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274 results on '"Sadikovic, B."'

1. Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype

Author

Sarli, C., van der Laan, L., Reilly, J., Trajkova, S., Carli, D., Brusco, A., Levy, M. A., Relator, R., Kerkhof, J., Mcconkey, H., Tedder, M. L., Skinner, C., Alders, M., Henneman, P., Hennekam, R. C. M., Ciaccio, C., D'Arrigo, S., Vitobello, A., Faivre, L., Weber, S., Vincent-Devulder, A., Perrin, L., Bourgois, A., Yamamoto, T., Metcalfe, K., Zollino, Marcella, Kini, U., Oliveira, D., Sousa, S. B., Williams, D., Cappuccio, G., Sadikovic, B., Brunetti-Pierri, N., Zollino M. (ORCID:0000-0003-4871-9519), Sarli, C., van der Laan, L., Reilly, J., Trajkova, S., Carli, D., Brusco, A., Levy, M. A., Relator, R., Kerkhof, J., Mcconkey, H., Tedder, M. L., Skinner, C., Alders, M., Henneman, P., Hennekam, R. C. M., Ciaccio, C., D'Arrigo, S., Vitobello, A., Faivre, L., Weber, S., Vincent-Devulder, A., Perrin, L., Bourgois, A., Yamamoto, T., Metcalfe, K., Zollino, Marcella, Kini, U., Oliveira, D., Sousa, S. B., Williams, D., Cappuccio, G., Sadikovic, B., Brunetti-Pierri, N., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

Blepharophimosis with intellectual disability (BIS) is a recently recognized disorder distinct from Nicolaides-Baraister syndrome that presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability. BIS is caused by pathogenic variants in SMARCA2, that encodes the catalytic subunit of the superfamily II helicase group of the BRG1 and BRM-associated factors (BAF) forming the BAF complex, a chromatin remodeling complex involved in transcriptional regulation. Individuals bearing variants within the bipartite nuclear localization (BNL) signal domain of ADNP present with the neurodevelopmental disorder known as Helsmoortel-Van Der Aa Syndrome (HVDAS). Distinct DNA methylation profiles referred to as episignatures have been reported in HVDAS and BAF complex disorders. Due to molecular interactions between ADNP and BAF complex, and an overlapping craniofacial phenotype with narrowing of the palpebral fissures in a subset of patients with HVDAS and BIS, we hypothesized the possibility of a common phenotype-specific episignature. A distinct episignature was shared by 15 individuals with BIS-causing SMARCA2 pathogenic variants and 12 individuals with class II HVDAS caused by truncating pathogenic ADNP variants. This represents first evidence of a sensitive phenotype-specific episignature biomarker shared across distinct genetic conditions that also exhibit unique gene-specific episignatures.

Published
2024

2. Identification of the DNA methylation signature of Mowat-Wilson syndrome

Author

Caraffi, S. G., van der Laan, L., Rooney, K., Trajkova, S., Zuntini, R., Relator, R., Haghshenas, S., Levy, M. A., Baldo, C., Mandrile, G., Lauzon, C., Cordelli, D. M., Ivanovski, I., Fetta, A., Sukarova, E., Brusco, A., Pavinato, L., Pullano, V., Zollino, Marcella, Mcconkey, H., Tartaglia, M., Ferrero, G. B., Sadikovic, B., Garavelli, L., Zollino M. (ORCID:0000-0003-4871-9519), Caraffi, S. G., van der Laan, L., Rooney, K., Trajkova, S., Zuntini, R., Relator, R., Haghshenas, S., Levy, M. A., Baldo, C., Mandrile, G., Lauzon, C., Cordelli, D. M., Ivanovski, I., Fetta, A., Sukarova, E., Brusco, A., Pavinato, L., Pullano, V., Zollino, Marcella, Mcconkey, H., Tartaglia, M., Ferrero, G. B., Sadikovic, B., Garavelli, L., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period. In order to define a novel diagnostic biomarker for MOWS, we determined the genome-wide DNA methylation profile of DNA samples from 29 individuals with confirmed clinical and molecular diagnosis. Through multidimensional scaling and hierarchical clustering analysis, we identified and validated a DNA methylation signature involving 296 differentially methylated probes as part of the broader MOWS DNA methylation profile. The prevalence of hypomethylated CpG sites agrees with the main role of ZEB2 as a transcriptional repressor, while differential methylation within the ZEB2 locus supports the previously proposed autoregulation ability. Correlation studies compared the MOWS cohort with 56 previously described DNA methylation profiles of other neurodevelopmental disorders, further validating the specificity of this biomarker. In conclusion, MOWS DNA methylation signature is highly sensitive and reproducible, providing a useful tool to facilitate diagnosis.

Published
2024

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

Author

LaFlamme, CW, Rastin, C, Sengupta, S, Pennington, HE, Russ-Hall, SJ, Schneider, AL, Bonkowski, ES, Almanza Fuerte, EP, Allan, TJ, Zalusky, MP-G, Goffena, J, Gibson, SB, Nyaga, DM, Lieffering, N, Hebbar, M, Walker, EV, Darnell, D, Olsen, SR, Kolekar, P, Djekidel, MN, Rosikiewicz, W, McConkey, H, Kerkhof, J, Levy, MA, Relator, R, Lev, D, Lerman-Sagie, T, Park, KL, Alders, M, Cappuccio, G, Chatron, N, Demain, L, Genevieve, D, Lesca, G, Roscioli, T, Sanlaville, D, Tedder, ML, Gupta, S, Jones, EA, Weisz-Hubshman, M, Ketkar, S, Dai, H, Worley, KC, Rosenfeld, JA, Chao, H-T, Undiagnosed Diseases Network, Neale, G, Carvill, GL, University of Washington Center for Rare Disease Research, Wang, Z, Berkovic, SF, Sadleir, LG, Miller, DE, Scheffer, IE, Sadikovic, B, Mefford, HC, LaFlamme, CW, Rastin, C, Sengupta, S, Pennington, HE, Russ-Hall, SJ, Schneider, AL, Bonkowski, ES, Almanza Fuerte, EP, Allan, TJ, Zalusky, MP-G, Goffena, J, Gibson, SB, Nyaga, DM, Lieffering, N, Hebbar, M, Walker, EV, Darnell, D, Olsen, SR, Kolekar, P, Djekidel, MN, Rosikiewicz, W, McConkey, H, Kerkhof, J, Levy, MA, Relator, R, Lev, D, Lerman-Sagie, T, Park, KL, Alders, M, Cappuccio, G, Chatron, N, Demain, L, Genevieve, D, Lesca, G, Roscioli, T, Sanlaville, D, Tedder, ML, Gupta, S, Jones, EA, Weisz-Hubshman, M, Ketkar, S, Dai, H, Worley, KC, Rosenfeld, JA, Chao, H-T, Undiagnosed Diseases Network, Neale, G, Carvill, GL, University of Washington Center for Rare Disease Research, Wang, Z, Berkovic, SF, Sadleir, LG, Miller, DE, Scheffer, IE, Sadikovic, B, and Mefford, HC

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

4. Refining the 9q34.3 microduplication syndrome reveals mild neurodevelopmental features associated with a distinct global DNA methylation profile.

Author

Rots, D., Rooney, K., Relator, R., Kerkhof, J., McConkey, H., Pfundt, R.P., Marcelis, C.L.M., Willemsen, M.H., Hagen, J.M. van, Zwijnenburg, P., Alders, M., Õunap, K., Reimand, T., Fjodorova, O., Berland, S., Liahjell, E.B., Bojovic, O., Kriek, M., Ruivenkamp, C., Bonati, M.T., Brunner, H.G., Vissers, L.E.L.M., Sadikovic, B., Kleefstra, T., Rots, D., Rooney, K., Relator, R., Kerkhof, J., McConkey, H., Pfundt, R.P., Marcelis, C.L.M., Willemsen, M.H., Hagen, J.M. van, Zwijnenburg, P., Alders, M., Õunap, K., Reimand, T., Fjodorova, O., Berland, S., Liahjell, E.B., Bojovic, O., Kriek, M., Ruivenkamp, C., Bonati, M.T., Brunner, H.G., Vissers, L.E.L.M., Sadikovic, B., and Kleefstra, T.

