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

Sampath, Srirangan; Keats, Bronya; Lacassie, Yves

Description

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...[Show more]

dc.contributor.authorSampath, Srirangan
dc.contributor.authorKeats, Bronya
dc.contributor.authorLacassie, Yves
dc.date.accessioned2015-12-10T23:33:18Z
dc.identifier.issn1552-4825
dc.identifier.urihttp://hdl.handle.net/1885/69226
dc.description.abstractWe 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 21kb of promoter regions showed a novel polymorphism 1,249bp 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.
dc.publisherJohn Wiley & Sons Inc
dc.sourceAmerican Journal of Medical Genetics, Part A
dc.subjectKeywords: adolescent; adult; article; autosomal dominant disorder; child; chromosome 14q; clinical article; clinical feature; comparative genomic hybridization; copy number variation; ear malformation; family history; female; gene sequence; haplotype; hearing impai Autosomal dominant; Chromosome 14q31; Deafness; Hypertelorism; Linkage mapping; New syndrome; Preauricular sinus; Punctal pits
dc.titleHPPD: A newly recognized autosomal dominant disorder involving hypertelorism, preauricular sinus, punctal pits, and deafness mapping to chromosome 14q31
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume155
dc.date.issued2011
local.identifier.absfor110311 - Medical Genetics (excl. Cancer Genetics)
local.identifier.ariespublicationf2965xPUB1961
local.type.statusPublished Version
local.contributor.affiliationSampath, Srirangan, Louisiana State University
local.contributor.affiliationKeats, Bronya, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLacassie, Yves, Louisiana State University
local.description.embargo2037-12-31
local.bibliographicCitation.issue5
local.bibliographicCitation.startpage976
local.bibliographicCitation.lastpage985
local.identifier.doi10.1002/ajmg.a.33971
local.identifier.absseo920199 - Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified
dc.date.updated2016-02-24T08:20:19Z
local.identifier.scopusID2-s2.0-79955020362
local.identifier.thomsonID000290716700005
CollectionsANU Research Publications

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