Complete genetic and epigenetic architecture of D4Z4 macrosatellites in FSHD, BAMS, and reference cohorts with D4Z4End2End - PubMed

3 hours ago

The D4Z4 locus is a macrosatellite array on Chromosome 4q, typically consisting of 8 to over 100 3.3-kb repeat units.
Current FSHD molecular testing is complex and low-resolution, relying on identifying contractions on permissive haplotypes (FSHD type 1) or epigenetic reactivation due to pathogenic variants (FSHD type 2).
The study introduces D4Z4End2End, a workflow leveraging ultra-long whole-genome and Cas9-targeted sequencing for comprehensive genetic and methylation analysis of D4Z4 alleles.
The method was applied to samples from controls, FSHD1 and FSHD2 patients, and Bosma arhinia microphthalmia syndrome (BAMS) patients, as well as publicly available data.
High-depth sequencing achieved full-length D4Z4 arrays of up to 40 repeat units (~132 kb), accurately capturing contracted arrays, genetic mosaicism, and pathogenic SMCHD1 variants.
New allelic variants were identified, complex D4Z4 rearrangements analyzed, and length- and SMCHD1-dependent methylation patterns revealed.
The findings provide insights into D4Z4 genetics and epigenetics, showcasing the potential of long-read nanopore sequencing for FSHD research and diagnostics.

Hasty Briefsbeta