Abstract

Contains fulltext : 306427.pdf (Publisher’s version ) (Open Access), Precise regulation of gene expression is important for correct neurodevelopment. 9q34.3 deletions affecting the EHMT1 gene result in a syndromic neurodevelopmental disorder named Kleefstra syndrome. In contrast, duplications of the 9q34.3 locus encompassing EHMT1 have been suggested to cause developmental disorders, but only limited information has been available. We have identified 15 individuals from 10 unrelated families, with 9q34.3 duplications <1.5 Mb in size, encompassing EHMT1 entirely. Clinical features included mild developmental delay, mild intellectual disability or learning problems, autism spectrum disorder, and behavior problems. The individuals did not consistently display dysmorphic features, congenital anomalies, or growth abnormalities. DNA methylation analysis revealed a weak DNAm profile for the cases with 9q34.3 duplication encompassing EHMT1, which could segregate the majority of the affected cases from controls. This study shows that individuals with 9q34.3 duplications including EHMT1 gene present with mild non-syndromic neurodevelopmental disorders and DNA methylation changes different from Kleefstra syndrome., 01 juni 2024

Published
2024

8. A genome-wide DNA methylation signature for SETD1B-related syndrome

Author

Krzyzewska, I. M., Maas, S. M., Henneman, P., Lip, K. v. d., Venema, A., Baranano, K., Chassevent, A., Aref-Eshghi, E., van Essen, A. J., Fukuda, T., Ikeda, H., Jacquemont, M., Kim, H.-G., Labalme, A., Lewis, S. M. E., Lesca, G., Madrigal, I., Mahida, S., Matsumoto, N., Rabionet, R., Rajcan-Separovic, E., Qiao, Y., Sadikovic, B., Saitsu, H., Sweetser, D. A., Alders, M., and Mannens, M. M. A. M.

Published
2019
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9. Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature.

Author

LaFlamme, CW, Rastin, C, Sengupta, S, Pennington, HE, Russ-Hall, SJ, Schneider, AL, Bonkowski, ES, Almanza Fuerte, EP, Galey, M, Goffena, J, Gibson, SB, Allan, TJ, Nyaga, DM, Lieffering, N, Hebbar, M, Walker, EV, Darnell, D, Olsen, SR, Kolekar, P, Djekidel, N, Rosikiewicz, W, McConkey, H, Kerkhof, J, Levy, MA, Relator, R, Lev, D, Lerman-Sagie, T, Park, KL, Alders, M, Cappuccio, G, Chatron, N, Demain, L, Genevieve, D, Lesca, G, Roscioli, T, Sanlaville, D, Tedder, ML, Hubshman, MW, Ketkar, S, Dai, H, Worley, KC, Rosenfeld, JA, Chao, H-T, Undiagnosed Diseases Network, Neale, G, Carvill, GL, University of Washington Center for Rare Disease Research, Wang, Z, Berkovic, SF, Sadleir, LG, Miller, DE, Scheffer, IE, Sadikovic, B, Mefford, HC, LaFlamme, CW, Rastin, C, Sengupta, S, Pennington, HE, Russ-Hall, SJ, Schneider, AL, Bonkowski, ES, Almanza Fuerte, EP, Galey, M, Goffena, J, Gibson, SB, Allan, TJ, Nyaga, DM, Lieffering, N, Hebbar, M, Walker, EV, Darnell, D, Olsen, SR, Kolekar, P, Djekidel, N, Rosikiewicz, W, McConkey, H, Kerkhof, J, Levy, MA, Relator, R, Lev, D, Lerman-Sagie, T, Park, KL, Alders, M, Cappuccio, G, Chatron, N, Demain, L, Genevieve, D, Lesca, G, Roscioli, T, Sanlaville, D, Tedder, ML, Hubshman, MW, Ketkar, S, Dai, H, Worley, KC, Rosenfeld, JA, Chao, H-T, Undiagnosed Diseases Network, Neale, G, Carvill, GL, University of Washington Center for Rare Disease Research, Wang, Z, Berkovic, SF, Sadleir, LG, Miller, DE, Scheffer, IE, Sadikovic, B, and Mefford, HC

Abstract

Sequence-based genetic testing currently identifies causative genetic 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. Rare epigenetic variations ("epivariants") can drive disease by modulating gene expression at single loci, whereas genome-wide DNA methylation changes can result in distinct "episignature" biomarkers for monogenic disorders in a growing number of rare diseases. Here, we interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 516 individuals with genetically unsolved DEEs who had previously undergone extensive genetic testing. We identified rare differentially methylated regions (DMRs) and explanatory episignatures to discover causative and candidate genetic etiologies in 10 individuals. We then used long-read sequencing to identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and two copy number variants. We also identify pathogenic sequence variants associated with episignatures; some had been missed by previous exome sequencing. Although most DEE genes lack known episignatures, the increase in diagnostic yield for DNA methylation analysis in DEEs is comparable to the added yield of genome sequencing. Finally, we refine an episignature for CHD2 using an 850K methylation array which was further refined at higher CpG resolution using 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 genetic causes as ∼2% (10/516) for unsolved DEE cases.

Published
2023

10. Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.

Author

Jaarsveld, R.H. van, Reilly, J., Cornips, M.C., Hadders, M.A., Agolini, E., Ahimaz, P., Anyane-Yeboa, K., Bellanger, S.A., Binsbergen, E. van, Boogaard, M.J. van den, Brischoux-Boucher, E., Caylor, R.C., Ciolfi, A., Essen, T.A. van, Fontana, P., Hopman, S., Iascone, M., Javier, M.M., Kamsteeg, E.J., Kerkhof, J., Kido, J., Kim, H.G., Kleefstra, T., Lonardo, F., Lai, A., Lev, D., Levy, M.A., Lewis, M.E.S., Lichty, A., Mannens, M.M., Matsumoto, N., Maya, I., McConkey, H., Megarbane, A., Michaud, V., Miele, E., Niceta, M., Novelli, A., Onesimo, R., Pfundt, R.P., Popp, B., Prijoles, E., Relator, R., Redon, S., Rots, D., Rouault, K., Saida, K., Schieving, J.H., Tartaglia, M., Tenconi, R., Uguen, K., Verbeek, N., Walsh, C.A., Yosovich, K., Yuskaitis, C.J., Zampino, G., Sadikovic, B., Alders, M., Oegema, R., Jaarsveld, R.H. van, Reilly, J., Cornips, M.C., Hadders, M.A., Agolini, E., Ahimaz, P., Anyane-Yeboa, K., Bellanger, S.A., Binsbergen, E. van, Boogaard, M.J. van den, Brischoux-Boucher, E., Caylor, R.C., Ciolfi, A., Essen, T.A. van, Fontana, P., Hopman, S., Iascone, M., Javier, M.M., Kamsteeg, E.J., Kerkhof, J., Kido, J., Kim, H.G., Kleefstra, T., Lonardo, F., Lai, A., Lev, D., Levy, M.A., Lewis, M.E.S., Lichty, A., Mannens, M.M., Matsumoto, N., Maya, I., McConkey, H., Megarbane, A., Michaud, V., Miele, E., Niceta, M., Novelli, A., Onesimo, R., Pfundt, R.P., Popp, B., Prijoles, E., Relator, R., Redon, S., Rots, D., Rouault, K., Saida, K., Schieving, J.H., Tartaglia, M., Tenconi, R., Uguen, K., Verbeek, N., Walsh, C.A., Yosovich, K., Yuskaitis, C.J., Zampino, G., Sadikovic, B., Alders, M., and Oegema, R.

Abstract

01 januari 2023, Item does not contain fulltext, PURPOSE: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD. METHODS: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature. RESULTS: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism. CONCLUSION: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.

Published
2023

12. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Author

Levy, MA, McConkey, H, Kerkhof, J, Barat-Houari, M, Bargiacchi, S, Biamino, E, Bralo, MP, Cappuccio, G, Ciolfi, A, Clarke, A, DuPont, BR, Elting, MW, Faivre, L, Fee, T, Fletcher, RS, Cherik, F, Foroutan, A, Friez, MJ, Gervasini, C, Haghshenas, S, Hilton, BA, Jenkins, Z, Kaur, S, Lewis, S, Louie, RJ, Maitz, S, Milani, D, Morgan, AT, Oegema, R, Østergaard, E, Pallares, NR, Piccione, M, Pizzi, S, Plomp, AS, Poulton, C, Reilly, J, Relator, R, Rius, R, Robertson, S, Rooney, K, Rousseau, J, Santen, GWE, Santos-Simarro, F, Schijns, J, Squeo, GM, St John, M, Thauvin-Robinet, C, Traficante, G, van der Sluijs, PJ, Vergano, SA, Vos, N, Walden, KK, Azmanov, D, Balci, T, Banka, S, Gecz, J, Henneman, P, Lee, JA, Mannens, MMAM, Roscioli, T ; https://orcid.org/0000-0003-1502-5000, Siu, V, Amor, DJ, Baynam, G, Bend, EG, Boycott, K, Brunetti-Pierri, N, Campeau, PM, Christodoulou, J, Dyment, D, Esber, N, Fahrner, JA, Fleming, MD, Genevieve, D, Kerrnohan, KD, McNeill, A, Menke, LA, Merla, G, Prontera, P, Rockman-Greenberg, C, Schwartz, C, Skinner, SA, Stevenson, RE, Vitobello, A, Tartaglia, M, Alders, M, Tedder, ML, Sadikovic, B, Levy, MA, McConkey, H, Kerkhof, J, Barat-Houari, M, Bargiacchi, S, Biamino, E, Bralo, MP, Cappuccio, G, Ciolfi, A, Clarke, A, DuPont, BR, Elting, MW, Faivre, L, Fee, T, Fletcher, RS, Cherik, F, Foroutan, A, Friez, MJ, Gervasini, C, Haghshenas, S, Hilton, BA, Jenkins, Z, Kaur, S, Lewis, S, Louie, RJ, Maitz, S, Milani, D, Morgan, AT, Oegema, R, Østergaard, E, Pallares, NR, Piccione, M, Pizzi, S, Plomp, AS, Poulton, C, Reilly, J, Relator, R, Rius, R, Robertson, S, Rooney, K, Rousseau, J, Santen, GWE, Santos-Simarro, F, Schijns, J, Squeo, GM, St John, M, Thauvin-Robinet, C, Traficante, G, van der Sluijs, PJ, Vergano, SA, Vos, N, Walden, KK, Azmanov, D, Balci, T, Banka, S, Gecz, J, Henneman, P, Lee, JA, Mannens, MMAM, Roscioli, T ; https://orcid.org/0000-0003-1502-5000, Siu, V, Amor, DJ, Baynam, G, Bend, EG, Boycott, K, Brunetti-Pierri, N, Campeau, PM, Christodoulou, J, Dyment, D, Esber, N, Fahrner, JA, Fleming, MD, Genevieve, D, Kerrnohan, KD, McNeill, A, Menke, LA, Merla, G, Prontera, P, Rockman-Greenberg, C, Schwartz, C, Skinner, SA, Stevenson, RE, Vitobello, A, Tartaglia, M, Alders, M, Tedder, ML, and Sadikovic, B

