ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000015.9) (NC_000015.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
27399968 Witteveen et al. (2016), report nine patients (from five families) with loss-of-function type variants (frameshift and nonsense) in SIN3A. The clinical features reported in these individuals included intellectual disability, developmental delay (speech and motor), structural brain anomalies, autism spectrum disorder, seizures, microcephaly, short stature, dysmorphic craniofacial features, hearing loss, digital anomalies, hypermobile joints, and additional clinical findings. The craniofacial findings included broad forehead, downslanting palpebral fissures, bilateral telecanthic/epicanthic folds, ear anomalies, small mouth, and a pointed chin. Parental testing identified that three of the five reported mutations were de novo. The two mutations that were inherited were identified in parents (one mother and one father) who were also clinically affected. The authors of this study also report four additional individuals with non-focal SIN3A whole gene deletions. These individuals presented with a similar clinical presentation to the patients with SIN3A loss-of-function type variants.
30267900 Narumi-Kishimoto et al. (2018), report a single individual with a frameshift variant (p.His283fs) in the in the SIN3A gene. The clinical features reported in this patient included intellectual disability, developmental delay (speech and motor), autism spectrum disorder, a long face, depressed nasal bridge, downslanting palpebral fissures, small hands, short 5th finger clinodactyly, hypermobile joints, and additional clinical findings. The identified frameshift mutation was not harbored by either parent, consistent with it representing a de novo event.

Haploinsufficiency phenotype comments:

At this time there is sufficient evidence to support a haploinsufficiency score of 3 for this gene. There have been at least six patients with loss-of-function type variants in SIN3A reported in the literature. These individuals presented with an overlapping clinical presentation that includes intellectual disability, developmental delay, structural brain anomalies, microcephaly, short stature, digital abnormalities, and dysmorphic craniofacial findings. The majority of the reported variants (4/6) represent de novo events, with the other variants (2/6) being inherited from affected parents.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

At this time there are no focal SIN3A duplications (involving just SIN3A) reported in the literature. Therefore, the triplosensitivity score for this gene is a 0.