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

Lookup NU author(s): Dr Anna Sarkozy, Dr Michelle Eagle, Dr Richard Charlton, Dr Rita Barresi, Professor Hanns Lochmuller, Emerita Professor Katherine Bushby, Professor Volker StraubORCiD


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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_Thr128inslle 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. European Journal of Human Genetics (2011) 19, 1038-1044; doi:10.1038/ejhg.2011.84; published online 1 June 2011

Publication metadata

Author(s): Sarkozy A, Windpassinger C, Hudson J, Dougan CF, Lecky B, Hilton-Jones D, Eagle M, Charlton R, Barresi R, Lochmuller H, Bushby K, Straub V

Publication type: Article

Publication status: Published

Journal: European Journal of Human Genetics

Year: 2011

Volume: 19

Issue: 10

Pages: 1038-1044

Print publication date: 01/10/2011

ISSN (print): 1018-4813

ISSN (electronic): 1476-5438

Publisher: Nature Publishing Group


DOI: 10.1038/ejhg.2011.84


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Funder referenceFunder name
National Commissioning Group (NCG)
MD-NET 01GM0887German Ministry of Education and Research (BMBF, Bonn, Germany)