Abstract

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

13. P1019: A PREDICTION RULE TO GUIDE JAK2 MUTATION TESTING IN PATIENTS WITH SUSPECTED POLYCYTHEMIA VERA: RESULTS FROM THE JAK2 PREDICTION COHORT (JAKPOT) STUDY

Author

Chin-Yee, B., primary, Bhai, P., additional, Cheong, I., additional, Matyashin, M., additional, Hsia, C., additional, Kawata, E., additional, Ho, J., additional, Levy, M., additional, Stuart, A., additional, Lin, H., additional, Chin-Yee, I., additional, Kadour, M., additional, Sadikovic, B., additional, and Lazo-Langner, A., additional

Published
2022
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15. Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood (vol 6, 92, 2021)

Author

Levy, M.A., Beck, D.B., Metcalfe, K., Douzgou, S., Sithambaram, S., Cottrell, T., Ansar, M., Kerkhof, J., Mignot, C., Nougues, M.C., Keren, B., Moore, H.W., Oegema, R., Giltay, J.C., Simon, M., Jaarsveld, R.H. van, Bos, J., Haelst, M. van, Motazacker, M.M., Boon, E.M.J., Santen, G.W.E., Ruivenkamp, C.A.L., Alders, M., Luperchio, T.R., Boukas, L., Ramsey, K., Narayanan, V., Schaefer, G.B., Bonasio, R., Doheny, K.F., Stevenson, R.E., Banka, S., Sadikovic, B., and Fahrner, J.A.

Published
2021

16. Additional file 3 of DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome

Author

L. C. Schenkel, E. Aref-Eshghi, K. Rooney, J. Kerkhof, M. A. Levy, H. McConkey, R. C. Rogers, K. Phelan, S. M. Sarasua, L. Jain, R. Pauly, L. Boccuto, B. DuPont, G. Cappuccio, N. Brunetti-Pierri, C. E. Schwartz, and Sadikovic, B.

Abstract

Additional file 3: Figure S1. Leave-2-out cross-validation using PHMDS large deletion samples. For each round of validation, nine of the eleven PHMDS large deletion samples were used for probe selection along with matched controls and the remaining two PHMDS large deletion samples were saved for testing. Multidimensional scaling was used to cluster the samples. Each time the two testing samples clustered with the other PHMDS samples. This was repeated 55 times for each combination of pairs of PHMDS large deletion samples, the first 12 are shown here. Figure S2. Gene Ontology enrichment analysis was performed using WEB-based GEne SeT AnaLysis Toolkit. Minimum number of IDs in the category: 3. Among the 24 unique genes, 15 were annotated to the selected functional categories, which are used for the enrichment analysis. Based on the above parameters, 3 positive related categories and 5 negative related categories are identified as enriched categories and all are shown in this report. Figure S3. Graphical representation of the metabolic profiles in PHMDS and PHMDS Small Del/Mut cell lines versus controls. The figure shows kinetic curves generated by optical density readings collected every 15 minutes for 24 hours, for a total of 96 data-points for each well. Plates PM-M5 to M8 are represented, average data from cases, either the 11 PHMDS cell lines or the 9 PHMDS Small Del/Mut ones, are in green while average data from 50 control cell lines are in red, the area where case and control data overlap is shown in yellow. Therefore, red edges indicate lower NADH levels in case cell lines as compared to controls for the compound in the give well, and green edges indicate higher NADH levels in case cell lines than in controls. The metabolic profiles of the PHMDS Small Del/Mut cohort show almost exclusively yellow curves, suggesting a substantial overlap of case and control data. On the other hand, the numerous red edges and the few green ones (limited to PM-M5) in the PHMDS cohort indicate numerous differences as compared to controls in the production of NADH when exposed to different metabolic effectors. Overall, these graphics illustrate a normal metabolic profile of cell lines from individuals of the PHMDS Small Del/Mut cohort as opposed to a largely disrupted one in the cells from the PHMDS cohort.

Published
2021
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17. Evaluation of DNA methylation episignatures for diagnosis and phenotype correlations in 42 Mendelian neurodevelopmental disorders

Author

Aref-Eshghi, E., Kerkhof, J., Pedro, V., DI France, Groupe, Barat-Houari, M., Ruiz-Pallares, N., Alders, M., Mannens, M., Henneman, P., Hennekam, R.C., Ciolf, A., Pizzi, S., Tartaglia, M., Campeau, P.M., Rousseau, J., Levy, M.A., Brick, L., Kozenko, M., Balci, T.B., Siu, V.M., Stuart, A., Kadour, M., Masters, J., Takano, K., Kleefstra, T., de Leeuw, N., Field, M., Shaw, M., Gecz, J., Merla, G., Ainsworth, P.J., Lin, H., Rodenhiser, D.I., Friez, M.J., Tedder, M., DuPont, J.A., Stevenson, R.E., Skinner, S.A., Schwartz, C.E., Genevieve, D., and Sadikovic, B.

Published
2020

18. Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Author

Weerts, M.J.A., Lanko, K., Guzmán-Vega, F.J., Jackson, A., Ramakrishnan, R., Cardona-Londoño, K.J., Peña-Guerra, K.A., Bever, Y. Van, Paassen, B.W. van, Kievit, A., Slegtenhorst, M. van, Allen, N.M., Kehoe, C.M., Robinson, H.K., Pang, L., Banu, S.H., Zaman, M., Efthymiou, S., Houlden, H., Järvelä, I., Lauronen, L., Määttä, T., Schrauwen, I., Leal, S.M., Ruivenkamp, C.A.L., Barge-Schaapveld, D., Peeters-Scholte, C., Galehdari, H., Mazaheri, N., Sisodiya, S.M., Harrison, V., Sun, A., Thies, J., Pedroza, L.A., Lara-Taranchenko, Y., Chinn, I.K., Lupski, J.R., Garza-Flores, A., McGlothlin, J., Yang, L., Huang, S., Wang, X, Jewett, T., Rosso, G., Lin, X., Mohammed, S, Merritt, J.L., 2nd, Mirzaa, G.M., Timms, A.E., Scheck, J., Elting, M.W., Polstra, A.M., Schenck, L., Ruzhnikov, M.R.Z., Vetro, A., Montomoli, M., Guerrini, R., Koboldt, D.C., Mosher, T.M., Pastore, M.T., McBride, K.L., Peng, J., Pan, Z., Willemsen, M.H., Koning, S. de, Turnpenny, P.D., Vries, B.B. de, Gilissen, C., Pfundt, R.P., Lees, M., Braddock, S.R., Klemp, K.C., Vansenne, F., Gijn, M.E. van, Quindipan, C., Deardorff, M.A., Hamm, J.A., Putnam, A.M., Baud, R., Walsh, L., Lynch, S.A., Baptista, J., Person, R.E., Monaghan, K.G., Crunk, A., Keller-Ramey, J., Reich, A., Elloumi, H.Z., Alders, M., Kerkhof, J., McConkey, H., Haghshenas, S., Maroofian, R., Sadikovic, B., Banka, S., Arold, Stefan T., Barakat, T.S., Weerts, M.J.A., Lanko, K., Guzmán-Vega, F.J., Jackson, A., Ramakrishnan, R., Cardona-Londoño, K.J., Peña-Guerra, K.A., Bever, Y. Van, Paassen, B.W. van, Kievit, A., Slegtenhorst, M. van, Allen, N.M., Kehoe, C.M., Robinson, H.K., Pang, L., Banu, S.H., Zaman, M., Efthymiou, S., Houlden, H., Järvelä, I., Lauronen, L., Määttä, T., Schrauwen, I., Leal, S.M., Ruivenkamp, C.A.L., Barge-Schaapveld, D., Peeters-Scholte, C., Galehdari, H., Mazaheri, N., Sisodiya, S.M., Harrison, V., Sun, A., Thies, J., Pedroza, L.A., Lara-Taranchenko, Y., Chinn, I.K., Lupski, J.R., Garza-Flores, A., McGlothlin, J., Yang, L., Huang, S., Wang, X, Jewett, T., Rosso, G., Lin, X., Mohammed, S, Merritt, J.L., 2nd, Mirzaa, G.M., Timms, A.E., Scheck, J., Elting, M.W., Polstra, A.M., Schenck, L., Ruzhnikov, M.R.Z., Vetro, A., Montomoli, M., Guerrini, R., Koboldt, D.C., Mosher, T.M., Pastore, M.T., McBride, K.L., Peng, J., Pan, Z., Willemsen, M.H., Koning, S. de, Turnpenny, P.D., Vries, B.B. de, Gilissen, C., Pfundt, R.P., Lees, M., Braddock, S.R., Klemp, K.C., Vansenne, F., Gijn, M.E. van, Quindipan, C., Deardorff, M.A., Hamm, J.A., Putnam, A.M., Baud, R., Walsh, L., Lynch, S.A., Baptista, J., Person, R.E., Monaghan, K.G., Crunk, A., Keller-Ramey, J., Reich, A., Elloumi, H.Z., Alders, M., Kerkhof, J., McConkey, H., Haghshenas, S., Maroofian, R., Sadikovic, B., Banka, S., Arold, Stefan T., and Barakat, T.S.

