Curation OPDM5 ABCD3

PMID:39068203 reported 35 affected individuals from eight unrelated OPDM families of European ancestry, with detailed clinical findings for 24 individuals; ABCD3 5′-UTR CCG expansions were identified across families using srWGS/EHdn, RP-PCR, optical genome mapping, and/or targeted ONT long-read sequencing.

Targeted ONT long-read sequencing showed heterozygous pure ABCD3 5′-UTR CCG expansions of 118–694 repeats in 19 affected individuals, while unaffected relatives had two 7-repeat alleles; larger expansions correlated with earlier onset in affected males (n=6, p=0.0063), and female expansions were larger and more variable than male expansions (p=0.0295).

Combined linkage analysis in AUS1 and AUS2 produced a maximum multipoint LOD score of 2.98 across a 24 Mb region containing ABCD3; the expansion segregated in UK2 (affected sister positive, unaffected mother negative), and affected individuals shared a 560 kb ancestral haplotype encompassing ABCD3.

RNA-seq and qPCR showed increased ABCD3 transcript in OPDM skeletal muscle compared with neuromuscular disease and healthy controls; HCR RNA-FISH showed increased cytoplasmic and intranuclear ABCD3 sense transcript signal, including nuclear foci-like clusters, in patient fibroblasts and muscle.

Patient-derived skin and fibroblast samples from ABCD3 expansion carriers showed rare p62-positive intranuclear inclusions, including in nuclei of skin exocrine glands, keratinocytes, and fibroblasts, and ultra-rare inclusions (<0.1%) in primary skin fibroblasts from AUS3-IV:3; these were absent or less prominent in controls.