S, Soler, MA, Scuderi, C, Borgione, E, Chimenz, R, Gitto, E, Dipasquale, V, Sallemi, A, Fusco, M, Cuppari, C, Cutrupi, MC, Ruggieri, M, Cama, A, Capra, V, Mencacci, NE, Boles, R, Gupta, N, Kabra, M, Papacostas, S, Zamba-Papanicolaou, E, Dardiotis, E, Maqbool, S, Rana, N, Atawneh, O, Lim, SY, Shaikh, F, Koutsis, G, Breza, M, Coviello, DA, Dauvilliers, YA, AlKhawaja, I, AlKhawaja, M, Al-Mutairi, F, Stojkovic, T, Ferrucci, V, Zollo, M, Alkuraya, FS, Kinali, M, Sherifa, H, Benrhouma, H, Turki, IBY, Tazir, M, Obeid, M, Bakhtadze, S, Saadi, NW, Zaki, MS, Triki, CC, Benfenati, F, Gustincich, S, Kara, M, Belcastro, V, Specchio, N, Capovilla, G, Karimiani, EG, Salih, AM, Okubadejo, NU, Ojo, OO, Oshinaike, OO, Oguntunde, O, Wahab, K, Bello, AH, Abubakar, S, Obiabo, Y, Nwazor, E, Ekenze, O, Williams, U, Iyagba, A, Taiwo, L, Komolafe, M, Senkevich, K, Shashkin, C, Zharkynbekova, N, Koneyev, K, Manizha, G, Isrofilov, M, Guliyeva, U, Salayev, K, Khachatryan, S, Rossi, S, Silvestri, G, Haridy, N, Ramenghi, LA, Xiromerisiou, G, David, E, Aguennouz, M, Fidani, L, Spanaki, C, Tucci, A, Salpietro, V, Dixon, CL, Guo, H, Bello, OD, Vandrovcova, J, Efthymiou, S, Maroofian, R, Heimer, G, Burglen, L, Valence, S, Torti, E, Hacke, M, Rankin, J, Tariq, H, Colin, E, Procaccio, V, Striano, P, Mankad, K, Lieb, A, Chen, S, Pisani, L, Bettencourt, C, Mannikko, R, Manole, A, Brusco, A, Grosso, E, Ferrero, GB, Armstrong-Moron, J, Gueden, S, Bar-Yosef, O, Tzadok, M, Monaghan, KG, Santiago-Sim, T, Person, RE, Cho, MT, Willaert, R, Yoo, Y, Chae, J-H, Quan, Y, Wu, H, Wang, T, Bernier, RA, Xia, K, Blesson, A, Jain, M, Motazacker, MM, Jaeger, B, Schneider, AL, Boysen, K, Muir, AM, Myers, CT, Gavrilova, RH, Gunderson, L, Schultz-Rogers, L, Klee, EW, Dyment, D, Osmond, M, Parellada, M, Llorente, C, Gonzalez-Penas, J, Carracedo, A, Van Haeringen, A, Ruivenkamp, C, Nava, C, Heron, D, Nardello, R, Iacomino, M, Minetti, C, Skabar, A, Fabretto, A, Chez, M, Tsai, A, Fassi, E, Shinawi, M, Constantino, JN, De Zorzi, R, Fortuna, S, Kok, F, Keren, B, Bonneau, D, Choi, M, Benzeev, B, Zara, F, Mefford, HC, Scheffer, IE, Clayton-Smith, J, Macaya, A, Rothman, JE, Eichler, EE, Kullmann, DM, Houlden, H, Raspall-Chaure, M, Hanna, MG, Bugiardini, E, Hostettler, I, O'Callaghan, B, Khan, A, Cortese, A, O'Connor, E, Yau, WY, Bourinaris, T, Kaiyrzhanov, R, Chelban, V, Madej, M, Diana, MC, Vari, MS, Pedemonte, M, Bruno, C, Balagura, G, Scala, M, Fiorillo, C, Nobili, L, Malintan, NT, Zanetti, MN, Krishnakumar, SS, Lignani, G, Jepson, JEC, Broda, P, Baldassari, S, Rossi, P, Fruscione, F, Madia, F, Traverso, M, De-Marco, P, Perez-Duenas, B, Munell, F, Kriouile, Y, El-Khorassani, M, Karashova, B, Avdjieva, D, Kathom, H, Tincheva, R, Van-Maldergem, L, Nachbauer, W, Boesch, S, Gagliano, A, Amadori, E, Goraya, JS, Sultan, T, Kirmani, S, Ibrahim, S, Jan, F, Mine, J, Banu, S, Veggiotti, P, Zuccotti, G, Ferrari, MD, Van Den Maagdenberg, AMJ, Verrotti, A, Marseglia, GL, Savasta, S, Soler, MA, Scuderi, C, Borgione, E, Chimenz, R, Gitto, E, Dipasquale, V, Sallemi, A, Fusco, M, Cuppari, C, Cutrupi, MC, Ruggieri, M, Cama, A, Capra, V, Mencacci, NE, Boles, R, Gupta, N, Kabra, M, Papacostas, S, Zamba-Papanicolaou, E, Dardiotis, E, Maqbool, S, Rana, N, Atawneh, O, Lim, SY, Shaikh, F, Koutsis, G, Breza, M, Coviello, DA, Dauvilliers, YA, AlKhawaja, I, AlKhawaja, M, Al-Mutairi, F, Stojkovic, T, Ferrucci, V, Zollo, M, Alkuraya, FS, Kinali, M, Sherifa, H, Benrhouma, H, Turki, IBY, Tazir, M, Obeid, M, Bakhtadze, S, Saadi, NW, Zaki, MS, Triki, CC, Benfenati, F, Gustincich, S, Kara, M, Belcastro, V, Specchio, N, Capovilla, G, Karimiani, EG, Salih, AM, Okubadejo, NU, Ojo, OO, Oshinaike, OO, Oguntunde, O, Wahab, K, Bello, AH, Abubakar, S, Obiabo, Y, Nwazor, E, Ekenze, O, Williams, U, Iyagba, A, Taiwo, L, Komolafe, M, Senkevich, K, Shashkin, C, Zharkynbekova, N, Koneyev, K, Manizha, G, Isrofilov, M, Guliyeva, U, Salayev, K, Khachatryan, S, Rossi, S, Silvestri, G, Haridy, N, Ramenghi, LA, Xiromerisiou, G, David, E, Aguennouz, M, Fidani, L, Spanaki, C, and Tucci, A

Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

Published
2019

35. Pathogenic Variants in GPC4 Cause Keipert Syndrome

Author

Amor, DJ, Stephenson, SEM, Mustapha, M, Mensah, MA, Ockeloen, CW, Lee, WS, Tankard, RM, Phelan, DG, Shinawi, M, de Brouwer, APM, Pfundt, R, Dowling, C, Toler, TL, Sutton, VR, Agolini, E, Rinelli, M, Capolino, R, Martinelli, D, Zampino, G, Dumic, M, Reardon, W, Shaw-Smith, C, Leventer, RJ, Delatycki, MB, Kleefstra, T, Mundlos, S, Mortier, G, Bahlo, M, Allen, NJ, Lockhart, PJ, Amor, DJ, Stephenson, SEM, Mustapha, M, Mensah, MA, Ockeloen, CW, Lee, WS, Tankard, RM, Phelan, DG, Shinawi, M, de Brouwer, APM, Pfundt, R, Dowling, C, Toler, TL, Sutton, VR, Agolini, E, Rinelli, M, Capolino, R, Martinelli, D, Zampino, G, Dumic, M, Reardon, W, Shaw-Smith, C, Leventer, RJ, Delatycki, MB, Kleefstra, T, Mundlos, S, Mortier, G, Bahlo, M, Allen, NJ, and Lockhart, PJ

