PABPN1 pathogenic expansion in the UK Biobank: reframing genetic prevalence of oculopharyngeal muscular dystrophy

Background Oculopharyngeal muscular dystrophy (OPMD) is a rare, late-onset, mostly autosomal dominant muscular dystrophy caused by a trinucleotide GCN repeat expansion in PABPN1 . OPMD affects approximately 1:100 000 individuals in Europe, with substantially higher prevalence in specific founder populations. Pathogenic alleles encoding 12–18 alanine residues within the first exon show dosage effect, incomplete dominance and expression variability. The (GCN)11 allele has a prevalence of 1%–2% in the European population and is considered pathogenic in homozygosity. Conversely, heterozygous carriers might display mild, late-onset phenotypes, suggesting reduced penetrance. Methods We investigated whole exome sequencing data from 470 000 individuals in the UK Biobank cohort, by extracting PABPN1 rare (Minor Allele Frequency (MAF) < 0.001) coding (NM_004643.3) variants and focusing on the polyalanine tract. Demographic data and neuromuscular International Classification of Diseases, Tenth Revision (ICD-10) codes were collected. Results We identified 46 individuals with a genotype compatible with OPMD: 35 with a (GCN)12 genotype, 10 with a (GCN)13 genotype and 1 with a homozygous (GCN)11 genotype. In addition, 1896 individuals were heterozygous carriers of the (GCN)11 allele. The majority of (GCN)11 carriers did not present OPMD-compatible diagnostic codes, while OPMD-compatible diagnostic codes occurred in 11.4% of (GCN)12 carriers and rose to 70% of (GCN)13 carriers, showing a positive correlation between polyalanine tract length and clinical expression. Conclusions The cumulative genetic prevalence of pathogenic expansion was 1:10 200, 10 times higher than the estimated clinical prevalence. This analysis is relevant in the context of emerging therapeutic strategies targeting the PABPN1 polyalanine expansion.