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

Anja E Pen; Mette Nyegaard; Mingyan Fang; Hui Jiang; Rikke Christensen; Henning Mølgaard; Henning Andersen; Benedicte Parm Ulhøi; John R Østergaard; Signe Væth; Mette Sommerlund; Arjan P M de Brouwer; Xiuqing Zhang; Uffe B Jensen

doi:10.1016/j.ejmg.2015.02.003

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

Anja E Pen, Mette Nyegaard, Mingyan Fang, Hui Jiang, Rikke Christensen, Henning Mølgaard, Henning Andersen, Benedicte Parm Ulhøi, John R Østergaard, Signe Væth, Mette Sommerlund, Arjan P M de Brouwer, Xiuqing Zhang, Uffe B Jensen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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 resurrected 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 FLH1C results in an extended phenotype of EDMD as recently shown by Tiffin et al. (2013).

Original language	English
Journal	European Journal of Medical Genetics
Volume	58
Issue	4
Pages (from-to)	222-229
Number of pages	8
ISSN	1769-7212
DOIs	https://doi.org/10.1016/j.ejmg.2015.02.003
Publication status	Published - Apr 2015

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Pen, A. E., Nyegaard, M., Fang, M., Jiang, H., Christensen, R., Mølgaard, H., Andersen, H., Ulhøi, B. P., Østergaard, J. R., Væth, S., Sommerlund, M., de Brouwer, A. P. M., Zhang, X., & Jensen, U. B. (2015). A novel single nucleotide splice site mutation in FHL1 confirms an Emery-Dreifuss plus phenotype with pulmonary artery hypoplasia and facial dysmorphology. European Journal of Medical Genetics, 58(4), 222-229. https://doi.org/10.1016/j.ejmg.2015.02.003

@article{317d78f37118447aac9ad6c58891d495,

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

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 resurrected 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 FLH1C results in an extended phenotype of EDMD as recently shown by Tiffin et al. (2013).",

author = "Pen, {Anja E} and Mette Nyegaard and Mingyan Fang and Hui Jiang and Rikke Christensen and Henning M{\o}lgaard and Henning Andersen and Ulh{\o}i, {Benedicte Parm} and {\O}stergaard, {John R} and Signe V{\ae}th and Mette Sommerlund and {de Brouwer}, {Arjan P M} and Xiuqing Zhang and Jensen, {Uffe B}",

note = "Copyright {\textcopyright} 2015. Published by Elsevier Masson SAS.",

year = "2015",

month = apr,

doi = "10.1016/j.ejmg.2015.02.003",

language = "English",

volume = "58",

pages = "222--229",

journal = "European Journal of Medical Genetics",

issn = "1769-7212",

publisher = "Elsevier Masson",

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Pen, AE, Nyegaard, M, Fang, M, Jiang, H, Christensen, R , Mølgaard, H , Andersen, H, Ulhøi, BP, Østergaard, JR , Væth, S , Sommerlund, M, de Brouwer, APM, Zhang, X & Jensen, UB 2015, 'A novel single nucleotide splice site mutation in FHL1 confirms an Emery-Dreifuss plus phenotype with pulmonary artery hypoplasia and facial dysmorphology', European Journal of Medical Genetics, vol. 58, no. 4, pp. 222-229. https://doi.org/10.1016/j.ejmg.2015.02.003

A novel single nucleotide splice site mutation in FHL1 confirms an Emery-Dreifuss plus phenotype with pulmonary artery hypoplasia and facial dysmorphology. / Pen, Anja E; Nyegaard, Mette; Fang, Mingyan et al.
In: European Journal of Medical Genetics, Vol. 58, No. 4, 04.2015, p. 222-229.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - A novel single nucleotide splice site mutation in FHL1 confirms an Emery-Dreifuss plus phenotype with pulmonary artery hypoplasia and facial dysmorphology

AU - Pen, Anja E

AU - Nyegaard, Mette

AU - Fang, Mingyan

AU - Jiang, Hui

AU - Christensen, Rikke

AU - Mølgaard, Henning

AU - Andersen, Henning

AU - Ulhøi, Benedicte Parm

AU - Østergaard, John R

AU - Væth, Signe

AU - Sommerlund, Mette

AU - de Brouwer, Arjan P M

AU - Zhang, Xiuqing

AU - Jensen, Uffe B

PY - 2015/4

Y1 - 2015/4

N2 - 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 resurrected 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 FLH1C results in an extended phenotype of EDMD as recently shown by Tiffin et al. (2013).

AB - 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 resurrected 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 FLH1C results in an extended phenotype of EDMD as recently shown by Tiffin et al. (2013).

U2 - 10.1016/j.ejmg.2015.02.003

DO - 10.1016/j.ejmg.2015.02.003

M3 - Journal article

C2 - 25724586

SN - 1769-7212

VL - 58

SP - 222

EP - 229

JO - European Journal of Medical Genetics

JF - European Journal of Medical Genetics

IS - 4

ER -

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

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