Abstract

Contains fulltext : 243955.pdf (Publisher’s version ) (Open Access), PURPOSE: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. RESULTS: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

Published
2021

19. Cross-oncopanel study reveals high sensitivity and accuracy with overall analytical performance depending on genomic regions

Author

Gong, B, Li, D, Kusko, R, Novoradovskaya, N, Zhang, Y, Wang, S, Pabón-Peña, C, Zhang, Z, Lai, K, Cai, W, LoCoco, JS, Lader, E, Richmond, TA, Mittal, VK, Liu, LC, Johann, DJ, Willey, JC, Bushel, PR, Yu, Y, Xu, C, Chen, G, Burgess, D, Cawley, S, Giorda, K, Haseley, N, Qiu, F, Wilkins, K, Arib, H, Attwooll, C, Babson, K, Bao, L, Bao, W, Lucas, AB, Best, H, Bhandari, A, Bisgin, H, Blackburn, J ; https://orcid.org/0000-0001-5216-8815, Blomquist, TM, Boardman, L, Burgher, B, Butler, DJ, Chang, CJ, Chaubey, A, Chen, T, Chierici, M, Chin, CR, Close, D, Conroy, J, Coleman, JC, Craig, DJ, Crawford, E, del Pozo, A, Deveson, IW ; https://orcid.org/0000-0003-3861-0472, Duncan, D, Eterovic, AK, Fan, X, Foox, J, Furlanello, C, Ghosal, A, Glenn, S, Guan, M, Haag, C, Hang, X, Happe, S, Hennigan, B, Hipp, J, Hong, H, Horvath, K, Hu, J, Hung, LY, Jarosz, M, Kerkhof, J, Kipp, B, Kreil, DP, Łabaj, P, Lapunzina, P, Li, P, Li, QZ, Li, W, Li, Z, Liang, Y, Liu, S, Liu, Z, Ma, C, Marella, N, Martín-Arenas, R, Megherbi, DB, Meng, Q, Mieczkowski, PA, Morrison, T, Muzny, D, Ning, B, Parsons, BL, Paweletz, CP, Pirooznia, M, Qu, W, Raymond, A, Rindler, P, Ringler, R, Sadikovic, B, Mercer, Timothy ; https://orcid.org/0000-0001-8780-894X, Thomas, David ; https://orcid.org/0000-0002-2527-5428, Gong, B, Li, D, Kusko, R, Novoradovskaya, N, Zhang, Y, Wang, S, Pabón-Peña, C, Zhang, Z, Lai, K, Cai, W, LoCoco, JS, Lader, E, Richmond, TA, Mittal, VK, Liu, LC, Johann, DJ, Willey, JC, Bushel, PR, Yu, Y, Xu, C, Chen, G, Burgess, D, Cawley, S, Giorda, K, Haseley, N, Qiu, F, Wilkins, K, Arib, H, Attwooll, C, Babson, K, Bao, L, Bao, W, Lucas, AB, Best, H, Bhandari, A, Bisgin, H, Blackburn, J ; https://orcid.org/0000-0001-5216-8815, Blomquist, TM, Boardman, L, Burgher, B, Butler, DJ, Chang, CJ, Chaubey, A, Chen, T, Chierici, M, Chin, CR, Close, D, Conroy, J, Coleman, JC, Craig, DJ, Crawford, E, del Pozo, A, Deveson, IW ; https://orcid.org/0000-0003-3861-0472, Duncan, D, Eterovic, AK, Fan, X, Foox, J, Furlanello, C, Ghosal, A, Glenn, S, Guan, M, Haag, C, Hang, X, Happe, S, Hennigan, B, Hipp, J, Hong, H, Horvath, K, Hu, J, Hung, LY, Jarosz, M, Kerkhof, J, Kipp, B, Kreil, DP, Łabaj, P, Lapunzina, P, Li, P, Li, QZ, Li, W, Li, Z, Liang, Y, Liu, S, Liu, Z, Ma, C, Marella, N, Martín-Arenas, R, Megherbi, DB, Meng, Q, Mieczkowski, PA, Morrison, T, Muzny, D, Ning, B, Parsons, BL, Paweletz, CP, Pirooznia, M, Qu, W, Raymond, A, Rindler, P, Ringler, R, Sadikovic, B, Mercer, Timothy ; https://orcid.org/0000-0001-8780-894X, and Thomas, David ; https://orcid.org/0000-0002-2527-5428

Abstract

Background: Targeted sequencing using oncopanels requires comprehensive assessments of accuracy and detection sensitivity to ensure analytical validity. By employing reference materials characterized by the U.S. Food and Drug Administration-led SEquence Quality Control project phase2 (SEQC2) effort, we perform a cross-platform multi-lab evaluation of eight Pan-Cancer panels to assess best practices for oncopanel sequencing. Results: All panels demonstrate high sensitivity across targeted high-confidence coding regions and variant types for the variants previously verified to have variant allele frequency (VAF) in the 5–20% range. Sensitivity is reduced by utilizing VAF thresholds due to inherent variability in VAF measurements. Enforcing a VAF threshold for reporting has a positive impact on reducing false positive calls. Importantly, the false positive rate is found to be significantly higher outside the high-confidence coding regions, resulting in lower reproducibility. Thus, region restriction and VAF thresholds lead to low relative technical variability in estimating promising biomarkers and tumor mutational burden. Conclusion: This comprehensive study provides actionable guidelines for oncopanel sequencing and clear evidence that supports a simplified approach to assess the analytical performance of oncopanels. It will facilitate the rapid implementation, validation, and quality control of oncopanels in clinical use.

Published
2021

20. FP07.08 A Pan-Canadian Validation Study for the Detection of EGFR-T790M Mutations Using Circulating Tumour DNA (ctDNA) from Blood

Author

Selvarajah, S., primary, Plante, S., additional, Speevak, M., additional, Vaags, A., additional, Mccready, E., additional, Grafodatskaya, D., additional, Blais, N., additional, Tran-Thanh, D., additional, Greer, W., additional, Lo, B., additional, Demetrick, D., additional, Sadikovic, B., additional, Walton, R., additional, Stockley, T., additional, Feilotter, H., additional, and Joubert, P., additional

Published
2021
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21. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides–Baraitser syndrome

Author

Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, Marcella, Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., Zollino M. (ORCID:0000-0003-4871-9519), Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, Marcella, Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., and Zollino M. (ORCID:0000-0003-4871-9519)

Abstract

Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides–Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

Published
2020

23. OCTANE (Ontario-Wide Cancer Targeted Nucleic Acid Evaluation): A Platform for Intraprovincial, National, and International Clinical Data-Sharing

Author

Malone, E. R., primary, Saleh, R. R., additional, Yu, C., additional, Ahmed, L., additional, Pugh, T., additional, Torchia, J., additional, Bartlett, J., additional, Virtanen, C., additional, Hotte, S. J., additional, Hilton, J., additional, Welch, S., additional, Robinson, A., additional, McCready, E., additional, Lo, B., additional, Sadikovic, B., additional, Feilotter, H., additional, Hanna, T. P., additional, Kamel-Reid, S., additional, Stockley, T. L., additional, Siu, L. L., additional, and Bedard, Philippe L., additional

Published
2019
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27. BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes

Author

Aref-Eshghi, E, Bend, EG, Hood, RL, Schenkel, LC, Carere, DA, Chakrabarti, R, Nagamani, SCS, Cheung, SW, Campeau, PM, Prasad, C, Siu, VM, Brady, L, Tarnopolsky, MA, Callen, DJ, Innes, AM, White, SM, Meschino, WS, Shuen, AY, Pare, G, Bulman, DE, Ainsworth, PJ, Lin, H, Rodenhiser, DI, Hennekam, RC, Boycott, KM, Schwartz, CE, Sadikovic, B, Aref-Eshghi, E, Bend, EG, Hood, RL, Schenkel, LC, Carere, DA, Chakrabarti, R, Nagamani, SCS, Cheung, SW, Campeau, PM, Prasad, C, Siu, VM, Brady, L, Tarnopolsky, MA, Callen, DJ, Innes, AM, White, SM, Meschino, WS, Shuen, AY, Pare, G, Bulman, DE, Ainsworth, PJ, Lin, H, Rodenhiser, DI, Hennekam, RC, Boycott, KM, Schwartz, CE, and Sadikovic, B

Abstract

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening.

