DNMT3B – Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive facial, scapular, and humeral muscle weakness. FSHD type 2 (FSHD2) results from epigenetic derepression of the D4Z4 repeat array on chromosome 4q35, requiring both a permissive allele and a mutation in a chromatin regulator. In two unrelated FSHD2 probands, heterozygous DNMT3B variants, c.1579T>C (p.Cys527Arg) and c.2072C>T (p.Pro691Leu), co-segregated with disease in affected family members, confirming autosomal dominant inheritance and implicating DNMT3B as a genetic modifier of FSHD penetrance ([PMID:27153398]).

Functional analyses of patient‐derived myoblasts demonstrated a 30–50% reduction in D4Z4 CpG methylation and a corresponding increase in DUX4 transcript levels, indicating impaired de novo methylation by mutant DNMT3B and chromatin relaxation at the D4Z4 locus ([PMID:27153398]). These data support a haploinsufficiency mechanism and provide Moderate experimental evidence. No conflicting reports have disputed DNMT3B’s role in FSHD2. Overall, the limited number of probands and segregation data yield a Limited clinical validity classification. Key take-home: Heterozygous DNMT3B mutations act as epigenetic modifiers, reducing D4Z4 methylation and derepressing DUX4 to increase FSHD penetrance.

References

• American Journal of Human Genetics • 2016 • Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy PMID:27153398

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