Suche eines Kandidatengens für das Branchio-Oculo-Facial-Syndrom durch genomweites Screening

Abstract

Branchio-Oculo-Facial Syndrome (BOFS) is an extremely rare autosomal dominant disorder. Pathognomonic are cervical/infra-auricular skin defects or branchial sinus defects. Craniofacial symptoms include pseudocleft of the upper lip or cleft lip/palate, upper lip pits, and low-set ears with malformed pinnae and auricular pits. The pathogenesis of BOFS is unknown. Some analyses (candidate gene approach) of genes that cause disorders that overlap with BOFS, have not identified any mutations for this syndrome. The largest known BOFS-family until now (with three generations and five BOFS-affected persons), allowed us to perform the first genome-wide analysis for BOFS. We looked for shared autosomal haplotypes in the affected individuals of this family (BOFS is an autosomal dominant disorder). We used more than 400 microsatellite markers for a DNA fragment analysis. This method allowed us to determine the size of the PCR-amplified DNA-sequences and to compare how alleles segregate in the family. We found no common haplotypes in BOFS-affected individuals of the family for chromosomes 1, 8, 9, 10, 16, 17, and 20. Thus, we conclude that the responsible gene for BOFS is not on any of these chromosomes. Parts of the remaining autosomes were also excluded by means of this method. We defined some candidate regions, summarizing up to 11 % of the total human genome (exactly 363 Mbp). We looked for genes and/or diseases in these favoured chromosomal regions, which could have some relation with BOFS. For that study, we considered some characteristics of genes like their expression profile, their function, their integration into pathways, or information about studies on transgenic animals. We summarized the results in tables for each chromosome. We present now a total of 651 genes and 11 disorders, which might be causative of or related with BOFS, respectively. We suggest sequencing genes like PAX6, FGFR4, or FOXI1 for future genetic analyses looking for BOFS-causing mutations.