ALG13 – Non-Syndromic X-Linked Intellectual Disability

X-linked non-syndromic intellectual disability (NSXLID) is characterized by isolated cognitive impairment without additional dysmorphic or systemic features. In 2014, X-chromosome exome sequencing in a single pedigree with four affected male siblings revealed a novel hemizygous missense variant, p.Tyr1074Cys, in ALG13; all affected males were hemizygous and the mother was heterozygous for this variant (PMID:24501762). This segregation in an X-linked recessive pattern supports ALG13 as a candidate NSXLID gene, but no additional unrelated cases have been reported to date. Functional impacts of this variant on ALG13 enzymatic activity or N-glycosylation pathways remain uncharacterized. Although de novo ALG13 variants underlie early infantile epileptic encephalopathy and congenital disorders of glycosylation, mechanistic links specific to NSXLID are lacking. Further replication in independent NSXLID cohorts and in vitro or in vivo functional assays are essential to establish causality and inform diagnostic testing.

Key take-home: ALG13 hemizygous p.Tyr1074Cys is a limited evidence candidate for X-linked NSXLID, warranting further genetic and functional validation.

References

• American journal of medical genetics. Part A • 2014 • X chromosome exome sequencing reveals a novel ALG13 mutation in a nonsyndromic intellectual disability family with multiple affected male siblings. PMID:24501762

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