Published
2018

30. An aggressive multifocal primary CNS histiocytosis with <italic>PTPN11 (Shp2)</italic> mutation.

Author

Zhang, Q., Shibani, A., Sadikovic, B., Howlett, C. J., and Ang, L.‐C.

Subjects
CENTRAL nervous system cancer, CENTRAL nervous system diseases, NEUROLOGICAL disorders, IMMUNOHISTOCHEMISTRY, IMMUNOCHEMISTRY, HISTOCHEMISTRY
Abstract

The article presents a study regarding an unusual case of aggressive multifocal primary central nervous system (CNS) histiocytosis. It cites the case of a 62-year-old male presented with a 6-month history of progressive difficulty with balance, numbness and weakness. It also mentions the laboratory examinations undergone by the patient that lead to his diagnosis of histiocytosis.

Published
2018
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31. Recurrent genomic alterations in sequential progressive leukoplakia and oral cancer: drivers of oral tumorigenesis?

Author

Cervigne, N. K., primary, Machado, J., additional, Goswami, R. S., additional, Sadikovic, B., additional, Bradley, G., additional, Perez-Ordonez, B., additional, Galloni, N. N., additional, Gilbert, R., additional, Gullane, P., additional, Irish, J. C., additional, Jurisica, I., additional, Reis, P. P., additional, and Kamel-Reid, S., additional

Published
2014
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37. Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome

Author

Aidin Foroutan, Sadegheh Haghshenas, Pratibha Bhai, Michael A. Levy, Jennifer Kerkhof, Haley McConkey, Marcello Niceta, Andrea Ciolfi, Lucia Pedace, Evelina Miele, David Genevieve, Solveig Heide, Mariëlle Alders, Giuseppe Zampino, Giuseppe Merla, Mélanie Fradin, Eric Bieth, Dominique Bonneau, Klaus Dieterich, Patricia Fergelot, Elise Schaefer, Laurence Faivre, Antonio Vitobello, Silvia Maitz, Rita Fischetto, Cristina Gervasini, Maria Piccione, Ingrid van de Laar, Marco Tartaglia, Bekim Sadikovic, Anne-Sophie Lebre, Foroutan A., Haghshenas S., Bhai P., Levy M.A., Kerkhof J., McConkey H., Niceta M., Ciolfi A., Pedace L., Miele E., Genevieve D., Heide S., Alders M., Zampino G., Merla G., Fradin M., Bieth E., Bonneau D., Dieterich K., Fergelot P., Schaefer E., Faivre L., Vitobello A., Maitz S., Fischetto R., Gervasini C., Piccione M., van de Laar I., Tartaglia M., Sadikovic B., Lebre A.-S., Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, University of Western Ontario (UWO), London Health Sciences Center (LHSC), IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Amsterdam UMC - Amsterdam University Medical Center, University of Amsterdam [Amsterdam] (UvA), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), University of Naples Federico II = Università degli studi di Napoli Federico II, Fondazione Casa Sollievo della Sofferenza [San Giovanni Rotondo, Italy] (FC2S), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), San Gerardo Hospital [Monza, Italy] (SGH), Hospital Papa Giovanni XXIII (Hosp P Giovanni XXIII), Università degli Studi di Milano = University of Milan (UNIMI), Università degli studi di Palermo - University of Palermo, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Foroutan, A., Haghshenas, S., Bhai, P., Levy, M. A., Kerkhof, J., Mcconkey, H., Niceta, M., Ciolfi, A., Pedace, L., Miele, E., Genevieve, D., Heide, S., Alders, M., Zampino, G., Merla, G., Fradin, M., Bieth, E., Bonneau, D., Dieterich, K., Fergelot, P., Schaefer, E., Faivre, L., Vitobello, A., Maitz, S., Fischetto, R., Gervasini, C., Piccione, M., van de Laar, I., Tartaglia, M., Sadikovic, B., Lebre, A. -S., Martinez Rico, Clara, and Clinical Genetics

Subjects
Wiedemann–Steiner syndrome, QH301-705.5, Intellectual disability, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Catalysis, Inorganic Chemistry, KMT2A gene, Neurodevelopmental disorder, Growth Disorder, Abnormalities, Multiple, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Biology (General), Physical and Theoretical Chemistry, Episignature, QD1-999, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Spectroscopy, DNA methylation, Organic Chemistry, Neurodevelopmental disorders, Craniofacial Abnormalitie, Epigenetic, Hypertrichosi, General Medicine, Facie, Computer Science Applications, Chemistry, epigenetics, episignature, intellectual disability, neurodevelopmental disorders, Phenotype, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Epigenetics, Human
Abstract

Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.

Published
2022
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38. DNA methylation episignature testing improves molecular diagnosis of Mendelian chromatinopathies

Author

Bekim Sadikovic, Maria Accadia, Gabriella Maria Squeo, Maria Rosaria Piemontese, Maria Piccione, Michael A. Levy, Marco Castori, Paolo Prontera, Daniela Melis, Elisa Biamino, Silvia Maitz, Haley McConkey, Angelo Selicorni, Cristina Gervasini, Matteo Della Monica, Jennifer Kerkhof, Marilena Carmela Di Giacomo, Giuseppe Merla, Donatella Milani, Kerkhof, J., Squeo, G. M., Mcconkey, H., Levy, M. A., Piemontese, M. R., Castori, M., Accadia, M., Biamino, E., Della Monica, M., Di Giacomo, M. C., Gervasini, C., Maitz, S., Melis, D., Milani, D., Piccione, M., Prontera, P., Selicorni, A., Sadikovic, B., Merla, G., Kerkhof J., Squeo G.M., McConkey H., Levy M.A., Piemontese M.R., Castori M., Accadia M., Biamino E., Della Monica M., Di Giacomo M.C., Gervasini C., Maitz S., Melis D., Milani D., Piccione M., Prontera P., Selicorni A., Sadikovic B., and Merla G.

Subjects
Chromatinopathies, DNA methylation, Epigenetics, Chromatinopathie, Biology, EPIC, DNA sequencing, symbols.namesake, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), Sequence (medicine), Genetics, DNA Methylation, Genome, Hematologic Diseases, Vestibular Diseases, Epigenetic, Methylation, Hematologic Disease, medicine.disease, Chromatin, Mendelian inheritance, symbols, Abnormalities, Kabuki syndrome, Multiple, Human
Abstract

Purpose Chromatinopathies include more than 50 disorders caused by disease-causing variants of various components of chromatin structure and function. Many of these disorders exhibit unique genome-wide DNA methylation profiles, known as episignatures. In this study, the methylation profile of a large cohort of individuals with chromatinopathies was analyzed for episignature detection. Methods DNA methylation data was generated on extracted blood samples from 129 affected individuals with the Illumina Infinium EPIC arrays and analyzed using an established bioinformatic pipeline. Results The DNA methylation profiles matched and confirmed the sequence findings in both the discovery and validation cohorts. Twenty-five affected individuals carrying a variant of uncertain significance, did not show a methylation profile matching any of the known episignatures. Three additional variant of uncertain significance cases with an identified KDM6A variant were re-classified as likely pathogenic (n = 2) or re-assigned as Wolf-Hirschhorn syndrome (n = 1). Thirty of the 33 Next Generation Sequencing negative cases did not match a defined episignature while three matched Kabuki syndrome, Rubinstein-Taybi syndrome and BAFopathy respectively. Conclusion With the expanding clinical utility of the EpiSign assay, DNA methylation analysis should be considered part of the testing cascade for individuals presenting with clinical features of Mendelian chromatinopathy disorders.

Published
2022

39. 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
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40. Identification of a dna methylation episignature in the 22q11.2 deletion syndrome

Author

Gabriella Maria Squeo, Eleonora Di Venere, Paolo Prontera, Matthew L. Tedder, Sadegheh Haghshenas, Kathleen Rooney, Giuseppe Merla, Daniela Rogaia, Amedea Mencarelli, Jennifer Kerkhof, Michael A. Levy, Bekim Sadikovic, Alberto Verrotti, Maria Giovanna Tedesco, Valentina Imperatore, Giuseppe Di Cara, Barbara R. DuPont, Rooney, K., Levy, M. A., Haghshenas, S., Kerkhof, J., Rogaia, D., Tedesco, M. G., Imperatore, V., Mencarelli, A., Squeo, G. M., Di Venere, E., Di Cara, G., Verrotti, A., Merla, G., Tedder, M. L., Dupont, B. R., Sadikovic, B., and Prontera, P.

