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

Abstract

BackgroundJuvenile‐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.MethodsWe performed whole exome sequencing of three Hutterite‐type cataract trios and follow‐up genotyping and mapping in four extended kindreds.ResultsTrio 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).ConclusionWe 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.

The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping

“…The integral NE protein LEMD2 (LEM domain-containing protein 2) is functionally and physically linked to A-type lamins, and experimental data suggest it has a role in the structural organization of the NE 6 as well as chromatin binding and distribution. 7,8 Although a single LEMD2 founder mutation has been implicated in an autosomal-recessive form of congenital cataracts (MIM: 212500), 9 LEMD2 has not been associated with a complex syndromic phenotype to date.…”

Characterization of a Unique Form of Arrhythmic Cardiomyopathy Caused by Recessive Mutation in LEMD2

“…Recently, a mutation in LEMD2 has been associated with juvenile cataract and a risk for sudden cardiac death in the Hutterite population (16). The Hutterite population is a genetic isolate who originated in Europe in the 16th century and emigrated to the United States and Canada in the 1870s.…”

Linker of nucleoskeleton and cytoskeleton complex proteins in cardiomyopathy

“…In humans, an autosomal recessive mutation in the LEM domain of Lem2 was recently identified that substitutes leucine 13 to arginine and leads to juvenile cataracts (Boone et al 2016 ). Notably, some of these patients also died from sudden cardiac death; however, the cause of this was unclear and warrants further investigation.…”