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HEPACAM encodes GlialCAM, an adhesion protein required for proper localization of MLC1 in astrocytic junctions. Biallelic pathogenic variants in HEPACAM cause MLC2A, an autosomal recessive leukodystrophy characterised by early-onset macrocephaly, developmental delay, seizures, motor impairment, and characteristic subcortical cysts on MRI.
Genetic evidence for MLC2A includes 11 unrelated probands from 11 families with biallelic HEPACAM variants—comprising loss-of-function and missense alleles—and segregation of carrier status in parents ([PMID:21419380]). A recent case reporting a homozygous intragenic duplication of exons 3–4 further expands the variant spectrum in a 9-year-old male presenting with macrocephaly, dysarthria, spasticity, hyperreflexia, gait disturbance, global developmental delay, and seizures ([PMID:38280046]).
Inheritance is autosomal recessive, with no additional affected relatives beyond the index cases. The variant spectrum includes frameshift and nonsense mutations (e.g., c.513del (p.Asn172fs)), as well as missense alleles disrupting GlialCAM function. No recurrent founder variants have been reported in MLC2A.
Functional studies demonstrate that disease-causing HEPACAM mutations disrupt GlialCAM homo- and hetero-complex formation with MLC1, impair plasma membrane trafficking, and lead to white matter vacuolation. Mouse models harbouring GlialcamArg92Trp and GlialcamLys68Met/Thr132Asn recapitulate brain vacuolization in subcortical white matter, confirming pathogenicity and mechanism ([PMID:31372844]).
No conflicting studies have been reported. The concordance of clinical, genetic, and experimental data supports a strong gene-disease association for HEPACAM and MLC2A. HEPACAM testing informs diagnosis and genetic counselling in patients with leukodystrophy and macrocephaly.
Key Take-home: Biallelic HEPACAM variants cause autosomal recessive MLC2A through loss of GlialCAM trafficking and MLC1 mislocalization, guiding molecular diagnosis and family screening.
Gene–Disease AssociationStrong11 unrelated probands across 11 families with biallelic HEPACAM variants and concordant functional data Genetic EvidenceStrongAutosomal recessive inheritance with 11 probands carrying biallelic loss-of-function and missense variants; segregation in parents supports pathogenicity Functional EvidenceModerateCellular assays and mouse models demonstrate GlialCAM trafficking defects, disrupted MLC1–GlialCAM localization, and white matter vacuolation |