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.

Exome Sequencing Identifies a Novel <b><i>SIN3A</i></b> Variant in a Patient with Witteveen-Kolk Syndrome

“…Our analysis of the clinical features presented in cases described to date suggest that the most common findings of WITKOS are developmental differences, which can be mild as found in this child, characteristic non-familial features, and behavioral differences in agreement with findings from Balasubramanian et al [2021] (Table 1). To our knowledge, intrauterine growth restriction and polyhydramnios have not been described in other patients with WITKOS.…”

“…Predominantly truncating variants have been ascribed to individuals with WITKOS, yet missense and splice site variants have also been described. Missense variants were predicted to be likely pathogenic given they occurred de novo, were located in a critical functional domain, were absent from controls, and showed deleterious predictions in silico [Balasubramanian et al, 2021]. SIN3A is an important regulator of mammalian cerebral cortex development.…”

“…To date, less than 50 individuals with WITKOS have been published in the medical literature [Witteveen et al, 2016;Ferrer et al, 2019;Narumi-Kishimoto et al, 2019;Balasubramanian et al, 2021;Ercoskun and Yuce Kahraman, 2021]. Herein, we a report the first patient with Hispanic-Caucasian ancestry affected by WITKOS with a novel truncating variant in the SIN3A gene.…”

“…WITKOS is caused by switch-insensitive 3 family member A (SIN3A) haploinsufficiency which is thought to lead to aberrant cortical neurogenesis, as demonstrated by the decrease in cortical progenitors observed in the Sin3a mouse model [Witteveen et al, 2016]. The causal role of haploinsufficiency for SIN3A is supported by the significant clinical overlap between the phenotypes of WITKOS and of patients with de novo, atypical chromosome 15q24 deletion syndrome [Mefford et al, 2012;Witteveen et al, 2016;Narumi-Kishimoto et al, 2019;Balasubramanian et al, 2021].…”

DECIPHER: Supporting the interpretation and sharing of rare disease phenotype‐linked variant data to advance diagnosis and research

“…The genotype‐linked phenotypic data allows, for example, new variant‐disease associations to be discovered, such as loss‐of‐function variants in ARFGEF1 causing developmental delay and epilepsy (Thomas et al, 2021 ). The data set also enables the extension of phenotypes for new syndromes to be uncovered (e.g., Witteveen–Kolk syndrome a SIN3A ‐related disorder; Balasubramanian et al, 2021 ), in addition to well‐established syndromes (e.g., ALG13 congenital disorder of glycosylation; Alsharhan et al, 2021 ). It also permits the understanding of contiguous gene effects, such as that around ERF which causes a novel craniosynostosis syndrome with varying degrees of intellectual disability (Calpena et al, 2021 ).…”