GEMIN4 – Neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities

GEMIN4 encodes a component of the survival motor neuron complex involved in snRNP assembly. Biallelic pathogenic variants in GEMIN4 underlie an autosomal recessive neurodevelopmental disorder characterized by severe microcephaly, congenital cataracts, global developmental delay, and renal anomalies (MONDO:0060664).

Whole-exome sequencing identified a homozygous missense variant, c.440A>G (p.His147Arg), in two affected siblings from a consanguineous Saudi family presenting with profound microcephaly, early-onset epilepsy, spastic quadriplegia, and bilateral cataracts (PMID:35052432). A subsequent retrospective review of 16 patients from 11 unrelated consanguineous families confirmed only two distinct homozygous missense variants in GEMIN4, consistent with a founder effect, and delineated a homogeneous phenotype of global developmental delay, cataracts, and renal involvement (PMID:35861185).

Inheritance is autosomal recessive based on segregation of homozygous GEMIN4 variants in multiple pedigrees, with segregation confirmed in affected siblings and extended family members ([PMID:35052432], [PMID:35861185]). A total of 11 unrelated probands and 5 additional affected relatives were documented with segregating pathogenic variants across these families.

Functional evidence supports a loss-of-function mechanism: in silico modeling predicts destabilization of Gemin4 by p.His147Arg ([PMID:35052432]), and neuron-specific knockdown of Drosophila Gemin4 recapitulates developmental defects and motor dysfunction analogous to patient phenotypes ([PMID:35861185]). These findings align with GEMIN4’s essential role in snRNP-mediated RNA splicing during neurodevelopment.

No conflicting evidence has been reported. The consistency of clinical features, robust segregation data, and concordant experimental modeling provide strong support for this gene–disease association.

Key Take-home: Biallelic GEMIN4 pathogenic variants cause a clinically distinctive autosomal recessive neurodevelopmental syndrome with microcephaly and cataracts; genetic testing enables definitive diagnosis, and functional models offer insight for future therapeutic strategies.

References

• Genes • 2021 • A Novel GEMIN4 Variant in a Consanguineous Family Leads to Neurodevelopmental Impairment with Severe Microcephaly, Spastic Quadriplegia, Epilepsy, and Cataracts PMID:35052432
• American journal of medical genetics. Part A • 2022 • Further delineation of GEMIN4 related neurodevelopmental disorder with microcephaly, cataract, and renal abnormalities syndrome PMID:35861185

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