Genetics: FSHD2

See also Genetic Testing.

Facioscapulohumeral muscular dystrophy Type 2 (also called FSHD1B or FSHMD1B) is much rarer than Type 1 and is thought to account for the majority of the 5 percent of FSHD cases that test negative for Type 1.

FSHD2 is clinically identical to FSHD1 but genetically distinct. In FSHD1, the tandem repeats called D4Z4 on chromosome 4 are deleted, whereas in FSHD2, the number of D4Z4 repeats is in the normal range. Another way of saying this is that there is no “contraction” in D4Z4 at 4q35.

Eighty percent of FSHD2 is caused by the inheritance of two independent genetic variations: a heterozygous loss-of-function mutation in the encoding Structural Maintenance of Chromosomes flexible Hinge Domain containing 1 (SMCHD1) gene combined with the 4qA allele carrying the DUX4 polyadenylation site (see FSHD1), making this allele permissive to expression of the toxic DUX4 gene.

More than 52 mutations associated with FSHD have been reported as of early 2014 in SMCHD1. These mutations result in hypomethylation and relaxation of chromatin in all D4Z4 repeat arrays on chromosomes 4 and 10, just as deletions of D4Z4 repeats do. In the presence of the 4qA allele, this is thought to create a permissive environment for the DUX4 gene to be expressed. However, in combination with two non-permissive 4qB alleles, SMCHD1 mutations will not cause FSHD. In other words, FSHD2 is a digenic disease. About 20 percent of FSHD2 individuals with hypomethylation at D4Z4, a SMCHD1 mutation, and a permissive D4Z4 haplotype were asymptomatic, indicating an incomplete penetrance.

Some FSHD families have been identified with an FSHD1 mutation as well as an FSHD2 mutation. Individuals who carry both mutations were shown to be more affected than family members with only one of the two mutations, showing that SMCHD1 can act as a modifier in FSHD1 families. Due to the digenic inheritance pattern and incomplete penetrance, FSHD2 was previously incorrectly referred to as non-chromosome 4-linked FSHD.

The online database Online Mendelian Inheritance in Man (OMIM) is an excellent source for further information on the science and medicine of FSHD2.


Lemmers RJ, Tawil R, Petek LM, et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012 Dec;44(12):1370-4. doi: 10.1038/ng.2454. Epub 2012 Nov 11. Click here to read Abstract

Sacconi S, Lemmers RJ, Balog J, et al. The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Sacconi S, Am J Hum Genet. 2013 Oct 3;93(4):744-751. Click here to read Abstract