A homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy

Objective: Facioscapulohumeral muscular dystrophy (FSHD) is a heterogenetic disorder predominantly characterized by progressive facial and scapular muscle weakness. FSHD patients either have a contraction of the D4Z4 repeat on chromosome 4q35 or mutations in D4Z4 chromatin modifiers SMCHD1 and DNMT3B, both causing D4Z4 chromatin relaxation and inappropriate expression of the D4Z4-encoded DUX4 gene in skeletal muscle. In this study we tested the hypothesis if LRIF1, a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2. 

Methods: Clinical examination of an idiopathic FSHD2 patient was combined with pathological muscle biopsy examination and with genetic, epigenetic and molecular studies.

Results: A homozygous LRIF1 mutation was identified in a patient with a clinical phenotype consistent with FSHD. This mutation resulted in the absence of the long isoform of LRIF1 protein, D4Z4 chromatin relaxation, and DUX4 and DUX4 target gene expression in myonuclei, all mole...