Subjects
Male, 22q11.2 deletion, Velocardiofacial syndrome, QH301-705.5, Biology, Article, Catalysis, Inorganic Chemistry, Epigenome, DiGeorge syndrome, Intellectual disability, diagnostic method, medicine, Humans, Biology (General), Physical and Theoretical Chemistry, Episignature, QD1-999, Molecular Biology, Transcription factor, Gene, Spectroscopy, Conotruncalanomaly face syndrome, Genetics, DNA methylation, Organic Chemistry, Infant, General Medicine, Methylation, medicine.disease, Phenotype, Computer Science Applications, Chromatin, episignature, Chemistry, Female, Diagnostic method, Human
Abstract

The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20–40 genes, respectively. The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.

Published
2021

41. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Gilles Morin, Krista Bluske, Nathaniel H. Robin, Laurence Faivre, Manuela Priolo, Dihong Zhou, Evangeline Kurtz-Nelson, Tianyun Wang, Omar Sherbini, Daryl A. Scott, Karen Stals, Fabíola Paoli Monteiro, Kaifang Pang, Sara Cabet, Francesca Clementina Radio, Bruno Dallapiccola, Marjon van Slegtenhorst, Rachel K. Earl, Katheryn Grand, Maria Iascone, Alice S. Brooks, Angelo Selicorni, July K. Jean Cuevas, Paolo Gasparini, Maria Lisa Dentici, Marialetizia Motta, Britt-Marie Anderlid, Kristin Lindstrom, Berrin Monteleone, Andrea Ciolfi, Karin Weiss, Katharina Steindl, Kirsty McWalter, Rosalba Carrozzo, Ruben Boers, Helen Kingston, Kym M. Boycott, Bekim Sadikovic, Laura Schultz-Rogers, Evan E. Eichler, Laura A Cross, Alison M R Castle, Louisa Kalsner, Lucia Pedace, Marijke R. Wevers, John M. Graham, Jessica Sebastian, Antonio Vitobello, Gaetan Lesca, Alexander P.A. Stegmann, Suneeta Madan-Khetarpal, Tahsin Stefan Barakat, Abdallah F. Elias, Teresa Robert Finestra, Adeline Vanderver, Peter D. Turnpenny, Bregje W.M. van Bon, Aida Telegrafi, David J. Amor, Deepali N. Shinde, Pedro A. Sanchez-Lara, Lisenka E.L.M. Vissers, Adam Jackson, Rolph Pfundt, Alessandro Bruselles, Andres Hernandez-Garcia, Karin E. M. Diderich, Flavio Faletra, Dana H. Goodloe, Joanne Baez, Sarit Ravid, Romano Tenconi, Sarah L. Sawyer, Lynn Pais, Bronwyn Kerr, Joost Gribnau, Lauren Carter, Melissa T. Carter, Zhandong Liu, Jennifer L. Kemppainen, Jennifer MacKenzie, Jimmy Holder, Elke de Boer, Margaret Au, Taila Hartley, Carol J Saunders, Luciana Musante, Bert B.A. de Vries, Tania Vertemati Secches, Haley McConkey, Willow Sheehan, Francesca Pantaleoni, Caterina Zanus, Christophe Philippe, Chelsea Roadhouse, Stefania Lo Cicero, Sian Ellard, R. Tanner Hagelstrom, Megha Desai, Fernando Kok, Joset Pascal, Marco Tartaglia, Eric W. Klee, Eva Morava, Michael A. Levy, Peggy Kulch, Lyndon Gallacher, Erica L. Macke, Emilia Stellacci, Siddharth Banka, Kristin G. Monaghan, Anita Rauch, Meghan C. Towne, Kate Chandler, Clinical Genetics, Developmental Biology, Radio, F. C., Pang, K., Ciolfi, A., Levy, M. A., Hernandez-Garcia, A., Pedace, L., Pantaleoni, F., Liu, Z., de Boer, E., Jackson, A., Bruselles, A., Mcconkey, H., Stellacci, E., Lo Cicero, S., Motta, M., Carrozzo, R., Dentici, M. L., Mcwalter, K., Desai, M., Monaghan, K. G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P. A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., Mackenzie, J. J., Monteleone, B., Saunders, C. J., Jean Cuevas, J. K., Cross, L., Zhou, D., Hartley, T., Sawyer, S. L., Monteiro, F. P., Secches, T. V., Kok, F., Schultz-Rogers, L. E., Macke, E. L., Morava, E., Klee, E. W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D. J., Pais, L., Gallacher, L., Turnpenny, P. D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A. M. R., Carter, M. T., Kalsner, L., de Vries, B. B. A., van Bon, B. W., Wevers, M. R., Pfundt, R., Stegmann, A. P. A., Kerr, B., Kingston, H. M., Chandler, K. E., Sheehan, W., Elias, A. F., Shinde, D. N., Towne, M. C., Robin, N. H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R. T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E. C., Earl, R. K., Anderlid, B. -M., Morin, G., van Slegtenhorst, M., Diderich, K. E. M., Brooks, A. S., Gribnau, J., Boers, R. G., Finestra, T. R., Carter, L. B., Rauch, A., Gasparini, P., Boycott, K. M., Barakat, T. S., Graham, J. M., Faivre, L., Banka, S., Wang, T., Eichler, E. E., Priolo, M., Dallapiccola, B., Vissers, L. E. L. M., Sadikovic, B., Scott, D. A., Holder, J. L., Tartaglia, M., MUMC+: DA KG Lab Centraal Lab (9), and RS: FHML non-thematic output

Subjects
0301 basic medicine, SHARP, Male, obesity, genotype-phenotype correlations, Autism Spectrum Disorder, PROTEIN, Chromosome Disorders, Haploinsufficiency, RNA-Binding Protein, PHENOTYPE CORRELATIONS, 1p36, distal 1p36 deletion syndrome, DNA methylome analysis, episignature, neurodevelopmental disorder, proximal 1p36 deletion syndrome, SPEN, X chromosome, Adolescent, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 1, Chromosomes, Human, X, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Female, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype, RNA-Binding Proteins, Young Adult, 0302 clinical medicine, Neurodevelopmental disorder, Neurodevelopmental Disorder, Intellectual disability, MOLECULAR CHARACTERIZATION, Genetics (clinical), Genetics, DNA methylome analysi, SPLIT-ENDS, Hypotonia, Autism spectrum disorder, MONOSOMY 1P36, Pair 1, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Human, DNA-Binding Protein, Biology, genotype-phenotype correlation, Chromosomes, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, Report, REVEALS, medicine, Epigenetics, Preschool, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 1p36 deletion syndrome, IDENTIFICATION, MUTATIONS, medicine.disease, GENE, 030104 developmental biology, Chromosome Disorder, 030217 neurology & neurosurgery, Epigenesis
Abstract

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Published
2021

42. DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome

Author

Barbara R. DuPont, Charles E. Schwartz, R. C. Rogers, G. Cappuccio, Jennifer Kerkhof, N. Brunetti-Pierri, Laila C. Schenkel, Luigi Boccuto, Sara M. Sarasua, K. Rooney, Michael A. Levy, Katy Phelan, Haley McConkey, Bekim Sadikovic, Erfan Aref-Eshghi, Lavanya Jain, Rini Pauly, Schenkel, L C, Aref-Eshghi, E, Rooney, K, Kerkhof, J, Levy, M A, Mcconkey, H, Rogers, R C, Phelan, K, Sarasua, S M, Jain, L, Pauly, R, Boccuto, L, Dupont, B, Cappuccio, G, Brunetti-Pierri, N, Schwartz, C E, and Sadikovic, B

Subjects
Male, Adolescent, Genotype, Chromosomes, Human, Pair 22, Chromosome Disorders, Biology, Cohort Studies, Genetics, Humans, Child, Molecular Biology, Gene, Genetics (clinical), Epigenomics, DNA methylation, Research, Breakpoint, Genetic Variation, Phenotype, Penetrance, Human genetics, Child, Preschool, BRD1, Microdeletion, Phelan-McDermid syndrome, Female, Chromosome Deletion, Epi-signature, Chromosome 22, Genome-Wide Association Study, Developmental Biology
Abstract

Background Phelan-McDermid syndrome is characterized by a range of neurodevelopmental phenotypes with incomplete penetrance and variable expressivity. It is caused by a variable size and breakpoint microdeletions in the distal long arm of chromosome 22, referred to as 22q13.3 deletion syndrome, including the SHANK3 gene. Genetic defects in a growing number of neurodevelopmental genes have been shown to cause genome-wide disruptions in epigenomic profiles referred to as epi-signatures in affected individuals. Results In this study we assessed genome-wide DNA methylation profiles in a cohort of 22 individuals with Phelan-McDermid syndrome, including 11 individuals with large (2 to 5.8 Mb) 22q13.3 deletions, 10 with small deletions (SHANK3 and one mosaic case. We describe a novel genome-wide DNA methylation epi-signature in a subset of individuals with Phelan-McDermid syndrome. Conclusion We identified the critical region including the BRD1 gene as responsible for the Phelan-McDermid syndrome epi-signature. Metabolomic profiles of individuals with the DNA methylation epi-signature showed significantly different metabolomic profiles indicating evidence of two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome.

