Why the study?
Genetic diagnosis of facioscapulohumeral muscular dystrophy is challenging because of the complex procedures required.
Does Nanopore CRISPR/Cas9-targeted resequencing allow for the diagnosis of FSHD by simultaneous detection of D4Z4 repeat length and methylation status?
Does Nanopore CRISPR/Cas9-targeted resequencing allow for the diagnosis of FSHD by simultaneous detection of D4Z4 repeat length and methylation status?
Nanopore CRISPR/Cas9-targeted resequencing enables simultaneous detection of D4Z4 repeat length and methylation status, revealing significant hypomethylation in FSHD1 that correlates with patient phenotype.
Summary Facioscapulohumeral muscular dystrophy (FSHD) can be subdivided into two types: FSHD1, caused by contraction of the D4Z4 repeat on chromosome 4q35, and FSHD2, caused by mild contraction of the D4Z4 repeat plus aberrant hypomethylation mediated by genetic variants in SMCHD1, DNMT3B , or LRIF1 . Genetic diagnosis of FSHD is challenging because of the complex procedures required. Here, we applied Nanopore CRISPR/Cas9-targeted resequencing for the diagnosis of FSHD by simultaneous detection of D4Z4 repeat length and methylation status at nucleotide level in genetically-confirmed and suspected patients. We found significant hypomethylation of contracted D4Z4 repeats in FSHD1 and strong correlation between methylation rate and patient phenotype. This finding can explain how repeat contraction contributes to disease pathogenesis by activating DUX4 expression.
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Hiramuki et al. (2022) studied this question.
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