Submission Details

Heterozygous loss of SIN3A was first highlighted in relation to syndromic intellectual disability in 2016 (PMID: 27399968). This study identified 4 individuals with de novo heterozygous 15q24 deletions associated with intellectual disability and dysmorphic facial features. The smallest region of overlap of the deletions was about 200 kb and included the SIN3A gene. Additionally, 8 individuals with SIN3A loss of function variants (frameshift and nonsense) were identified. Affected individuals with SIN3A-related intellectual disability syndrome or Witteveen-Kolk syndrome typically present with characteristic distinctive facial features, microcephaly, short stature, and mildly impaired intellectual development with delayed cognitive and motor development and subtle anomalies on MRI-brain imaging. To date, at least 27 de novo unique variants including frameshift, nonsense and missense variants have been reported (PMIDs: 33437032, 36158056). This gene is intolerant to truncating variants, as indicated by its pLI score of 1 in gnomAD (v2.1.1). This gene-disease relationship is supported by studies in mouse models with gene knockdown showing reduction of cortical progenitor neurons, change in neuronal identity, and aberrant corticocortical projections with abnormal axon elongation (PMID: 27399968). In summary, SIN3A is definitively associated with SIN3A-related intellectual disability syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel Expert Panel on 01/19/2022 (SOP Version 9).