Open AccessHutterite‐type cataract maps to chromosome 6p21.32‐p21.31, cosegregates with a homozygous mutation in LEMD 2 , and is associated with sudden cardiac death
Author(s) -
Boone Philip M.,
Yuan Bo,
Gu Shen,
Ma Zhiwei,
Gambin Tomasz,
GonzagaJauregui Claudia,
Jain Mahim,
Murdock Todd J.,
White Janson J.,
Jhangiani Shalini N.,
Walker Kimberly,
Wang Qiaoyan,
Muzny Donna M.,
Gibbs Richard A.,
Hejtmancik J. Fielding,
Lupski James R.,
Posey Jennifer E.,
Lewis Richard A.
Publication year - 2016
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.181
Subject(s) - genetics , cataracts , missense mutation , exome sequencing , biology , locus (genetics) , haplotype , genotyping , exome , candidate gene , sudden death , mutation , gene , genotype , medicine , cardiology
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, LEMD 2 c.T38G and MUC 21 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 LEMD 2 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 LEMD 2 but not MUC 21 . LEMD 2 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 LEMD 2 .