Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Meena Balasubramanian*, Alexander J.M. Dingemans, Shadi Albaba, Ruth Richardson, Thabo M. Yates, Helen Cox, Sofia Douzgou, Ruth Armstrong, Francis H. Sansbury, Katherine B. Burke, Andrew E. Fry, Nicola Ragge, Saba Sharif, Alison Foster, Annachiara De Sandre-Giovannoli, Sahar Elouej, Pradeep Vasudevan, Sahar Mansour, Kate Wilson, Helen StewartSolveig Heide, Caroline Nava, Boris Keren, Serwet Demirdas, Alice S. Brooks, Marie Vincent, Bertrand Isidor, Sebastien Küry, Meyke Schouten, Erika Leenders, Wendy K. Chung, Arie van Haeringen, Thomas Scheffner, Francois Guillaume Debray, Susan M. White, Maria Irene Valenzuela Palafoll, Rolph Pfundt, Ruth Newbury-Ecob, Tjitske Kleefstra

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)
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Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12.

Original languageEnglish
Pages (from-to)625-636
Number of pages12
JournalEuropean Journal of Human Genetics
Issue number4
Publication statusPublished - 12 Jan 2021

Bibliographical note

Acknowledgements: We are grateful to the patients and their families for their cooperation. This study makes use of data generated by the DECIPHER Consortium. A full list of centres who contributed to the generation of the data is available from and via email from Funding for the project was provided by the Wellcome Trust and by grants from the Netherlands Organization for Health Research and Development (ZonMw grant 91718310 and the Dutch Scientific Organization (NWO, grant NWA 1160.18.320). WKC is supported by grants from SFARI and the JPB Foundation

Funding Information:
DDD statement The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number

Publisher Copyright: © 2021, The Author(s).


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