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

Abstract

Mutations in the four-and-a-half LIM domain 1 (FHL1) gene, which encodes a 280-amino-acid protein containing four 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 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 three 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.

Selective muscle involvement in a family affected by a second LIM domain mutation of fhl1: An imaging study using computed tomography

“…We found a prominent involvement of the paraspinal muscles at the early stage and preservation of the triceps brachii and intrinsic hand muscles at the progressed stage. Two recent studies reported cases with mutations in the second LIM domain that showed a relatively marked involvement of the biceps brachii muscles [9,11]. Our imaging results also confirmed these clinical observations.…”

“…Subsequent reports identified other mutations in FHL1, such as those associated with reducing body myopathy (RBM), rigid spine syndrome, Emery-Dreifuss muscular dystrophy (EDMD), EDMD-like joint contracture and cardiomyopathy, and pathological diagnosed myofibrillar myopathy [4][5][6][7][8][9]. Nearly 30 mutations in the FHL1 myopathies have been reported [9,10], with variations in the age of onset, muscle involvement, and severity even within the same mutation [11].…”

Novel FHL1 mutation in a family with reducing body myopathy

“…Mutations causing this phenotype are distributed across the FHL1 gene. The latest report of a novel founder mutation in FHL1 described a heterogeneous spectrum of phenotypes caused by a 3‐bp insertion mutation (p.Phe127Thr128insIle) 23. Onset of disease was mostly in adulthood with proximal lower limb weakness and cervical rigidity but no heart involvement.…”

Prenatal diagnosis of congenital myopathies and muscular dystrophies

“…Remarkable inter‐ and intrafamilial variability of phenotypes has been noted, ranging from early, severe presentations in childhood to slow progressive onset in adulthood. However, most affected individuals develop symptoms in the second decade of life .…”