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.