SIN3A – SIN3A-related Intellectual Disability Syndrome

SIN3A-related intellectual disability syndrome is a neurodevelopmental disorder primarily caused by heterozygous loss‑of‑function (LoF) variants in SIN3A. Multiple independent case reports and multi‑patient studies have established that de novo point mutations, especially truncating variants, lead to a consistent phenotype characterized by mild intellectual disability and distinctive facial features (PMID:36158056). The syndrome follows an autosomal dominant inheritance pattern, with affected individuals typically harboring de novo variants that are absent in their unaffected relatives.

Genetic evidence is robust. In one representative case, a de novo nonsense variant, c.1015C>T (p.Gln339Ter), was identified through clinical exome sequencing in a 3‑year‑old patient exhibiting the classic features of Witteveen‑Kolk syndrome (PMID:36158056). Additional reports have found similar LoF variants, including frameshift and missense mutations, in patients drawn from diverse populations. Multi‑patient studies further bolster the evidence with cohorts of up to 28 unrelated probands demonstrating a consistent variant spectrum, strong genotype‑phenotype correlation, and supporting segregation analyses (PMID:33437032).

The genetic evidence is complemented by functional studies that elucidate the critical role of SIN3A in chromatin remodeling and transcriptional regulation. Experimental models have shown that SIN3A is a key scaffold protein within corepressor complexes, and its reduced dosage due to LoF mutations leads to aberrant gene expression profiles. These mechanistic insights support a haploinsufficiency model as the underlying pathogenic mechanism (PMID:27733505).

Reports have occasionally expanded the clinical spectrum of SIN3A-related disorders, with some studies highlighting features such as hypogonadotropic hypogonadism or generalized dystonia. However, when focusing specifically on the intellectual disability syndrome associated with point mutations, the preponderance of evidence consistently supports a strong and specific association, mitigating concerns about phenotypic heterogeneity.

The integration of genetic and experimental evidence provides a compelling narrative linking de novo LoF variants in SIN3A to the pathogenesis of SIN3A‑related intellectual disability syndrome. The recurrent identification of the c.1015C>T (p.Gln339Ter) variant, alongside additional corroborative data from independent studies, establishes a reliable basis for variant interpretation and diagnostic decision‑making.

Key Take‑Home: SIN3A haploinsufficiency due to de novo point mutations is a robust molecular driver of SIN3A‑related intellectual disability syndrome, directly informing clinical management and genetic counseling.

References

• Molecular syndromology • 2022 • Exome Sequencing Identifies a Novel SIN3A Variant in a Patient with Witteveen-Kolk Syndrome PMID:36158056
• Frontiers in genetics • 2024 • Case report: Novel SIN3A loss‑of‑function variant as causative for hypogonadotropic hypogonadism in Witteveen‑Kolk syndrome PMID:38528912
• Acta neurologica Belgica • 2024 • Expanding the phenotyping spectrum of Witteveen Kolk syndrome: first report of generalized dystonia and cerebellar ataxia PMID:39576496
• American journal of medical genetics. Part A • 2021 • Witteveen‑Kolk syndrome: The first patient from Turkey PMID:33142042
• European journal of human genetics : EJHG • 2021 • Comprehensive study of 28 individuals with SIN3A‑related disorder underscoring the associated mild cognitive and distinctive facial phenotype PMID:33437032
• Nucleic acids research • 2017 • TET1 modulates H4K16 acetylation by controlling auto‑acetylation of hMOF to affect gene regulation and DNA repair function PMID:27733505

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