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

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

  • Mol Genet Genomic Med. 2015 Nov 14;4(1):77-94. doi: 10.1002/mgg3.181.
Philip M Boone 1,  Bo Yuan 1,  Shen Gu 1,  Zhiwei Ma 2,  Tomasz Gambin 1,  Claudia Gonzaga-Jauregui 1,  Mahim Jain 1,  Todd J Murdock 3,  Janson J White 1,  Shalini N Jhangiani 4,  Kimberly Walker 4,  Qiaoyan Wang 4,  Donna M Muzny 4,  Richard A Gibbs 5,  J Fielding Hejtmancik 2,  James R Lupski 6,  Jennifer E Posey 1,  Richard A Lewis 7
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas.
  • 2 Ophthalmic Genetics and Visual Function Branch National Eye Institute Rockville Maryland.
  • 3 Rocky Mountain Eye Center Missoula Montana.
  • 4 Human Genome Sequencing Center Baylor College of Medicine Houston Texas.
  • 5 Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas; Human Genome Sequencing CenterBaylor College of MedicineHoustonTexas.
  • 6 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.
  • 7 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.
PMID: 26788539 DOI: 10.1002/mgg3.181
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).

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 LEMD2.

Keywords

Cataract; Hutterite; LEM domain; LEMD2; MUC21; recessive; sudden death.

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