HPPD: A newly recognized autosomal dominant disorder involving hypertelorism, preauricular sinus, punctal pits, and deafness mapping to chromosome 14q31

Authors

  • Srirangan Sampath,

    1. Department of Genetics, LSU Health Sciences Center, New Orleans, Louisiana
    Current affiliation:
    1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD.
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    • Postdoctoral Fellow.

  • Bronya J.B. Keats,

    1. Department of Genetics, LSU Health Sciences Center, New Orleans, Louisiana
    Current affiliation:
    1. Research School of Biology, Australian National University, Canberra, Australia.
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  • Yves Lacassie M.D., FACMG

    Corresponding author
    1. Department of Pediatrics, LSU Health Sciences Center, New Orleans and Children's Hospital, New Orleans, Louisiana
    • Division of Clinical Genetics, Department of Pediatrics LSUHSC and Children's Hospital New Orleans, 200 Henry Clay Avenue, New Orleans, LA 70118.
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  • How to Cite this Article: Sampath S, Keats BJB, Lacassie Y. 2011. HPPD: A newly recognized autosomal dominant disorder involving hypertelorism, preauricular sinus, punctal pits, and deafness mapping to chromosome 14q31. Am J Med Genet Part A 155:976–985.

Abstract

We report on a novel autosomal dominant disorder with variable phenotypic expression in a three-generation family; the major features include hypertelorism, preauricular sinus, deafness, and punctal pits with lacrimal-duct obstruction. We ruled out the involvement of EYA1, SIX1, and SIX5 as candidate genes by direct sequencing of their exons and by SNP-based linkage analysis. Subsequent SNP-based whole-genome genotyping and parametric multipoint linkage analysis gave lod scores >1 at 14q31 (LOD = 3.14), 11q25 (LOD = 1.87), and 8p23 (LOD = 1.18). By genotyping additional microsatellite markers at two of these three loci and using an expanded phenotype definition, the LOD at 14q31 increased to 3.34. Direct sequencing of the gene exons within the 14q31 critical interval and a custom aCGH experiment did not show any pathogenic mutation or copy-number changes. Further sequencing of 21 kb of promoter regions showed a novel polymorphism 1,249 bp upstream from the SELIL start codon that segregated with the disease haplotype. Cloning the novel polymorphism into luciferase reporter constructs resulted in a 20% reduction in the expression levels. The identification of this family with a distinctive clinical phenotype and linkage to a novel locus at 14q31 supports the existence of a new syndrome of the branchial cleft. © 2011 Wiley-Liss, Inc.

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