ABCA13 – Schizophrenia

Schizophrenia is a complex neuropsychiatric disorder with high heritability and heterogeneous genetic architecture. The ATP-binding cassette transporter gene ABCA13 has been implicated through rare coding variants and familial linkage studies as a susceptibility locus for schizophrenia. Initial disruption of ABCA13 by a chromosomal abnormality in a schizophrenia patient led to exon resequencing in 100 unrelated cases and 100 controls, revealing one nonsense and nine missense mutations enriched in cases (OR = 1.93, p = 0.0057) (PMID:19944402).

Compound heterozygosity or homozygosity for these rare variants was observed in six probands, suggesting an autosomal recessive contribution to disease risk. In a cohort of over 1 600 schizophrenia cases and 950 controls, the collective frequency of rare ABCA13 variants was significantly higher in affected individuals (PMID:19944402). Family linkage analysis across 21 pedigrees demonstrated significant co-segregation of rare alleles with a spectrum of psychiatric phenotypes (LOD 4.3) (PMID:19944402).

Further support comes from two multiplex families with dominant transmission of schizophrenia and bipolar disorder: in one family, an ABCA13 missense variant c.13662G>T (p.Met4554Ile) co-segregated with disease across three generations; in a second family, the same variant was observed in affected siblings (PMID:34947986). This variant represents a recurring allele in independent pedigrees, underscoring its potential pathogenicity.

The inheritance pattern for ABCA13-related schizophrenia appears mixed, with evidence for autosomal recessive compound heterozygosity and autosomal dominant segregation of specific missense alleles. The variant spectrum includes at least one protein-truncating and multiple deleterious missense changes; the most compelling recurrent allele is c.13662G>T (p.Met4554Ile). No direct functional assays of ABCA13 variants in neuronal or model systems have been reported to date.

Integrating genetic data, ABCA13 meets criteria for a strong gene-disease association: significant case-control enrichment, multi-family linkage, and segregation of rare coding alleles. Additional functional characterization is needed to elucidate the mechanistic role of ABCA13 in neural lipid transport and synaptic function. Key take-home: ABCA13 should be considered in genetic testing panels for schizophrenia, particularly in families with multiple affected members.

References

• American Journal of Human Genetics • 2009 • A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. PMID:19944402
• International Journal of Molecular Sciences • 2021 • Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder. PMID:34947986

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