HPPD: A newly recognized autosomal dominant disorder involving hypertelorism, preauricular sinus, punctal pits, and deafness mapping to chromosome 14q31†
Article first published online: 7 APR 2011
Copyright © 2011 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Volume 155, Issue 5, pages 976–985, May 2011
How to Cite
Sampath, S., Keats, B. J.B. and 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., 155: 976–985. doi: 10.1002/ajmg.a.33971
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.
- Issue published online: 19 APR 2011
- Article first published online: 7 APR 2011
- Manuscript Accepted: 4 FEB 2011
- Manuscript Received: 19 AUG 2010
- new syndrome;
- preauricular sinus;
- punctal pits;
- linkage mapping;
- chromosome 14q31;
- autosomal dominant
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.