Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death

Philip M. Boone , Bo Yuan , Shen Gu , Zhiwei Ma , Tomasz Gambin , Claudia Gonzaga-Jauregui , Mahim Jain , Todd J. Murdock , Janson J. White , Shalini N. Jhangiani , Kimberly Walker , Qiaoyan Wang , Donna M. Muzny , Richard A. Gibbs , J. Fielding Hejtmancik , James R. Lupski

Abstract

Background Juvenile-onset cataracts are known among the Hutterites of North America. Despite being identified over 30 years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown.

Methods We performed whole exome sequencing of three Hutterite-type cataract trios and follow-up genotyping and mapping in four extended kindreds.

Results Trio exomes enabled genome-wide autozygosity mapping, which localized the disease gene to a 9.5-Mb region on chromosome 6p. This region contained two candidate variants, LEMD2 c.T38G and MUC21 c.665delC. Extended pedigrees recruited for variant genotyping revealed multiple additional relatives with juvenile-onset cataract, as well as six deceased relatives with both cataracts and sudden cardiac death. The candidate variants were genotyped in 84 family members, including 17 with cataracts; only the variant in LEMD2 cosegregated with cataracts (LOD = 9.62). SNP-based fine mapping within the 9.5 Mb linked region supported this finding by refining the cataract locus to a 0.5- to 2.9-Mb subregion (6p21.32-p21.31) containing LEMD2 but not MUC21. LEMD2 is expressed in mouse and human lenses and encodes a LEM domain-containing protein; the c.T38G missense mutation is predicted to mutate a highly conserved residue within this domain (p.Leu13Arg).

Conclusion We performed a genetic and genomic study of Hutterite-type cataract and found evidence for an association of this phenotype with sudden cardiac death. Using combined genetic and genomic approaches, we mapped cataracts to a small portion of chromosome 6 and propose that they result from a homozygous missense mutation in LEMD2.

Author Philip M. Boone - Department of Molecular and Human Genetics (DMHG) [Baylor College of Medicine (BCM)]
Philip M. Boone,,
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, Bo Yuan - [Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA (DMHG)]
Bo Yuan,,
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- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
, Shen Gu - Department of Molecular and Human Genetics (DMHG) [Baylor College of Medicine (BCM)]
Shen Gu,,
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, Zhiwei Ma
Zhiwei Ma,,
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, Tomasz Gambin II - [Department of Molecular and Human Genetics (DMHG) [Baylor College of Medicine (BCM)]]
Tomasz Gambin,,
- The Institute of Computer Science
- Department of Molecular and Human Genetics
, Claudia Gonzaga-Jauregui - Department of Molecular and Human Genetics (DMHG) [Baylor College of Medicine (BCM)]
Claudia Gonzaga-Jauregui,,
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, Mahim Jain - Department of Molecular and Human Genetics (DMHG) [Baylor College of Medicine (BCM)]
Mahim Jain,,
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, Todd J. Murdock
Todd J. Murdock,,
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, Janson J. White - Department of Molecular and Human Genetics (DMHG) [Baylor College of Medicine (BCM)]
Janson J. White,,
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, Shalini N. Jhangiani - Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas
Shalini N. Jhangiani,,
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et al.`
Journal seriesMolecular Genetics & Genomic Medicine, ISSN , e-ISSN 2324-9269
Issue year2016
Vol4
No1
Pages77-94
Publication size in sheets0.85
DOIDOI:10.1002/mgg3.181
URL http://onlinelibrary.wiley.com/doi/10.1002/mgg3.181/full
Languageen angielski
File
LEMD2.pdf 1.57 MB
Score (nominal)5
ScoreMinisterial score = 0.0, 27-03-2017, ArticleFromJournal
Ministerial score (2013-2016) = 5.0, 27-03-2017, ArticleFromJournal
Citation count*3 (2018-06-20)
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