Published
2021

43. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome

Author

Gerarda Cappuccio, Camille Sayou, Pauline Le Tanno, Emilie Tisserant, Ange-Line Bruel, Sara El Kennani, Joaquim Sá, Karen J. Low, Cristina Dias, Markéta Havlovicová, Miroslava Hančárová, Evan E. Eichler, Françoise Devillard, Sébastien Moutton, Julien Van-Gils, Christèle Dubourg, Sylvie Odent, Bénédicte Gerard, Amélie Piton, Toshiyuki Yamamoto, Nobuhiko Okamoto, Helen Firth, Kay Metcalfe, Anna Moh, Kimberly A. Chapman, Erfan Aref-Eshghi, Jennifer Kerkhof, Annalaura Torella, Vincenzo Nigro, Laurence Perrin, Juliette Piard, Gwenaël Le Guyader, Thibaud Jouan, Christel Thauvin-Robinet, Yannis Duffourd, Jaya K. George-Abraham, Catherine A. Buchanan, Denise Williams, Usha Kini, Kate Wilson, Nicola Brunetti-Pierri, Giorgio Casari, Michele Pinelli, Francesco Musacchia, Margherita Mutarelli, Diego Carrella, Giuseppina Vitiello, Valeria Capra, Giancarlo Parenti, Vincenzo Leuzzi, Angelo Selicorni, Silvia Maitz, Sandro Banfi, Marcella Zollino, Mario Montomoli, Donatelli Milani, Corrado Romano, Albina Tummolo, Daniele De Brasi, Antonietta Coppola, Claudia Santoro, Angela Peron, Chiara Pantaleoni, Raffaele Castello, Stefano D’Arrigo, Sérgio B. Sousa, Raoul C.M. Hennekam, Bekim Sadikovic, Julien Thevenon, Jérôme Govin, Antonio Vitobello, Università degli studi di Napoli Federico II, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Motol [Prague], University of Washington [Seattle], Centre Hospitalier Universitaire [Grenoble] (CHU), Université de Bordeaux (UB), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), 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), London Health Sciences Center (LHSC), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), GSP15001, Fondazione Telethon, 209568/Z/17/Z, Wellcome Trust, Cappuccio, G., Sayou, C., Tanno, P. L., Tisserant, E., Bruel, A. -L., Kennani, S. E., Sa, J., Low, K. J., Dias, C., Havlovicova, M., Hancarova, M., Eichler, E. E., Devillard, F., Moutton, S., Van-Gils, J., Dubourg, C., Odent, S., Gerard, B., Piton, A., Yamamoto, T., Okamoto, N., Firth, H., Metcalfe, K., Moh, A., Chapman, K. A., Aref-Eshghi, E., Kerkhof, J., Torella, A., Nigro, V., Perrin, L., Piard, J., Le Guyader, G., Jouan, T., Thauvin-Robinet, C., Duffourd, Y., George-Abraham, J. K., Buchanan, C. A., Williams, D., Kini, U., Wilson, K., Brunetti-Pierri, N., Casari, G., Pinelli, M., Musacchia, F., Mutarelli, M., Carrella, D., Vitiello, G., Capra, V., Parenti, G., Leuzzi, V., Selicorni, A., Maitz, S., Banfi, S., Zollino, M., Montomoli, M., Milani, D., Romano, C., Tummolo, A., De Brasi, D., Coppola, A., Santoro, C., Peron, A., Pantaleoni, C., Castello, R., D'Arrigo, S., Sousa, S. B., Hennekam, R. C. M., Sadikovic, B., Thevenon, J., Govin, J., Vitobello, A., University of Naples Federico II = Università degli studi di Napoli Federico II, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, General Paediatrics, APH - Quality of Care, and Brunetti-Pierri, Nicola

Subjects
Foot Deformities, Foot Deformities, Congenital, [SDV]Life Sciences [q-bio], Biology, Blepharophimosis, Settore MED/03 - GENETICA MEDICA, Hypotrichosis, Chromatin remodeling, 03 medical and health sciences, Congenital, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, SMARCA2, medicine, Humans, Gene, Genetics (clinical), 030304 developmental biology, Genetics, 0303 health sciences, BIS, Facies, medicine.disease, Phenotype, neurodevelopmental disorder, Nicolaides–Baraitser syndrome, intellectual disability, DNA methylation, 030217 neurology & neurosurgery, Transcription Factors
Abstract

International audience; Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.Results: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification.Conclusion: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

Published
2020
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44. Skipping of Exon 20 in EP300: A Novel Variant Linked to Rubinstein-Taybi Syndrome With Atypical and Severe Clinical Manifestations.

Author

Pavinato L, Carestiato S, Trajkova S, Sorasio L, Mantovani G, De Sanctis L, Kerkhof J, McConkey H, Rzasa J, Todd E, Balzo M, Cardaropoli S, Bruselles A, De Rubeis S, Buxbaum JD, Tartaglia M, Sadikovic B, Ferrero GB, and Brusco A

Subjects
Humans, Male, Female, Genetic Association Studies, Child, Phenotype, Exome Sequencing, Child, Preschool, Mutation, DNA Methylation genetics, CREB-Binding Protein genetics, Genetic Predisposition to Disease, Haploinsufficiency genetics, Rubinstein-Taybi Syndrome genetics, Rubinstein-Taybi Syndrome pathology, E1A-Associated p300 Protein genetics, Exons genetics
Abstract

Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder linked to haploinsufficiency of CREBBP (RSTS1) and EP300 (RSTS2) genes. Characteristic features often include distinctive facial traits, broad thumbs and toes, short stature, and various degrees of intellectual disability. The clinical presentation of RSTS is notably variable, making it challenging to establish a clear genotype-phenotype correlation, except for specific variants which cause the allelic Menke-Hennekam syndrome. Trio exome analysis, data collection via networking and GeneMatcher platforms, transcript processing analysis, and DNA methylation profiling were performed. We identified two unrelated patients with de novo variants in EP300 (NM&#95;001429.4: c.3671+5G>C; c.3671+5&#95;3671+8delGTAA) predicted to cause in-frame exon 20 skipping, confirmed in one patient. In silico 3D protein modeling suggested that exon 20 deletion (comprising 27 amino acids) likely alters the structural conformation between the RING&#95;CBP-p300 and HAT-KAT11 domains. Clinically, both patients displayed severe RSTS2-like clinical features, including autism spectrum disorder, speech delay, hearing loss, microcephaly, developmental delay, and intellectual disability, alongside ocular, respiratory, and cardiovascular abnormalities. Additionally, one patient developed early-onset colorectal cancer. DNA methylation profiling in Subject #1 confirmed RSTS but did not align with the specific episignatures for RSTS1 or RSTS2. We propose that skipping of exon 20 in EP300 is associated with a distinct form of Rubinstein-Taybi syndrome featuring clinical characteristics not fully aligning with RSTS1 or RSTS2. Our findings increase the understanding of RSTS genetic and molecular basis and stress the need for further research to establish definitive genotype-phenotype correlations., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

Published
2025
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45. Sexual dimorphism in SMAD3 pathogenic variant-harbouring individuals.

Author

Richer J, Velchev JD, Goobie S, Boswell-Patterson CA, van de Laar IMBH, Verhagen JMA, Wessels MW, Roos-Hesselink JW, Luyckx I, Al-Amodi H, Chu MWA, Laberge AM, Sadikovic B, Balci T, Verstraeten A, and Loeys B

Subjects
Humans, Female, Male, Adult, Middle Aged, Genetic Predisposition to Disease, Mutation, Missense genetics, Aged, Aortic Aneurysm, Thoracic genetics, Aortic Aneurysm, Thoracic pathology, Smad3 Protein genetics, Pedigree, Sex Characteristics
Abstract

Background: Individuals harbouring SMAD3 pathogenic variants are at risk for aneurysms/dissections throughout the arterial tree. Based on prior reports of sex differences in thoracic aortic aneurysm/dissection, we investigated the sexual dimorphism for vascular events in SMAD3- variant-harbouring patients., Methods: We analysed two large pedigrees comprising 84 individuals segregating pathogenic missense variants affecting the same p.Arg287 residue in SMAD3 . We excluded individuals<40 years without vascular involvement, as they were too young to be classified. Individuals were subcategorised according to sex, the presence or absence and localisation (aneurysm/dissection with or without involvement of the aortic root/ascending aorta) of vascular lesions. We complemented our familial patient cohort with 178 SMAD3 patients reported in the literature between 2011 and 2023., Results: In our two pedigrees, 11/30 (37%) variant-harbouring females had no vascular involvement, whereas none of the variant-harboring males (n=23) had no vascular involvement (p=0.001). While the two groups did not differ by age, males were at higher risk of vascular complications (p=0.037), there was no age difference between sexes. Of the 19 females with vascular involvement, six (32%) had vascular involvment sparing the aortic root/ascending aorta, whereas of the 23 males with vascular invovlement, only one (4%) had vascular involvement sparing the aortic root/ascending aorta (p=0.034). In the literature, we identified 116 male and 62 female additional patients. In the combined cohort of 220 patients, we demonstrated an over-representation of males (p<0.001) and non-penetrance in females for vascular pathology involving the aortic root/ascending aorta (p=0.028)., Conclusions: Non-penetrance is more common in women, and normal echocardiography in at-risk females is not as reassuring for risk of vasculopathy in other locations. The higher non-penetrance in women creates an ascertainment bias and results in an over-representation of male patients in the literature., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Published
2025
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46. SCN1A pathogenic variants do not have a distinctive blood-derived DNA methylation signature.

