Abstract
Aim: To identify disease-causing mutations in four Lebanese families: three families with Bardet–Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS). Methods: We applied targeted NGS in two families and whole exome sequencing (WES) in two other families. Pathogenicity of candidate mutations was evaluated according to frequency, conservation, in silico prediction tools, segregation with disease, and compatibility with inheritance pattern. The presence of pathogenic variants was confirmed via Sanger sequencing followed by segregation analysis. Results: Most likely disease-causing mutations were identified in all included patients. In BBS patients, we found (M1): c.2258A > T, p. (Glu753Val) in BBS9, (M2): c.68T > C; p. (Leu23Pro) in ARL6, (M3): c.265_266delTT; p. (Leu89Valfs*11) and (M4): c.880T > G; p. (Tyr294Asp) in BBS12. A previously known variant (M5): c.551A > G; p. (Asp184Ser) was also detected in BBS5. In the USH patient, we found (M6): c.188A > C, p. (Tyr63Ser) in CLRN1. M2, M3, M4, and M6 were novel. All of the candidate mutations were shown to be likely disease-causing through our bioinformatic analysis. They also segregated with the corresponding phenotype in available family members. Conclusion: This study expanded the mutational spectrum and showed the genetic diversity of BBS and USH. It also spotlighted the efficiency of NGS techniques in revealing mutations underlying clinically and genetically heterogeneous disorders.
Highlights
Inherited retinal diseases (IRD) are a large group of clinically and genetically heterogeneous disorders characterized by loss of function of retinal photoreceptors, eventually leading to blindness [1].Genes 2019, 10, 1047; doi:10.3390/genes10121047 www.mdpi.com/journal/genesAltogether, they affect approximately 1 in 3000 people [2,3], and can be inherited according to any Mendelian inheritance pattern [1]
next generation sequencing (NGS) showed that she harbors a homozygous missense mutation (M1): c.2258A > T, p. (Glu753Val), rs61764068 in exon 20 of Bardet–Biedl syndrome 9 gene (BBS9)
NGS followed by extensive bioinformatic analysis revealed the presence of four novel and two known mutations in four Lebanese families
Summary
Inherited retinal diseases (IRD) are a large group of clinically and genetically heterogeneous disorders characterized by loss of function of retinal photoreceptors, eventually leading to blindness [1].Genes 2019, 10, 1047; doi:10.3390/genes10121047 www.mdpi.com/journal/genesAltogether, they affect approximately 1 in 3000 people [2,3], and can be inherited according to any Mendelian inheritance pattern [1]. Inherited retinal diseases (IRD) are a large group of clinically and genetically heterogeneous disorders characterized by loss of function of retinal photoreceptors, eventually leading to blindness [1]. They affect approximately 1 in 3000 people [2,3], and can be inherited according to any Mendelian inheritance pattern [1]. IRD may affect the retina alone (non-syndromic IRD) or may occur in conjunction with other systemic disorders (syndromic IRD). Among the non-syndromic forms, the most frequent subtype is retinitis pigmentosa (RP) known as rod-cone dystrophy (RCD) [5] which affects primarily the rod photoreceptors responsible for dim light vision, and secondarily the cone photoreceptors responsible for day light and precise color vision [7].
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