Novel biallelic variant in BBS9 causative of Bardet-Biedl syndrome: expanding the spectrum of disease-causing genetic alterations.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy disorder. Many BBS disease-causing genetic variants have been identified due to the advancement of molecular diagnostic tools. We report on a novel pathogenic variant in a consanguineous Pakistani family with an affected child. CASE PRESENTATION: Clinical exome sequencing was used to search for BBS causing variants in the affected individual and identified a novel homozygous splice-site variant in the BBS9 gene (c.702 + 1del). Sanger sequencing was performed for variant validation and segregation studies. Expression analysis using mRNA levels to assess the functional impact of the novel variant demonstrated skipping of exon 7 in the affected alleles, suggesting a truncating effect. Three-dimensional structural modelling was used to predict pathogenicity of the variant residue and the alteration leads to a partial deletion of the PHTB1_N domain and a total deletion of the PHTB1_C domain. CONCLUSION: The study of this case expands the spectrum of biallelic variants in the BBS9 gene associated with BBS and increased the knowledge on the molecular consequences of splicing variation c.702 + 1del.

Haplotype analysis of CLDN19 single nucleotide polymorphisms in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

BACKGROUND: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disease caused by mutations in the CLDN16 or CLDN19 gene. Previous studies using microsatellite markers flanking the CLDN19 locus estimated that p.G20D (c.59G>A), a recurrent mutation in Spanish families, is a founder mutation. In the present study, we assessed the haplotype of Spanish patients using single nucleotide polymorphisms (SNPs). METHODS: Twenty-seven FHHNC patients were included in this study. We analyzed four SNPs located in CLDN19 introns 3 and 4 by polymerase chain reaction amplification and DNA sequencing. RESULTS: Three new patients with homozygous p.G20D were identified. The SNP genotyping analysis showed that alleles carrying this mutation shared a common SNP haplotype. CONCLUSIONS: Our findings suggest the existence of a founder effect responsible for FHHNC in our cohort. Testing for the presence of mutation p.G20D should be the first genetic screening in Spanish patients.