Identification of variants in the 4q35 gene FAT1 in patients with a facioscapulohumeral dystrophy-like phenotype

Hum Mutat. 2015 Apr;36(4):443-53. doi: 10.1002/humu.22760. Epub 2015 Mar 19.


Facioscapulohumeralmuscular dystrophy (FSHD) is linked to copy-number reduction (N < 10) of the 4q D4Z4 subtelomeric array, in association with DUX4-permissive haplotypes. This main form is indicated as FSHD1. FSHD-like phenotypes may also appear in the absence of D4Z4 copy-number reduction. Variants of the SMCHD1 gene have been reported to associate with D4Z4 hypomethylation in DUX4-compatible haplotypes, thus defining FSHD2. Recently, mice carrying a muscle-specific knock-out of the protocadherin gene Fat1 or its constitutive hypomorphic allele were shown to develop muscular and nonmuscular defects mimicking human FSHD. Here, we report FAT1 variants in a group of patients presenting with neuromuscular symptoms reminiscent of FSHD. The patients do not carry D4Z4 copy-number reduction, 4q hypomethylation, or SMCHD1 variants. However, abnormal splicing of the FAT1 transcript is predicted for all identified variants. To determine their pathogenicity, we elaborated a minigene approach coupled to an antisense oligonucleotide (AON) assay. In vitro, four out of five selected variants induced partial or complete alteration of splicing by creating new splice sites or modifying splicing regulators. AONs confirmed these effects. Altered transcripts may affect FAT1 protein interactions or stability. Altogether, our data suggest that defective FAT1 is associated with an FSHD-like phenotype.

Keywords: FAT1-protocadherin; facioscapulohumeral dystrophy; neuromuscular pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Alternative Splicing
  • Cadherins / genetics*
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 4*
  • DNA Methylation
  • Exons
  • Gene Expression
  • Genes, Reporter
  • Genetic Variation*
  • Humans
  • Infant
  • Infant, Newborn
  • Middle Aged
  • Muscular Dystrophy, Facioscapulohumeral / diagnosis*
  • Muscular Dystrophy, Facioscapulohumeral / genetics*
  • Mutation
  • Phenotype*
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA
  • Young Adult


  • Cadherins
  • FAT1 protein, human