Abstract

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

Published
2019

39. The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies

Author

Shen, W., Heeley, J.M., Carlston, C.M., Acuna Hidalgo, R., Nillesen, W.M., Dent, K.M., Douglas, G.V., Levine, K.L., Bayrak-Toydemir, P., Marcelis, C.L., Shinawi, M., Carey, J.C., Shen, W., Heeley, J.M., Carlston, C.M., Acuna Hidalgo, R., Nillesen, W.M., Dent, K.M., Douglas, G.V., Levine, K.L., Bayrak-Toydemir, P., Marcelis, C.L., Shinawi, M., and Carey, J.C.

Abstract

Item does not contain fulltext, De novo, germline variants in DNMT3A cause Tatton-Brown-Rahman syndrome (TBRS). This condition is characterized by overgrowth, distinctive facial appearance, and intellectual disability. Somatic DNMT3A variants frequently occur in hematologic malignances, particularly acute myeloid leukemia. The Arg882 residue is the most common site of somatic DNMT3A variants, and has also been altered in patients with TBRS. Here we present three additional patients with this disorder attributed to DNMT3A germline variants that disrupt the Arg882 codon, suggesting that this codon may be a germline mutation hotspot in this disorder. Furthermore, based on the investigation of previously reported variants in patients with TBRS, we found overlap in the spectrum of DNMT3A variants observed in this disorder and somatic variants in hematological malignancies.

Published
2017

45. Recurrent reciprocal 1q21.1 deletions and duplications are novel genomic disorders associated with micro- or macrocephaly and a spectrum of developmental and behavioral abnormalities

Author

BRUNETTI PIERRI, NICOLA, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham H, Lee B, Shinawi M, Shen J, Kang S. HL, Pursley A, Lotze T, Kennedy G, Lansky Shafer S, Weaver C, Roeder ER, Grebe TA, Arnold GL, Hutchison T, Reimschisel T, Amato S, Geragthy MT, Innis JW, Obersztyn E, Nowakowska B, Rosengren SS, Bader PI, Grange DK, Naqvi S, Garnica AD, Bernes SM, Fong C. T, Summers A, Walters WD, Lupski JR, Stankiewicz P, Cheung S. W, Patel A., BRUNETTI PIERRI, Nicola, Berg, J, Scaglia, F, Belmont, J, Bacino, Ca, Sahoo, T, Lalani, Sr, Graham, H, Lee, B, Shinawi, M, Shen, J, Kang S., Hl, Pursley, A, Lotze, T, Kennedy, G, Lansky Shafer, S, Weaver, C, Roeder, Er, Grebe, Ta, Arnold, Gl, Hutchison, T, Reimschisel, T, Amato, S, Geragthy, Mt, Innis, Jw, Obersztyn, E, Nowakowska, B, Rosengren, S, Bader, Pi, Grange, Dk, Naqvi, S, Garnica, Ad, Bernes, Sm, Fong, C. T., Summers, A, Walters, Wd, Lupski, Jr, Stankiewicz, P, Cheung, S. W., and Patel, A.

Published
2008

46. FBXL4defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome

Author

Dai, H., primary, Zhang, V.W., additional, El-Hattab, A.W., additional, Ficicioglu, C., additional, Shinawi, M., additional, Lines, M., additional, Schulze, A., additional, McNutt, M., additional, Gotway, G., additional, Tian, X., additional, Chen, S., additional, Wang, J., additional, Craigen, W.J., additional, and Wong, L.-J., additional

Published
2017
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47. The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations

