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.

Fig. 1. Characteristic facial appearance of patients with variants in SIN3A.

Note the high forehead, small, pointed chin and down-slanting palpebral fissures. A: Patient 1, B Patient 2, C Patient 4, D Patient 5, E Patient 9, F Patient 11, G Patient 12, H Patient 13, I Patient 16, J Patient 18, K Patient 25, L Patient 27, M Patient 28.

Fig. 2. Schematic SIN3A protein structure and variant location.

ITD: intragenic deletion; Plot of variants done using St. Jude Cloud protein paint (https://pecan.stjude.cloud/proteinpaint).

Fig. 3. 3D model to demonstrate predicted consequences of SIN3A missense variant in our cohort.

This 3D-model is based on the solution structure of mouse Sin3A PAH1 bound to the Sin3 interaction domain (SID) of SAP25 (Sin3A Associated Protein 25) displayed using UCSF Chimera v1.14 (Pattersen et al. 2004). The PAH1 domain of Sin3A (residues 119-189; sphere model, light grey) with residues Ala126 (red) and Lys155 (blue) highlighted. The SAP25 protein SID domain (residues 126-186; ball and stick model, dark grey) binds in the fold formed by the four helices of Sin3A PAH1. Sin3A Lys155 is predicted to form a 2.2A hydrogen bond with the polar side chain of Gln143 of SAP25 (orange line).