Abstract
Juvenile-onset cataracts are known among the Hutterites of North America. Despite being identified over 30years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown. We performed whole exome sequencing of three Hutterite-type cataract trios and follow-up genotyping and mapping in four extended kindreds. 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 9.5Mb 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). 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.
Highlights
Juvenile cataracts develop in childhood in the crystalline lens that was clear at birth (Francis and Moore 2004)
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
Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc
Summary
Juvenile cataracts develop in childhood in the crystalline lens that was clear at birth (Francis and Moore 2004). Hutterites are an Anabaptist religious isolate living in the northwestern United States and southwestern Canada Because of both their geographic and social isolation and their common ancestry, the coefficient of inbreeding of Hutterite unions is high (Pearce et al 1987). The high coefficient of inbreeding and the pattern of trait segregation led Shokeir and Lowry (1985) to hypothesize autosomal recessive inheritance for the cataract phenotype. In those several reports, age of onset ranged from infancy through school age, mostly between 3 and 7 years. Despite being identified over 30 years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown
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