Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping.

BACKGROUND: Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive disorder characterised by the five cardinal features retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity and hypogenitalism. In addition, renal cysts and other anomalies of the kidney and urinary tract can be present. To date, mutations in 12 BBS genes as well as in MKS1 and CEP290 have been identified as causing BBS. The vast genetic heterogeneity of BBS renders molecular genetic diagnosis difficult in terms of the time and cost required to screen all 204 coding exons. METHOD: Here, the use of genome-wide homozygosity mapping as a tool to identify homozygous segments at known BBS loci, in BBS individuals from inbred and outbred background, is reported. RESULTS: In a worldwide cohort of 45 families, causative homozygous mutations in 20 families were identified via direct exon sequencing. Eleven of these mutations were novel, thereby increasing the number of known BBS mutations by 5% (11/218). CONCLUSIONS: Thus, in the presence of extreme genetic locus heterogeneity, homozygosity mapping provides a valuable approach to the molecular genetic diagnosis of BBS and will facilitate the discovery of novel pathogenic mutations.

New insights into the origin of the Gaucher disease-causing mutation N370S: extended haplotype analysis using the 5GC3.2, 5470 G/A, and ITG6.2 polymorphisms.

Gaucher disease is a lysosomal storage disorder inherited as an autosomal recessive trait. It is highly prevalent among Ashkenazi Jews but also present in other populations. Mutations in the glucocerebrosidase gene are the main cause of the disorder. One of these gene defects, N370S, is the most prevalent disease allele in the Ashkenazi Jewish patient population and also frequent in others, such as the Spanish and Portuguese Gaucher disease populations. Previous results based on haplotype analysis support the hypothesis of a single origin for this mutation. We have extended the haplotype analysis to include three newly described polymorphisms, 5GC3.2, ITG6.2 (very close to the gene), and 5470 G/A (in intron 7 of the GBA gene) in a sample of Spanish and Ashkenazi Jewish patients. The results confirm the single origin of the mutation in these two populations. The 5470A allele is only found in N370S chromosomes and was believed to be limited to the Portuguese population. Here we describe that it is also present with a similar frequency in Spain. Moreover, most of the 5470A alleles are found within particular haplotypes, which have some differences from the common N370S haplotype.