title: 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: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Philip M
authors.identifier: 0000-0001-9528-252X
authors.initials: PM
authors.lastname: Boone
authors.affiliation: Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Shen
authors.initials: S
authors.lastname: Gu
authors.affiliation: Ophthalmic Genetics and Visual Function Branch National Eye Institute Rockville Maryland.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.affiliation: Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Mahim
authors.initials: M
authors.lastname: Jain
authors.affiliation: Rocky Mountain Eye Center Missoula Montana.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Murdock
authors.affiliation: Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Janson J
authors.initials: JJ
authors.lastname: White
authors.affiliation: Human Genome Sequencing Center Baylor College of Medicine Houston Texas.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Human Genome Sequencing Center Baylor College of Medicine Houston Texas.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Walker
authors.affiliation: Human Genome Sequencing Center Baylor College of Medicine Houston Texas.
authors.forename: Qiaoyan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Human Genome Sequencing Center Baylor College of Medicine Houston Texas.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas; Human Genome Sequencing CenterBaylor College of MedicineHoustonTexas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Ophthalmic Genetics and Visual Function Branch National Eye Institute Rockville Maryland.
authors.forename: J Fielding
authors.initials: JF
authors.lastname: Hejtmancik
authors.affiliation: Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas; Human Genome Sequencing CenterBaylor College of MedicineHoustonTexas; Department of PediatricsBaylor College of MedicineHoustonTexas; Texas Children's HospitalHoustonTexas.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Posey
authors.affiliation: Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas; Department of PediatricsBaylor College of MedicineHoustonTexas; Texas Children's HospitalHoustonTexas; Department of OphthalmologyBaylor College of MedicineHoustonTexas; Department of MedicineBaylor College of MedicineHoustonTexas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
keywords: Cataract; Hutterite; LEM domain; LEMD2; MUC21; recessive; sudden death