SET – Intellectual Disability

The SET nuclear proto-oncogene encodes an inhibitor of histone acetyltransferases complex component critical for chromatin remodeling. Disruptive heterozygous variants have been implicated in autosomal dominant intellectual disability. Genetic and functional data converge to support a strong gene–disease association.

In a cohort of four unrelated patients and one mother–child pair with nonsyndromic intellectual disability, whole-exome sequencing identified de novo missense and frameshift variants in SET, with an additional four cases reported in the literature (total 8 probands) ([PMID:29688601]). A subsequent study described two unrelated Chinese patients with moderate intellectual disability harboring novel heterozygous SET variants (2 probands) ([PMID:37737486]). Overall, 10 probands have been documented with pathogenic SET variants.

Segregation analysis includes one familial transmission (affected mother and child) confirming co-segregation of a frameshift variant (SET c.650_651dup (p.Gln218fs)) within a nuclear proto-oncogene family ([PMID:29688601]). This provides additional support for an autosomal dominant inheritance model with one affected relative beyond the index cases.

The variant spectrum comprises missense (e.g., c.244T>G (p.Trp82Gly)), frameshift (c.650_651dup (p.Gln218fs), c.130_133del (p.Arg44fs)), and splice-region (c.532-3>A) changes, all predicted to disrupt SET’s protein-interaction domains. Loss-of-function alleles are exceedingly rare in population databases, consistent with a haploinsufficiency mechanism.

Functional studies demonstrate that SET is indispensable for neurogenesis: in vitro knockdown and animal models recapitulate neuronal differentiation defects and abnormal chromosome condensation, concordant with human cognitive impairment ([PMID:29688601]). These experiments underscore a loss-of-function mechanism leading to impaired chromatin modulation during brain development.

Integrating genetic and experimental findings, heterozygous pathogenic SET variants cause autosomal dominant intellectual disability via haploinsufficiency, supported by multiple unrelated de novo cases, familial segregation, and mechanistic concordance. This evidence reaches a Strong ClinGen classification. Key Take-home: SET haploinsufficiency is a clinically actionable cause of autosomal dominant intellectual disability.

References

• Human mutation • 2018 • De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability PMID:29688601
• Journal of human genetics • 2023 • Whole exome sequencing and transcriptome analysis in two unrelated patients with novel SET mutations PMID:37737486

Evidence Based Scoring (AI generated)