Sampath et al. (2011) studied a large 5-generation African American pedigree in which the 29-day-old proband and his 32-year-old father had bilateral preauricular sinus, bilateral punctal pits, lacrimal duct obstruction, hypertelorism, bilateral distal axial triradii, abnormal palmar flexion creases, and deafness. The infant also displayed shawl scrotum, which was not present in the father. Evaluation of family members revealed significant variability in the phenotype. Of 13 individuals who displayed hypertelorism, it was the only feature in 7; 2 of those individuals had children with more severe manifestations, suggesting that hypertelorism might be the mildest expression of the phenotype. Preauricular sinuses were seen in 6 individuals, including the proband and his father, and were bilateral in all but 1 individual. Deafness was present in 4 individuals, 3 of whom had preauricular sinuses; all of the deaf individuals wore hearing aids. Variation of the palmar flexion creases and presence of a vertical crease in the interdigital area were seen in many members of the family, whereas lacrimal duct obstruction and punctal pits were seen only in the proband and his father. Sampath et al. (2011) stated that the collection of manifestations in this family appeared to be unique, and designated the syndrome HPPD, for hypertelorism, preauricular sinus, punctal pits, and deafness.

The large 5-generation African American pedigree studied by Sampath et al. (2011) presented a syndrome involving branchial cleft anomalies that segregated as an autosomal dominant trait with variable expression.

After exclusion of mutations in the candidate genes EYA1 (601653), SIX1 (601205), and SIX5 (600963) in a large 5-generation African American pedigree segregating variable branchial cleft anomalies in an autosomal dominant fashion, Sampath et al. (2011) performed whole-genome genotyping and parametric multipoint linkage analysis. They identified 3 loci with lod scores greater than 1.0, obtaining a lod score of 3.14 for the largest region, located on chromosome 14q31.1-q31.3. Subsequent analyses with additional SNPs and microsatellite markers excluded 2 of the loci but increased the lod score at 14q31 to 3.3 and defined a critical 8.3-Mb interval.

In a large 5-generation African American pedigree with variable branchial cleft anomalies mapping to chromosome 14q31.1-q31.3, Sampath et al. (2011) analyzed 7 candidate genes but did not identify any pathogenic mutations in the exons or splice junctions, and array CGH analysis of DNA from 4 family members revealed no segregating copy number change in the 14q31 critical interval. Analysis of promoter sequences, however, revealed a -1249A-C variant within the promoter of the SEL1L gene (602329) that segregated with disease in the family, with all affected individuals being heterozygous for the -1249C allele. Because the C allele was also found at low frequencies in control populations and has a relatively minor effect on expression levels (20% reduction compared to the A allele), Sampath et al. (2011) concluded that it probably did not represent the causative mutation but might be in linkage disequilibrium with it.