Investigating the Molecular Basis of Bardet-Biedl Syndrome in Familial Cases

Abstract

Bardet-Biedl (BBS) syndrome is a ciliopathy and it was first time identified by Laurence and Moon in 1866. BBS syndrome is recognized by its primary and secondary features. Rod/cone dystrophy (RCD), polydactyly (PD), obesity, genetal defects, renal abnormalities and learning problems are the primary symptoms of BBS. Developmental delay, dental issues, heart defects, speech problem, syndactyly or brachydactyly, poor coordination, olfactory defects, diabetes mellitus, hepertension, liver defects and craniofacial dismorphism are common BBS secondary symptoms. The appearance of symptoms of BBS are related to age, in early age only few symptoms are apparent other symptoms evolve during or after first decade of life, most individuals having polydactyly at birth appears healthy but at later stages of life they are diagnosed with BBS. BBS is thought to affect 1 in 150000 people worldwide, but its prevalence varies in isolated, inbred, and consanguineous cultures. Since around 26 genes are thought to be involved in BBS, many investigations have found that BBS patients experience a range of symptoms. Autosomal recessive mode of inheritance was observed in BBS syndrome by initial gene discovery studies but further more research complicated the genetics of BBS and prevailed incomplete penetrance and triallelic inheritance. BBS10 and BBS3/ARL6 are most mutated genes in Pakistan and India. The aim of present studys was to investigate the molecular basis of Bardet-Biedl syndrome in familial cases.Ethical approval was obtained from Bio-ethical review committee, Faculty of Biological Sciences, Quaid-i Azam University Islamabad, Pakistan and Al-Shifa Trust Eye Hospital Rawalpindi, Pakistan. All the enrolled families were diagnosed with Retinitus Pigmentosa (RP) by ophthalmologist and then after conducting detailed interview BBS families were selected. Partiticipating members were interviewed for family history of disease, pedigree drawing, and clinical records were collected from affected and unaffected members after written consent. The genomic DNA was extracted for genetic analysis. Primers were designed to amplify exon 2 and 5 of ARL6 gene for mutation analysis. After the amplification of selected exon, the amplified products were purified and sent for Sanger‘s sequencing. Sequencing data identified previously reported mutation c.281T>C causing (p.I94T) in exon 5 of ARL6 gene in enrolled family RP 43. However, other previously reported and novel variants were identified in exon 5 of ARL6 gene but no variation was observed in exon 2 of ARL6 gene of selected families. For families in which no disease causing variant was identified, screening of remaining exon of ARL6 and other genes should be performed to identify molecular genetic defect. Results of this study also showed that consanguinity contributes to high incidence of recessively inherited disorders including BBS in our population. For this reason genetic counseling was provided to all participating families