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

Abstract

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.

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Item Type:	Article
Authors/Creators:	This paper has 39 authors. You can scroll the list below to see them all or them all. Balasubramanian, M. https://orcid.org/0000-0003-1488-3695 Dingemans, A.J.M. Albaba, S. Richardson, R. Yates, T.M. Cox, H. Douzgou, S. Armstrong, R. Sansbury, F.H. Burke, K.B. Fry, A.E. Ragge, N. Sharif, S. Foster, A. De Sandre-Giovannoli, A. Elouej, S. Vasudevan, P. Mansour, S. Wilson, K. Stewart, H. Heide, S. Nava, C. Keren, B. Demirdas, S. Brooks, A.S. Vincent, M. Isidor, B. Küry, S. Schouten, M. Leenders, E. Chung, W.K. Haeringen, A.V. Scheffner, T. Debray, F.-G. White, S.M. Palafoll, M.I.V. Pfundt, R. Newbury-Ecob, R. Kleefstra, T.
Copyright, Publisher and Additional Information:	© 2021 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 21 October 2020 Published (online): 12 January 2021 Published: April 2021
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	11 Feb 2021 14:38
Last Modified:	10 Feb 2022 14:35
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1038/s41431-020-00769-7
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:170091

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

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