Exome sequencing in a family with restless legs syndrome

Anne Weissbach; Katharina Siegesmund; Norbert Brüggemann; Alexander Schmidt; Meike Kasten; Irene Pichler; Hiltrud Muhle; Ebba Lohmann; Thora Lohnau; Eberhard Schwinger; Johann Hagenah; Ulrich Stephani; Peter P. Pramstaller; Christine Klein; Katja Lohmann

doi:10.1002/mds.25191

Exome sequencing in a family with restless legs syndrome

Anne Weissbach, Katharina Siegesmund, Norbert Brüggemann, Alexander Schmidt, Meike Kasten, Irene Pichler, Hiltrud Muhle, Ebba Lohmann, Thora Lohnau, Eberhard Schwinger, Johann Hagenah, Ulrich Stephani, Peter P. Pramstaller, Christine Klein^*, Katja Lohmann

^*Corresponding author for this work

13 Citations (Scopus)

Abstract

Background:: Restless legs syndrome (RLS) has a high familial aggregation. To date, several loci and genetic risk factors have been identified, but no causative gene mutation has been found. Methods:: We evaluated a German family with autosomal dominantly inherited RLS in 7 definitely and 2 possibly affected members by genome-wide linkage analysis and exome sequencing. Results:: We identified three novel missense and one splice site variant in the PCDHA3, WWC2, ATRN, and FAT2 genes that segregated with RLS in the family. All four exons of the PCDHA3 gene, the most plausible candidate, were sequenced in 64 unrelated RLS cases and 250 controls. This revealed three additional rare missense variants (frequency <1%) of unknown pathogenicity in 2 patients and 1 control. Conclusions:: We present the first next-generation sequencing study on RLS and suggest PCDHA3 as a candidate gene for RLS.

Original language	English
Journal	Movement Disorders
Volume	27
Issue number	13
Pages (from-to)	1686-1689
Number of pages	4
ISSN	0885-3185
DOIs	https://doi.org/10.1002/mds.25191
Publication status	Published - 01.11.2012

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@article{712cc9d190b7464ebe78fd330d17b713,

title = "Exome sequencing in a family with restless legs syndrome",

abstract = "Background:: Restless legs syndrome (RLS) has a high familial aggregation. To date, several loci and genetic risk factors have been identified, but no causative gene mutation has been found. Methods:: We evaluated a German family with autosomal dominantly inherited RLS in 7 definitely and 2 possibly affected members by genome-wide linkage analysis and exome sequencing. Results:: We identified three novel missense and one splice site variant in the PCDHA3, WWC2, ATRN, and FAT2 genes that segregated with RLS in the family. All four exons of the PCDHA3 gene, the most plausible candidate, were sequenced in 64 unrelated RLS cases and 250 controls. This revealed three additional rare missense variants (frequency <1%) of unknown pathogenicity in 2 patients and 1 control. Conclusions:: We present the first next-generation sequencing study on RLS and suggest PCDHA3 as a candidate gene for RLS.",

author = "Anne Weissbach and Katharina Siegesmund and Norbert Br{\"u}ggemann and Alexander Schmidt and Meike Kasten and Irene Pichler and Hiltrud Muhle and Ebba Lohmann and Thora Lohnau and Eberhard Schwinger and Johann Hagenah and Ulrich Stephani and Pramstaller, {Peter P.} and Christine Klein and Katja Lohmann",

year = "2012",

month = nov,

day = "1",

doi = "10.1002/mds.25191",

language = "English",

volume = "27",

pages = "1686--1689",

journal = "Movement Disorders",

issn = "0885-3185",

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TY - JOUR

T1 - Exome sequencing in a family with restless legs syndrome

AU - Weissbach, Anne

AU - Siegesmund, Katharina

AU - Brüggemann, Norbert

AU - Schmidt, Alexander

AU - Kasten, Meike

AU - Pichler, Irene

AU - Muhle, Hiltrud

AU - Lohmann, Ebba

AU - Lohnau, Thora

AU - Schwinger, Eberhard

AU - Hagenah, Johann

AU - Stephani, Ulrich

AU - Pramstaller, Peter P.

AU - Klein, Christine

AU - Lohmann, Katja

PY - 2012/11/1

Y1 - 2012/11/1

N2 - Background:: Restless legs syndrome (RLS) has a high familial aggregation. To date, several loci and genetic risk factors have been identified, but no causative gene mutation has been found. Methods:: We evaluated a German family with autosomal dominantly inherited RLS in 7 definitely and 2 possibly affected members by genome-wide linkage analysis and exome sequencing. Results:: We identified three novel missense and one splice site variant in the PCDHA3, WWC2, ATRN, and FAT2 genes that segregated with RLS in the family. All four exons of the PCDHA3 gene, the most plausible candidate, were sequenced in 64 unrelated RLS cases and 250 controls. This revealed three additional rare missense variants (frequency <1%) of unknown pathogenicity in 2 patients and 1 control. Conclusions:: We present the first next-generation sequencing study on RLS and suggest PCDHA3 as a candidate gene for RLS.

AB - Background:: Restless legs syndrome (RLS) has a high familial aggregation. To date, several loci and genetic risk factors have been identified, but no causative gene mutation has been found. Methods:: We evaluated a German family with autosomal dominantly inherited RLS in 7 definitely and 2 possibly affected members by genome-wide linkage analysis and exome sequencing. Results:: We identified three novel missense and one splice site variant in the PCDHA3, WWC2, ATRN, and FAT2 genes that segregated with RLS in the family. All four exons of the PCDHA3 gene, the most plausible candidate, were sequenced in 64 unrelated RLS cases and 250 controls. This revealed three additional rare missense variants (frequency <1%) of unknown pathogenicity in 2 patients and 1 control. Conclusions:: We present the first next-generation sequencing study on RLS and suggest PCDHA3 as a candidate gene for RLS.

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U2 - 10.1002/mds.25191

DO - 10.1002/mds.25191

M3 - Journal articles

C2 - 23192925

AN - SCOPUS:84870336681

SN - 0885-3185

VL - 27

SP - 1686

EP - 1689

JO - Movement Disorders

JF - Movement Disorders

IS - 13

ER -

Exome sequencing in a family with restless legs syndrome

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