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

Molecular Genetics & Genomic Medicine
Philip M BooneRichard A Lewis

Abstract

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. 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 9.5 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 ...Continue Reading

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Citations

Sep 7, 2019·International Journal of Molecular Sciences·Andreas BrodehlHendrik Milting
Jan 14, 2021·Nucleus·Norma E Padilla-MejiaMark C Field
May 8, 2019·JACC. Basic to Translational Science·Nelly AbdelfatahBrenda Gerull
Jun 15, 2021·Experimental Eye Research·Alan Shiels, J Fielding Hejtmancik
Jul 10, 2021·The International Journal of Biochemistry & Cell Biology·Jacob A Ross, Matthew J Stroud
Mar 24, 2021·Cold Spring Harbor Perspectives in Biology·Sumit Pawar, Ulrike Kutay

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Methods Mentioned

BETA
exome sequencing
Human Genome Sequencing
PCR
electrophoresis
Feature Extraction
genotyping

Software Mentioned

UCSC Genome Browser
FASTLINK
Agilent Feature Extraction
Cat Map
PolyPhen2
AgileVariantMapper
Agilent Genomic Workbench
MutationTaster2
SIFT

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