Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy
Richard J L F Lemmers1, Russell Butterfield2, Patrick J van der Vliet1
1Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
Brain : a Journal of Neurology
|September 13, 2023
Summary
Facioscapulohumeral muscular dystrophy (FSHD) involves D4Z4 repeat array changes causing DUX4 expression. In cis duplications are common, and specific repeat sizes determine their pathogenicity, aiding diagnosis.
Area of Science:
- Genetics
- Molecular Biology
- Epigenetics
Background:
- Facioscapulohumeral muscular dystrophy (FSHD) arises from D4Z4 macrosatellite repeat array alterations.
- This leads to D4Z4 chromatin relaxation and inappropriate DUX4 transcription factor expression in skeletal muscle.
Purpose of the Study:
- To investigate the pathogenic nature of D4Z4 in cis duplication alleles in FSHD.
- To compare these alleles in patients with and without SMCHD1 variants.
Main Methods:
- Pulsed-field gel electrophoresis-based Southern blotting and molecular combing.
- Nanopore sequencing for array composition, methylation, breakpoints, and spacer identification.
- Development of an algorithm to predict pathogenicity.
Main Results:
- In cis duplication alleles exhibit DUX4 expression regardless of SMCHD1 mutation status.
- Specific combinations of proximal and distal repeat array sizes in duplications determine pathogenicity.
- Challenges in characterizing these complex rearrangements were highlighted.
Conclusions:
- D4Z4 in cis duplications are pathogenic in FSHD, with pathogenicity determined by specific repeat array size combinations.
- The developed algorithm aids diagnostic laboratories in accurately interpreting these complex alleles.
- Accurate interpretation of these often-missed alleles is crucial for FSHD diagnosis.
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