Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene

Volker Straub (1) , Anna Sarkozy (1) , Christian Windpassinger (1) , Judith Hudson (1) , Charlotte F Dougan (1) , Brian Lecky (1) , David Hilton-Jones (1) , Michelle Eagle (1) , Richard Charlton (1) , Rita Barresi (1) , Hans Lochmuller (1) , Kate Bushby (1)

1 Department of Neurology

Mutations in the four-and-a-half LIM domain 1 (FHL1) gene, which encodes a 280 amino acid protein containing 4 LIM domains and a single zinc finger domain in the N-terminal region, have been associated with a broad clinical spectrum of X-linked muscle diseases encompassing a variety of different phenotypes. Patients might either present with a scapuloperoneal myopathy, a myopathy with postural muscle atrophy and generalized hypertrophy, an Emery-Dreifuss muscular dystrophy or an early-onset myopathy with reducing bodies. It has been proposed that the phenotypic variability is related to the position of the mutation within the FHL1 gene. Here we report on 3 British families with a heterogeneous clinical presentation segregating a single FHL1 gene mutation and haplotype, suggesting that this represents a founder mutation. The underlying FHL1 gene mutation was detected by direct sequencing and the founder effect was verified by haplotype analysis of the FHL1 gene locus. A 3 bp insertion mutation (p.Phe127_Thr128insIle) within the second LIM domain of the FHL1 gene was identified in all available affected family members of the three families. Haplotype analysis of the FHL1 region on Xq26 revealed that the families shared a common haplotype. The p.Phe127_Thr128insIle mutation in the FHL1 gene therefore appears to be a British founder mutation and FHL1 gene screening, in particular of exon 6, should therefore be indicated in British patients with a broad phenotypic spectrum of X-linked muscle diseases

Mots clés: FHL1; myopathy; founder mutation

Volker Straub, Anna Sarkozy, Christian Windpassinger, Judith Hudson, Charlotte F Dougan, et al.. Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2011.84⟩. ⟨hal-00646918⟩