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

Abstract

Witteveen-Kolk syndrome (WITKOS; OMIM #613406) is a recently described, rare neurodevelopmental syndrome characterized by mild intellectual disability and a recognizable facial gestalt. WITKOS is caused by heterozygous loss-of-function variants in &lt;i&gt;SIN3A&lt;/i&gt;. It shares some features with 15q24 deletion syndrome but to date has only been described in a limited number of patients mostly of Northern European ancestry. Here, we report the first patient with Hispanic ancestry to our knowledge diagnosed with WITKOS, who has a novel, truncating variant in the &lt;i&gt;SIN3A&lt;/i&gt; gene. Clinical exome sequencing performed in-house using a custom bioinformatics pipeline identified a de novo heterozygous, nonsense variant in &lt;i&gt;SIN3A&lt;/i&gt;, c.1015C&amp;#x3e;T (p.Gln339Ter) that has not been previously described in the literature. This 3-year-old boy with WITKOS demonstrated classic features including mild developmental delay and triangular facies with hypotelorism and deep-set, hooded eyes. This patient supports the currently described phenotype for WITKOS in more diverse populations.

A Witteveen-Kolk Syndrome Patient with Reflux Disease and a de novo Deletion of the SIN3A Gene

“…We summarize the clinical features of all previously reported patients with WITKOS in Table 1. According to this review, most common clinical manifestations of WITKOS were DD (75%), dysmorphic facial features (97%), microcephaly (55%), short stature (30%), hypotonia (49%), behavioral problems (52%), epilepsy (18%), ectodermal differences (25%), brain abnormalities (38%), and cardiac abnormalities (40%) (Table 1) [1,5,6,[9][10][11][12][13]. Consistent with these reports, our patient showed DD, microcephaly, short stature, autistic behavior, and hypotonia but not epilepsy nor ectodermal anomalies.…”