Author

Chen, C.A., Bosch, D.G.M., Cho, M.T., Rosenfeld, J.A., Shinawi, M., Lewis, R.A., Mann, J., Jayakar, P., Payne, K., Walsh, L., Moss, T., Schreiber, A., Schoonveld, C., Monaghan, K.G., Elmslie, F., Douglas, G., Boonstra, F.N., Millan, F., Cremers, F.P.M., McKnight, D., Richard, G., Juusola, J., Kendall, F., Ramsey, K., Anyane-Yeboa, K., Malkin, E., Chung, W.K., Niyazov, D., Pascual, J.M., Walkiewicz, M., Veluchamy, V., Li, C., Hisama, F.M., Vries, B.B. de, Schaaf, C., Chen, C.A., Bosch, D.G.M., Cho, M.T., Rosenfeld, J.A., Shinawi, M., Lewis, R.A., Mann, J., Jayakar, P., Payne, K., Walsh, L., Moss, T., Schreiber, A., Schoonveld, C., Monaghan, K.G., Elmslie, F., Douglas, G., Boonstra, F.N., Millan, F., Cremers, F.P.M., McKnight, D., Richard, G., Juusola, J., Kendall, F., Ramsey, K., Anyane-Yeboa, K., Malkin, E., Chung, W.K., Niyazov, D., Pascual, J.M., Walkiewicz, M., Veluchamy, V., Li, C., Hisama, F.M., Vries, B.B. de, and Schaaf, C.

Abstract

Item does not contain fulltext, PURPOSE: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype-phenotype correlations. METHODS: Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis. RESULTS: We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%). CONCLUSION: BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes.Genet Med 18 11, 1143-1150.

Published
2016

48. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy

Author

Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., Weckhuysen, S., Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., and Weckhuysen, S.

Abstract

Contains fulltext : 168130.pdf (publisher's version ) (Closed access), OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

Published
2016

49. The Cognitive and Behavioral Phenotypes of Individuals with CHRNA7 Duplications

Author

Gillentine, M. A., primary, Berry, L. N., additional, Goin-Kochel, R. P., additional, Ali, M. A., additional, Ge, J., additional, Guffey, D., additional, Rosenfeld, J. A., additional, Hannig, V., additional, Bader, P., additional, Proud, M., additional, Shinawi, M., additional, Graham, B. H., additional, Lin, A., additional, Lalani, S. R., additional, Reynolds, J., additional, Chen, M., additional, Grebe, T., additional, Minard, C. G., additional, Stankiewicz, P., additional, Beaudet, A. L., additional, and Schaaf, C. P., additional

Published
2016
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50. FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome.

Author

Dai, H., Zhang, V.W., El ‐ Hattab, A.W., Ficicioglu, C., Shinawi, M., Lines, M., Schulze, A., McNutt, M., Gotway, G., Tian, X., Chen, S., Wang, J., Craigen, W.J., and Wong, L. ‐ J.

Subjects
ACIDOSIS, MITOCHONDRIAL pathology, SEQUENCE analysis, HEMOGLOBIN polymorphisms, HEPATIC encephalopathy, PATIENTS
Abstract

Mutations in FBXL4 have recently been recognized to cause a mitochondrial disorder, with clinical features including early onset lactic acidosis, hypotonia, and developmental delay. FBXL4 sequence analysis was performed in 808 subjects suspected to have a mitochondrial disorder. In addition, 28 samples from patients with early onset of lactic acidosis, but without identifiable mutations in 192 genes known to cause mitochondrial diseases, were examined for FBXL4 mutations. Definitive diagnosis was made in 10 new subjects with a total of 7 novel deleterious variants; 5 null and 2 missense substitutions. All patients exhibited congenital lactic acidemia, most of them with severe encephalopathic presentation, and global developmental delay. Overall, FBXL4 defects account for at least 0.7% (6 out of 808) of subjects suspected to have a mitochondrial disorder, and as high as 14.3% (4 out of 28) in young children with congenital lactic acidosis and clinical features of mitochondrial disease. Including FBLX4 in the mitochondrial diseases panel should be particularly important for patients with congenital lactic acidosis. [ABSTRACT FROM AUTHOR]

Published
2017
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