ABCA2 – Intellectual developmental disorder with poor growth and with or without seizures or ataxia

Biallelic loss-of-function variants in the ATP binding cassette transporter gene ABCA2 cause an autosomal recessive neurodevelopmental syndrome characterized by intellectual disability, growth delay, seizures, and ataxia. Three affected individuals from two families have been reported: a 28-year-old Korean female with compound heterozygous intronic and nonsense variants and two consanguineous Pakistani siblings with a homozygous frameshift variant. Segregation analysis confirmed the frameshift variant in both affected siblings and heterozygous carrier status in their parents.

Genetic evidence includes one proband with compound heterozygous ABCA2 variants (c.5300-17C>A; c.6379C>T) and two siblings homozygous for c.4993del (p.Val1665TrpfsTer36), all absent from population databases (gnomAD) (PMID:38228874)(PMID:31047799). Segregation of c.4993del with ataxia and dysarthria in two affected relatives supports pathogenicity (affected_relatives=2).

The variant spectrum comprises an intronic splice-altering change (c.5300-17C>A) and truncating alleles including nonsense (c.6379C>T) and frameshift (c.4993del (p.Val1665TrpfsTer36)). No recurrent or founder alleles have been described to date.

Functional assays demonstrate that c.5300-17C>A activates a cryptic acceptor site with aberrant transcripts confirmed by RT-PCR in patient lymphoblasts, consistent with loss of ABCA2 function (PMID:38228874). A mouse knockout model recapitulates the human ataxic phenotype, supporting a loss-of-function mechanism (PMID:31047799).

No studies have disputed the association. Independent isoform characterization has not revealed dominant-negative effects, indicating haploinsufficiency or null alleles underlie disease.

Taken together, genetic segregation, absence from controls, and concordant functional data support a strong gene-disease association. Key take-home: ABCA2 biallelic truncating and splice variants reliably underlie this autosomal recessive neurodevelopmental disorder, informing molecular diagnosis and genetic counseling.

References

• Journal of human genetics • 2024 • Novel compound heterozygous ABCA2 variants cause IDPOGSA, a variable phenotypic syndrome with intellectual disability. [PMID:38228874]
• Parkinsonism & related disorders • 2019 • Ataxia and dysarthria due to an ABCA2 variant: Extension of the phenotypic spectrum. [PMID:31047799]

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