Use of whole genome sequencing to determine the genetic basis of visceral myopathies including Prune Belly syndrome

• DOI: 10.1007/s44162-023-00012-z
• Publication Date: 2023-06-05T09:02:26Z
• Authors: Robert M. Geraghty; Sarah Orr; Eric Olinger; Ruxandra Neatu; Miguel Barroso-Gil; Holly Mabillard; Genomics England ...; Ian Wilson; John A. Sayer
• Keywords: 1000 Genomes Project

Abstract Objectives/aims The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle. They manifest in both the GI and GU tracts, ranging from megacystis to Prune Belly syndrome. We aimed apply bespoke virtual genetic panel describe novel variants associated with this condition using whole genome sequencing data within Genomics England 100,000 Genomes Project. Methods screened Project rare diseases database for patients VM-related phenotypes. These were sequence copy number (CNV) ACTG2 , ACTA2 MYH11 MYLK LMOD1 CHRM3 MYL9 FLNA KNCMA1 analysing data. identified analysed variant effect predictor online tool, any possible segregation other family members missense mutations was modelled silico tools. VM cohort also used perform genome-wide burden test order identify confirm gene associations cohort. Results 76 phenotypes consistent diagnosis VM. range presentations included megacystis/microcolon hypoperistalsis syndrome, syndrome chronic intestinal pseudo-obstruction. Of whom we heterozygous variants, 7 had likely pathogenic including 1 allele. There 4 uncertain significance which leads frameshift predicted protein elongation. one found KCNMA1 models be disease causing may explain phenotype seen. did not find CNV changes known genes leading In selected cohort, is largest monogenic cause accounting 9% supported approach, as contributor Conclusions that easily classified given different diagnostic labels depending on their phenotype. Molecular analysis these valuable it allows precise aids understanding underlying manifestations. most frequent recommend nomenclature change ‘autosomal dominant myopathy’ s .