Author

LaFlamme CW, Karimi K, Rastin C, Almanza Fuerte EP, Allan T, Russ-Hall SJ, Schneider AL, Stobo D, Lesca G, Symonds JD, Brunklaus A, Sadleir LG, Scheffer IE, Sadikovic B, and Mefford HC

Abstract

DNA methylation signatures ("episignatures") can be used as biomarkers of genetic aberrations, clinical phenotypes, and environmental exposures in rare diseases. Episignatures are utilized in molecular diagnostics and can clarify variants of uncertain significance. A growing number of disease genes, including epilepsy genes, exhibit robust and reproducible episignatures. However, whether SCN1A, the most prominent epilepsy gene, has one or more episignatures has not yet been determined. We generated genome-wide DNA methylation data and performed episignature analysis on 64 individuals with Dravet syndrome due to pathogenic loss-of-function (LOF) variants in SCN1A and seven individuals with early infantile SCN1A developmental and epileptic encephalopathy due to pathogenic gain-of-function (GOF) variants in SCN1A, relative to a large reference database of controls and rare disease episignature-positive cohorts. We analyzed all samples with LOF variants together and performed separate analyses for missense, nonsense, and GOF variant cohorts. A reproducible blood-derived episignature was not evident in any of the cohorts using current analytical approaches and reference data., (© 2025 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2025
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47. Discovery of a DNA methylation profile in individuals with Sifrim-Hitz-Weiss syndrome.

Author

Karimi K, Lichtenstein Y, Reilly J, McConkey H, Relator R, Levy MA, Kerkhof J, Bouman A, Symonds JD, Ghoumid J, Smol T, Clarkson K, Drazba K, Louie RJ, Miranda V, McCann C, Motta J, Lancaster E, Sallevelt S, Sidlow R, Morrison J, Hannibal M, O'Shea J, Marin V, Prasad C, Patel C, Raskin S, Maria-Noelia SM, Diaz de Bustamante A, Marom D, Barkan T, Keren B, Poirsier C, Cohen L, Colin E, Gorman K, Gallant E, Menke LA, Valenzuela Palafoll I, Hauser N, Wentzensen IM, Rankin J, Turnpenny PD, Campeau PM, Balci TB, Tedder ML, Sadikovic B, and Weiss K

Subjects
Humans, Male, Female, Mutation, Missense, Heart Defects, Congenital genetics, Abnormalities, Multiple genetics, Hypogonadism genetics, Megalencephaly genetics, Adult, DNA Helicases genetics, Neurodevelopmental Disorders genetics, Child, Pedigree, DNA-Binding Proteins genetics, Adolescent, DNA Methylation
Abstract

Pathogenic heterozygous variants in CHD4 cause Sifrim-Hitz-Weiss syndrome, a neurodevelopmental disorder associated with brain anomalies, heart defects, macrocephaly, hypogonadism, and additional features with variable expressivity. Most individuals have non-recurrent missense variants, complicating variant interpretation. A few were reported with truncating variants, and their role in disease is unclear. DNA methylation episignatures have emerged as highly accurate diagnostic biomarkers in a growing number of rare diseases. We aimed to study evidence for the existence of a CHD4-related DNA methylation episignature. We collected blood DNA samples and/or clinical information from 39 individuals with CHD4 variants, including missense and truncating variants. Genomic DNA methylation analysis was performed on 28 samples. We identified a sensitive and specific DNA methylation episignature in samples with pathogenic missense variants within the ATPase/helicase domain. The same episignature was observed in a family with variable expressivity, a de novo variant near the PHD domain, variants of uncertain significance within the ATPase/helicase domain, and a sample with compound heterozygous variants. DNA methylation data revealed higher percentages of shared probes with BAFopathies, CHD8, and the terminal ADNP variants encoding a protein known to form the ChAHP complex with CHD4. Truncating variants, as well as a sample with a recurrent pathogenic missense variant, exhibited DNA methylation profiles distinct from the ATPase/helicase domain episignature. These DNA methylation differences, together with the distinct clinical features observed in those individuals, provide preliminary evidence for clinical and molecular sub-types in the CHD4-related disorder., Competing Interests: Declaration of interests B.S. is a shareholder in EpiSign, Inc., a company involved in commercial uses of EpiSign technology. I.M.W. is an employee of GeneDx, LLC., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2025
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48. Diagnosis of TET3-Related Beck-Fahrner Syndrome in an Individual With Chorioretinal and Iris Colobomata Using a DNA Methylation Signature.

Author

Man A, Di Scipio M, McConkey H, Hough R, Stein N, Diehl E, Marshall CR, Sadikovic B, and Ejaz R

Subjects
Humans, Male, Phenotype, Intellectual Disability genetics, Intellectual Disability diagnosis, Intellectual Disability pathology, Female, Developmental Disabilities genetics, Developmental Disabilities pathology, Developmental Disabilities diagnosis, DNA-Binding Proteins genetics, Epigenesis, Genetic genetics, Coloboma genetics, Coloboma diagnosis, Coloboma pathology, DNA Methylation genetics, Dioxygenases genetics
Abstract

Disorders of developmental delay can occur from pathogenic variants in genes responsible for epigenetic regulation. Heterozygous and biallelic pathogenic variants in TET3 have recently been described in TET3-related Beck-Fahrner syndrome (TET3-BEFAHRS), representing an autosomal dominant disorder with variable expressivity. Typical features include intellectual disability and developmental delay. Patients can also present with facial dysmorphism, seizure disorder, ophthalmic findings, and other neurobehavioral features. As the condition has recently been described and few patients have been reported in literature, the full scope of the phenotypic spectrum and approaches to identify them are still emerging. We report an individual meeting the criteria for TET3-BEFAHRS confirmed through clinical, genetic, and DNA methylation episignature analysis, who uniquely presents with bilateral chorioretinal and unilateral right iris colobomata. This case suggests a broader ophthalmic phenotype to TET3-BEFAHRS and demonstrates the utility of episignatures for the diagnosis of Mendelian disorders of epigenetic machinery., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Published
2025
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49. A novel KDM5C variant corrects a previously erroneous diagnosis.

Author

Chapin J, Sadikovic B, Kerkhof J, Schwartz CE, Stevenson RE, Skinner C, May M, Friez M, and Lebel RR

Abstract

Over two decades ago, a primigravid female presented with concern for recurrence of an adverse phenotype affecting her three brothers. The three brothers presented with intellectual disability, developmental delay, behavior problems and dysmorphic features. The screening tools available at the time revealed an FGD1 variant present in all three brothers, their mother being a carrier, absent in their unaffected uncle, and absent in the proband herself. This variant was hypothesized to be explanatory, but years later more advanced genetic screening showed that it was benign. Episign analysis revealed the true cause, a novel pathogenic KDM5C variant. This case study provides further insight into the KDM5C phenotype and demonstrates the importance of amending past errors as science evolves., (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Published
2025
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50. Validation of a hypomorphic variant in CDK13 as the cause of CHDFIDD with autosomal recessive inheritance through determination of an episignature.

Author

Fischer J, Alders M, Mannens MMAM, Genevieve D, Hackmann K, Schröck E, Sadikovic B, and Porrmann J

Subjects
Humans, Male, CDC2 Protein Kinase genetics, DNA Methylation genetics, Mutation, Missense, Genes, Recessive genetics, Developmental Disabilities genetics, Developmental Disabilities diagnosis, Intellectual Disability genetics, Heart Defects, Congenital genetics
Abstract

Autosomal dominant CDK13-related disease is characterized by congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD). Heterozygous pathogenic variants, particularly missense variants in the kinase domain, have previously been described as disease causing. Using the determination of a methylation pattern and comparison with an established episignature, we reveal the first hypomorphic variant in the kinase domain of CDK13, leading to a never before described autosomal recessive form of CHDFIDD in a boy with characteristic features. This highlights the utility of episignatures in variant interpretation, as well as a potential novel diagnostic approach in unsolved cases or for disease prognosis., Competing Interests: Declarations. Consent for publication: Consent for publication was obtained from all participants. Ethics approval and consent to participate: Ethics approval for the study was obtained through the local ethics committee at the Technical University Dresden (reference number: EK 273072018). Consent to participate in the study was obtained from all individuals or their legal guardian. Competing Interests: B.S. is an employee and shareholder of EpiSign, Inc., a biotech firm involved in commercial application of EpiSign technology., (© 2025. The Author(s).)

Published
2025
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