Exome sequence analysis in consanguineous Pakistani families inheriting Bardet‐Biedle syndrome determined founder effect of mutation c.299delC (p.Ser100Leufs*24) in BBS9 gene

Abstract

Background Bardet‐Biedl syndrome (BBS) is characterized by a heterogeneous phenotypic spectrum of retinopathy, intellectual disability (ID), obesity, polydactyly, and kidney dysfunctions as the major clinical features. Genetic investigations have reported 21 BBS genes, the products of which are mostly located at the centrosome, basal body or the ciliary transition zone. Methods In the present genetic report, we analyzed two apparently unrelated consanguineous BBS families from Dera Ismail Khan (D.I.Khan) district, Pakistan. Genetic mapping was performed using Whole exome sequencing and Sanger sequencing. Results Whole exome sequencing identified a recently reported single base deletion NM_001033604.1:c.299delC in the fourth exon of BBS9 in both families. The identified frameshift mutation is predicted to cause premature truncation of the expressed protein (p.Ser100Leufs*24). This mutation has previously been mapped in a consanguineous Pakistani family; therefore this is the second report of this particular mutation in two additional BBS families originating from different locations. Conclusion We speculate the evolutionary significance of this mutation and assume its strong founder effect in the Khaisoori tribe of D.I.Khan. Based on these findings, we suggest developing a molecular diagnostic test that may be used for premarital and prenatal screening of families at risk of BBS.

A Novel BBS9 Mutation Identified via Whole-Exome Sequencing in a Chinese Family with Bardet-Biedl Syndrome

“…The patients' parents are nonconsanguineous, but the mutation analysis indicated that this family might be inbred. In previous reports, the founder effect of mutation c.299delC (p.Ser100Leufs * 24) in the BBS9 gene was observed in consanguineous Pakistani families [15,16].…”

Delineating the Spectrum of Genetic Variants Associated with Bardet-Biedl Syndrome in Consanguineous Pakistani Pedigrees

“…Previously, three different mutations in the BBS3 gene have been identified in three Pakistani families affected with BBS; one of the homozygous variants is a deletion of 54 Kb [31,40,41]. Notably, four other large deletions in BBS3 were found in BBS families from Saudi Arabia, France and USA [37,38].…”

Identification of a Novel Homozygous Missense (c.443A>T:p.N148I) Mutation in BBS2 in a Kashmiri Family with Bardet-Biedl Syndrome

“…BBS is a ciliopathy disorder that involves various body systems and mostly follows an autosomal recessive inheritance pattern; however, triallelic inheritance is also reported as a possible mechanism by some studies [ 18 – 20 ]. There are 21 genes that are associated with BBS so far; among those, BBS1 and BBS10 are mostly reported from North America and Europe, respectively, whereas BBS2 , BBS4 , BBS5 , and BBS12 are more prevalent in the Middle East and North Africa [ 11 , 21 , 22 ]. Based on previous and our current study, only eight BBS mutated genes ( BBS1 (OMIM #209901) [ 23 ], BBS2 (OMIM #606151), BBS3 / ARL6 (OMIM #608845), BBS5 (OMIM #603650) [ 24 ], BBS8 / TTC8 (OMIM #608132) [ 25 , 26 ], BBS9 (OMIM #615986) [ 9 , 27 ], BBS10 (OMIM #610148) [ 28 – 30 ], and BBS12 (OMIM #610683)) [ 31 ] have been reported in the Pakistani population.…”