A number sign (#) is used with this entry because of evidence that facioscapulohumeral muscular dystrophy-4 (FSHD4) is caused by the combination of a heterozygous mutation in the DNMT3B gene (602900) on chromosome 20q11 and presence of a haplotype on chromosome 4 that is permissive for DUX4 (606009) expression.

Facioscapulohumeral muscular dystrophy (FSHD) is a skeletal muscle disorder characterized by adult onset of progressive muscle weakness of the face and upper extremity muscles. With disease progression, other muscles also may become affected. There is significant clinical variability and incomplete penetrance (summary by van den Boogaard et al., 2016).

For a discussion of genetic heterogeneity of FSHD, see FSHD1 (158900).

Van den Boogaard et al. (2016) reported 2 unrelated families with FSHD. Clinical details were limited, but family Rf210 had 4 clinically affected individuals, 2 of whom were deceased. The patients had onset of disease between 30 and 63 years of age. There was only 1 clinically affected individual in the other family (Rf732) who had disease onset at age 45 years.

The transmission pattern of FSHD4 in the families reported by van den Boogaard et al. (2016) was consistent with autosomal dominant inheritance of mutation in the DNMT3B gene combined with a 'permissive haplotype' on chromosome 4 (4qA) that promotes DUX4 expression, consistent with digenic inheritance. There is incomplete penetrance.

In 5 members of 2 unrelated families with FSHD4, van den Boogaard et al. (2016) identified 2 different heterozygous missense mutations in the DNMT3B gene (C527R, 602900.0014 and P691L, 602900.0015). The mutations, which were identified by whole-exome sequencing, were not found in public databases, including ExAC. The mutations segregated with hypomethylation of the D4Z4 repeat in the families, but not with clinical presentation. In family Rf210, 2 severely affected individuals carried a heterozygous C527R mutation in the DNMT3B gene that was associated with severe hypomethylation of D4Z4 (-29 and -30%). These patients also carried a 9-unit D4Z4 repeat in a permissive 4qA allele. A third family member with the DNMT3B mutation was clinically unaffected: this individual had hypomethylation at -29%, but the permissive 4qA allele contained 44 units, rather than 9. Two affected family members without the DNMT3B mutation had mild hypomethylation (-8%) on a permissive 4qA allele. There was another clinically unaffected family member with the 9-unit repeat and -6% hypomethylation, but without the DNMT3B mutation. In family Rf732, the clinically affected proband and his unaffected 74-year-old father both carried a heterozygous P691L mutation in the DNMT3B gene. In addition, both had a hypomethylated D4Z4 repeat (-22%) on a permissive 4qA allele with 13 D4Z4 units. The patient's 38-year-old unaffected brother, who did not carry the P691L mutation, had a 13 unit D4Z4 repeat and the permissive 4qA-S haplotype; his D4Z4 repeat was hypomethylated at -10%. These findings, which were consistent with incomplete penetrance in both families, implicated DNMT3B mutations as modifiers of FSHD. Fibroblasts isolated from a symptomatic FSHD4 patient with a DNMT3B mutation that were transdifferentiated into myotubes showed increased expression of DUX4 and DUX4 target genes compared to controls. Van den Boogaard et al. (2016) concluded that DNMT3B mutations confer increased penetrance of FSHD if other genetic factors are present.