Expanding the ABCA2-associated neurodevelopmental phenotype.

The ATP-binding cassette subfamily A member 2 (ABCA2) gene encodes an ABC transporter protein. Bi-allelic loss-of-function variants in ABCA2 have been associated with an intellectual disability disorder. We aimed to delineate the phenotypic spectrum of individuals with monoallelic (MV) or bi-allelic (BV) variants in the ABCA2 gene. We collected clinical data via questionnaires and literature review. The ABCA2 protein was constructed using homology modeling. Untargeted plasma metabolomics was performed at Metabolon. A docetaxel toxicity cell culture model system was used to study the effects of plasmid-encoded ABCA2 and four ABCA2 variants (p.Asp615Glu [c.1845C>A], p.Phe754Ser [c.2261T>C], p.Ile786del [c.2356_2358del], and p.Arg926Trp [c.2776C>T]) on cell viability. Seventeen individuals with seventeen candidate ABCA2 variants were identified (seven MVs and ten BVs). Protein modeling predicted a likely significant impact for eight of 13 assessed variants. In cell viability assays, enforced expression of wild-type ABCA2 reduced viability in docetaxel-exposed cells. In contrast, none of the four variants affected viability, suggesting a loss or a marked reduction in transporter function. Untargeted metabolomics of three samples from two individuals showed a trend toward lower levels of polyunsaturated acylcarnitines. This study describes 17 individuals with candidate variants in the ABCA2 gene. The cell viability assays revealed that four variants (p.Asp615Glu, p.Phe754Ser, p.Ile786del, and p.Arg926Trp) had an altered ability to function as a transporter compared to wild-type ABCA2. Further studies are needed to clarify the pathomechanism of ABCA2 and the clinical significance of the variants.