SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

Al-Jawahiri R, Foroutan A, Kerkhof J, McConkey H, Levy M, Haghshenas S, Rooney K, Turner J, Shears D, Holder M, Lefroy H, Castle B, Reis LM, Semina EV, Lachlan K, Chandler K, Wright T, Clayton-Smith J, Hug FP, Pitteloud N, Bartoloni L, Hoffjan S, Park SM, Thankamony A, Lees M, Wakeling E, Naik S, Hanker B, Girisha KM, Agolini E, Giuseppe Z, Alban Z, Tessarech M, Keren B, Afenjar A, Zweier C, Reis A, Smol T, Tsurusaki Y, Nobuhiko O, Sekiguchi F, Tsuchida N, Matsumoto N, Kou I, Yonezawa Y, Ikegawa S, Callewaert B, Freeth M, Kleinendorst L, Donaldson A, Alders M, De Paepe A, Sadikovic B, McNeill A, Nickerson D, Bamshad M, Leal S, Ambrose JC, Arumugam P, Bevers R, Bleda M, Boardman-Pretty F, Boustred CR, Brittain H, Caulfield MJ, Chan GC, Elgar G, Fowler T, Giess A, Hamblin A, Henderson S, Hubbard TJ, Jackson R, Jones LJ, Kasperaviciute D, Kayikci M, Kousathanas A, Lahnstein L, Leigh SE, Leong IU, Lopez JF, FionaMaleady-Crowe , McEntagart M, Minneci F, Moutsianas L, Mueller M, Murugaesu N, Need AC, O'Donovan P, Odhams CA, Patch C, Pereira MB, Perez-Gil D, Pullinger J, TahrimaRahim , Rendon A, TimRogers , Savage K, Sawant K, Scott RH, Siddiq A, Sieghart A, Smith SC, Sosinsky A, Stuckey A, Tanguy M, Taylor Tavares AL, Thomas ER, Thompson SR, Tucci A, Welland MJ, Williams E, Witkowska K, Wood SM (2022)

Publication Type: Journal article

Publication year: 2022

Journal

DOI: 10.1016/j.gim.2022.02.013

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.

Involved external institutions

Western University Canada (CA) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) Switzerland (CH) Great Ormond Street Hospital (GOSH) United Kingdom (GB) Manchester University NHS Foundation Trust (MFT) United Kingdom (GB) Cambridge University Hospitals United Kingdom (GB) Ruhr-Universität Bochum (RUB) Germany (DE) Medical College of Wisconsin (MCW) United States (USA) (US) Osaka Women's and Children's Hospital / 大阪母子医療センター Japan (JP) Oxford University Hospitals NHS Foundation Trust United Kingdom (GB) University Hospital Southampton NHS United Kingdom (GB) Riken Institute of Physical and Chemical Research / 理研 Japan (JP) University of Sheffield United Kingdom (GB) Yokohama City University Japan (JP) University of Amsterdam Netherlands (NL) University Hospital Ghent Belgium (BE) Sagami Women's University Japan (JP) University Hospitals Bristol NHS Foundation Trust United Kingdom (GB) Royal Devon & Exeter NHS Foundation Trust United Kingdom (GB) Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille) France (FR) Fondazione Policlinico Universitario Agostino Gemelli IRCCS Italy (IT) Kasturba Medical College (KMC) India (IN) Inselspital, Universitätsspital Bern Switzerland (CH) Birmingham Women's and Children's NHS Foundation Trust United Kingdom (GB) Centre hospitalier universitaire (CHU) d'Angers France (FR) Ospedale Pediatrico Bambino Gesu Italy (IT) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Guy's and St Thomas' (NHS Foundation Trust) United Kingdom (GB) Newcastle University United Kingdom (GB)

How to cite

APA:

Al-Jawahiri, R., Foroutan, A., Kerkhof, J., McConkey, H., Levy, M., Haghshenas, S.,... Wood, S.M. (2022). SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile. Genetics in Medicine. https://dx.doi.org/10.1016/j.gim.2022.02.013

MLA:

Al-Jawahiri, Reem, et al. "SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile." Genetics in Medicine (2022).

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