Abstract
Purpose: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. Methods: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. Results: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. Conclusion: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.
| Original language | English |
|---|---|
| Pages (from-to) | 1261-1273 |
| Number of pages | 13 |
| Journal | Genetics in Medicine |
| Volume | 24 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 06-2022 |
All Science Journal Classification (ASJC) codes
- Genetics(clinical)
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In: Genetics in Medicine, Vol. 24, No. 6, 06.2022, p. 1261-1273.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile
AU - University of Washington Center for Mendelian Genomics (UW-CMG)
AU - Genomics England Research Consortium
AU - Al-Jawahiri, Reem
AU - Foroutan, Aidin
AU - Kerkhof, Jennifer
AU - McConkey, Haley
AU - Levy, Michael
AU - Haghshenas, Sadegheh
AU - Rooney, Kathleen
AU - Turner, Jasmin
AU - Shears, Debbie
AU - Holder, Muriel
AU - Lefroy, Henrietta
AU - Castle, Bruce
AU - Reis, Linda M.
AU - Semina, Elena V.
AU - Lachlan, Katherine
AU - Chandler, Kate
AU - Wright, Thomas
AU - Clayton-Smith, Jill
AU - Hug, Franziska Phan
AU - Pitteloud, Nelly
AU - Bartoloni, Lucia
AU - Hoffjan, Sabine
AU - Park, Soo Mi
AU - Thankamony, Ajay
AU - Lees, Melissa
AU - Wakeling, Emma
AU - Naik, Swati
AU - Hanker, Britta
AU - Girisha, Katta M.
AU - Agolini, Emanuele
AU - Giuseppe, Zampino
AU - Alban, Ziegler
AU - Tessarech, Marine
AU - Keren, Boris
AU - Afenjar, Alexandra
AU - Zweier, Christiane
AU - Reis, Andre
AU - Smol, Thomas
AU - Tsurusaki, Yoshinori
AU - Nobuhiko, Okamoto
AU - Sekiguchi, Futoshi
AU - Tsuchida, Naomi
AU - Matsumoto, Naomichi
AU - Kou, Ikuyo
AU - Yonezawa, Yoshiro
AU - Ikegawa, Shiro
AU - Callewaert, Bert
AU - Freeth, Megan
AU - Kleinendorst, Lotte
AU - Donaldson, Alan
N1 - Funding Information: We thank the families who kindly agreed to participate in this study. This work was supported by a grant from the Baily Thomas Charitable Foundation (TRUST/VC/AC/SG/5399-8436) (atypical neurogenesis) to M.F. and A.M. This work was supported by a grant from the Waterloo Foundation to A.M., AMED grants under grant numbers JP21ek0109486, JP21ek0109549, and JP21ek0109493 to N.M., and grant number JP21ek0109486 to S.I. In addition, funding for this study was provided, in part, by the London Health Sciences Molecular Diagnostics Development Fund and Genome Canada Genomic Applications Partnership Program Grant (Beyond Genomics: Assessing the Improvement in Diagnosis of Rare Diseases using Clinical Epigenomics in Canada, EpiSign-CAN). Sequencing for case 29 was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by National Human Genome Research Institute and National Heart, Lung, and Blood Institute grants UM1 HG006493 and U24 HG008956, by the Office of the Director, and National Institutes of Health (NIH) grants under award number S10OD021553 as well as NIH grant number R01EY025718 to E.V.S. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funding Information: We thank the families who kindly agreed to participate in this study. This work was supported by a grant from the Baily Thomas Charitable Foundation (TRUST/VC/AC/SG/5399-8436) (atypical neurogenesis) to M.F. and A.M. This work was supported by a grant from the Waterloo Foundation to A.M. AMED grants under grant numbers JP21ek0109486, JP21ek0109549, and JP21ek0109493 to N.M. and grant number JP21ek0109486 to S.I. In addition, funding for this study was provided, in part, by the London Health Sciences Molecular Diagnostics Development Fund and Genome Canada Genomic Applications Partnership Program Grant (Beyond Genomics: Assessing the Improvement in Diagnosis of Rare Diseases using Clinical Epigenomics in Canada, EpiSign-CAN). Sequencing for case 29 was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by National Human Genome Research Institute and National Heart, Lung, and Blood Institute grants UM1 HG006493 and U24 HG008956, by the Office of the Director, and National Institutes of Health (NIH) grants under award number S10OD021553 as well as NIH grant number R01EY025718 to E.V.S. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and National Health Service England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. We thank Dr Michela Adamo for help with obtaining clinical data on one of the reproted cases. Conceptualization: A.M.; B.S.; Data Curation: A.M.; Formal Analysis: A.M. B.S. A.F. J.T.; Investigation: R.A.-J. D.S. M.H. H.L. L.M.R. K.L. K.C. N.P. S.H. S.-M.P. M.L. E.W. S.N. B.H. F.S. K.M.G. E.A. Z.A. B.K. C.Z. M.T. T.S. S.I. B.S. E.V.S. B.S. A.M.; Writing-original draft: A.M. A.F. J.T.; Writing-review and editing: A.M. B.S. M.H. D.S. M.F. L.M.R. E.V.S. B.C. A relative or carer gave written consent for publication of clinical details and photographs of the participants in this study. Exome sequencing in the Deciphering Developmental Disorders study has United Kingdom Research Ethics Committee (REC) approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). Genome sequencing undertaken in the 100,000 Genomes Project has approval from the East of England—Cambridge South REC (REC Ref 14/EE/1112). The Human Developmental Brain Resources has approval from the North East—Newcastle and North Tyneside 1 REC (18/NE/0290). The study was approved by the Western University Research Ethics Board (REB 106302 and 116108). Funding Information: This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and National Health Service England . The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. We thank Dr Michela Adamo for help with obtaining clinical data on one of the reproted cases. Publisher Copyright: © 2022 The Authors
PY - 2022/6
Y1 - 2022/6
N2 - Purpose: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. Methods: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. Results: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. Conclusion: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.
AB - Purpose: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. Methods: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. Results: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. Conclusion: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.
UR - http://www.scopus.com/inward/record.url?scp=85127338633&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127338633&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2022.02.013
DO - 10.1016/j.gim.2022.02.013
M3 - Article
C2 - 35341651
AN - SCOPUS:85127338633
SN - 1098-3600
VL - 24
SP - 1261
EP - 1273
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 6
ER -