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Eur J Med Genet. 2015 Apr;58(4):222-9. doi: 10.1016/j.ejmg.2015.02.003. Epub 2015 Feb 25.

A novel single nucleotide splice site mutation in FHL1 confirms an Emery-Dreifuss plus phenotype with pulmonary artery hypoplasia and facial dysmorphology.

Author information

1
Department of Clinical Genetics, Aarhus University Hospital, Skejby, Denmark.
2
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
3
BGI-Shenzhen, Shenzhen 518083, China.
4
BGI-Shenzhen, Shenzhen 518083, China; Shenzhen Key Laboratory of Genomics, Shenzhen 518083, China; The Guangdong Enterprise Key Laboratory of Human Disease Genomics, Shenzhen 518083, China.
5
Department of Cardiology, Aarhus University, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
6
Department of Neurology, Aarhus University, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
7
Department of Pathology, Aarhus University Hospital, Aarhus, Denmark.
8
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
9
Department of Clinical Genetics, Aarhus University Hospital, Skejby, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
10
Department of Dermatology, Aarhus University, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
11
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Holland.
12
Department of Clinical Genetics, Aarhus University Hospital, Skejby, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address: uffejens@rm.dk.

Abstract

We describe a Danish family with an, until recently, unknown X-linked disease with muscular dystrophy (MD), facial dysmorphology and pulmonary artery hypoplasia. One patient died suddenly before age 20 and another was resuscitated from cardiac arrest at the age of 28. Linkage analysis pointed to a region of 25 Mb from 123.6 Mb to 148.4 Mb on chromosome X containing over 100 genes. Exome sequencing identified a single nucleotide splice site mutation c.502-2A > T, which is located 5' to exon 6 in the gene encoding four and a half LIM domain 1 (FHL1) protein. FHL1 expresses three main splice variants, known as FHL1A, FHL1B and FHL1C. In healthy individuals, FHL1A is the predominant splice variant and is mainly found in skeletal and cardiac muscle. The FHL1 transcript profiles from two affected individuals were investigated in skin fibroblasts with quantitative real-time PCR. This demonstrated loss of isoform A and B, and an almost 200-fold overexpression of isoform C confirming that lack of FHL1A and overexpression of FHL1C results in an extended phenotype of EDMD as recently shown by Tiffin et al. [2013].

KEYWORDS:

Exome sequencing; Linkage analysis; Muscular dystrophy; Splice site mutation; X-linked

PMID:
25724586
DOI:
10.1016/j.ejmg.2015.02.003
[Indexed for MEDLINE]

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