SGSM3 – Neurodevelopmental Disorder with Intellectual Disability

SGSM3 (small G protein signalling modulator 3) is a member of the RAS superfamily, which includes established contributors to neurodevelopmental disorders (PMID:37833060). The gene encodes a modulator of RAP and RAB GTPases, suggesting a role in neuronal signalling pathways. No prior reports had linked SGSM3 to human disease until recently.

A multi-center exome sequencing study identified a homozygous frameshift variant in SGSM3 in 13 patients from 8 unrelated Ashkenazi Jewish families (PMID:37833060). All affected individuals harboured the same c.???del (p.?) loss-of-function allele, establishing a clear founder effect. Variant confirmation was achieved by Sanger sequencing across all probands.

Inheritance is autosomal recessive, with complete co-segregation of the variant in all available family members (PMID:37833060). Unaffected parents were obligate carriers, and no phenotypes were reported in heterozygous relatives.

Affected individuals presented with mild global developmental delay (HP:0011342), mild to moderate intellectual disability, hypotonia (HP:0001252), short stature (HP:0004322) and behavioural challenges (PMID:37833060). There was no evidence of additional organ system involvement.

Genetic evidence is strong, with 13 homozygous probands from 8 families and full segregation. The variant spectrum is presently limited to a single recurrent loss-of-function allele. No other variant classes or deep-intronic alleles have been reported.

Functional assays for SGSM3 LoF are lacking. A targeted sequencing study of schwannomatosis candidate genes, including SGSM3, found no pathogenic alleles and did not perform in vitro or in vivo modelling for SGSM3 (PMID:34747535). The mechanism is inferred to be haploinsufficiency or complete loss of function.

Integration of genetic and limited experimental data supports a strong association between SGSM3 loss-of-function and autosomal recessive neurodevelopmental disorder. Additional functional studies are needed to elucidate molecular mechanisms. Key take-home: SGSM3 homozygous loss-of-function variants cause a consistent syndromic neurodevelopmental phenotype, warranting inclusion in diagnostic gene panels.

References

• Journal of medical genetics • 2024 • Intellectual disability syndrome associated with a homozygous founder variant in SGSM3 in Ashkenazi Jews. PMID:37833060
• Human mutation • 2022 • Targeted massively parallel sequencing of candidate regions on chromosome 22q predisposing to multiple schwannomas: An analysis of 51 individuals in a single-center experience. PMID:34747535

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