A novel missense variant in the BBS7 gene underlying Bardet-Biedl syndrome in a consanguineous Pakistani family

Abstract Background Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, affecting approximately 1 in 4000 individuals worldwide. The most common form of syndromic RP is Usher syndrome (USH) accounting for approximately 20–30 % of RP cases. Mutations in the USH2A gene cause a significant proportion of recessive non-syndromic RP and USH type II (USH2). This study aimed to determine the causative role of the USH2A gene in autosomal recessive inherited ocular diseases and to establish genotype-phenotype correlation associated with USH2A variants. Methods We performed direct Sanger sequencing and co-segregation analysis of the USH2A gene to identify disease causing variants in a non-syndromic RP family, two USH2 families and two Keratoconus (KC) families. Results Disease causing variants in the USH2A gene were identified in two families displayed KC and USH2 phenotypes. A novel variant c.4029T > G, p.Asn1343Lys in the USH2A gene was detected in a Pakistani family with KC phenotype. In addition, a missense variant (c.7334 C > T, p. Ser2445Phe) in the USH2A gene was found segregating in another Pakistani family with USH2 phenotype. Homozygosity of identified missense USH2A variants was found associated with autosomal recessive inherited KC and USH2 phenotypes in investigated families. These variants were not detected in ethnically matched healthy controls. Moreover, the USH2A variants were predicted to be deleterious or potentially disease causing by PolyPhen-2, PROVEAN and SIFT. Conclusions This study provided first evidence for association of a novel USH2A variant with KC phenotype in a Pakistani family as well as established the phenotype-genotype correlation of a USH2A variant (c.7334 C > T, p. Ser2445Phe) with USH2 phenotype in another Pakistani family. The phenotype-genotype correlations established in present study may improve clinical diagnosis of affected individuals for better management and counseling.

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BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107626 ◽

2021 ◽

pp. jmedgenet-2020-107626

Author(s):

Zeinab Fadaie ◽

Laura Whelan ◽

Adrian Dockery ◽

Catherina H Z Li ◽

L Ingeborgh van der Born ◽

...

Keyword(s):

Functional Analysis ◽

Retinitis Pigmentosa ◽

Missense Variant ◽

Compound Heterozygous ◽

Bardet Biedl Syndrome ◽

Coding Regions ◽

Pathogenic Variants ◽

Splice Assay ◽

Variant Analysis

BackgroundInherited retinal diseases (IRDs) can be caused by variants in >270 genes. The Bardet-Biedl syndrome 1 (BBS1) gene is one of these genes and may be associated with syndromic and non-syndromic autosomal recessive retinitis pigmentosa (RP). Here, we identified a branchpoint variant in BBS1 and assessed its pathogenicity by in vitro functional analysis.MethodsWhole genome sequencing was performed for three unrelated monoallelic BBS1 cases with non-syndromic RP. A fourth case received MGCM 105 gene panel analysis. Functional analysis using a midigene splice assay was performed for the putative pathogenic branchpoint variant in BBS1. After confirmation of its pathogenicity, patients were clinically re-evaluated, including assessment of non-ocular features of Bardet-Biedl syndrome.ResultsClinical assessments of probands showed that all individuals displayed non-syndromic RP with macular involvement. Through detailed variant analysis and prioritisation, two pathogenic variants in BBS1, the most common missense variant, c.1169T>G (p.(Met390Arg)), and a branchpoint variant, c.592-21A>T, were identified. Segregation analysis confirmed that in all families, probands were compound heterozygous for c.1169T>G and c.592-21A>T. Functional analysis of the branchpoint variant revealed a complex splicing defect including exon 8 and exon 7/8 skipping, and partial in-frame deletion of exon 8.ConclusionA putative severe branchpoint variant in BBS1, together with a mild missense variant, underlies non-syndromic RP in four unrelated individuals. To our knowledge, this is the first report of a pathogenic branchpoint variant in IRDs that results in a complex splice defect. In addition, this research highlights the importance of the analysis of non-coding regions in order to provide a conclusive molecular diagnosis.

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A Missense Variant in the Bardet-Biedl Syndrome 2 Gene (BBS2) Leads to a Novel Syndromic Retinal Degeneration in the Shetland Sheepdog

Genes ◽

10.3390/genes12111771 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1771

Author(s):

Rebekkah J. Hitti-Malin ◽

Louise M. Burmeister ◽

Frode Lingaas ◽

Maria Kaukonen ◽

Inka Pettinen ◽

...

Keyword(s):

Missense Variant ◽

Clinical History ◽

Causal Variant ◽

Hereditary Diseases ◽

Single Nucleotide ◽

Progressive Retinal Atrophy ◽

Bardet Biedl Syndrome ◽

Dna Test ◽

Development And Utilization ◽

Exon 11

Canine progressive retinal atrophy (PRA) describes a group of hereditary diseases characterized by photoreceptor cell death in the retina, leading to visual impairment. Despite the identification of multiple PRA-causing variants, extensive heterogeneity of PRA is observed across and within dog breeds, with many still genetically unsolved. This study sought to elucidate the causal variant for a distinct form of PRA in the Shetland sheepdog, using a whole-genome sequencing approach. Filtering variants from a single PRA-affected Shetland sheepdog genome compared to 176 genomes of other breeds identified a single nucleotide variant in exon 11 of the Bardet–Biedl syndrome-2 gene (BBS2) (c.1222G>C; p.Ala408Pro). Genotyping 1386 canids of 155 dog breeds, 15 cross breeds and 8 wolves indicated the c.1222G>C variant was only segregated within Shetland sheepdogs. Out of 505 Shetland sheepdogs, seven were homozygous for the variant. Clinical history and photographs for three homozygotes indicated the presence of a novel phenotype. In addition to PRA, additional clinical features in homozygous dogs support the discovery of a novel syndromic PRA in the breed. The development and utilization of a diagnostic DNA test aim to prevent the mutation from becoming more prevalent in the breed.

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Whole exome sequencing identified a heterozygous KCNJ2 missense variant underlying autosomal dominant familial hypokalemic periodic paralysis in a Pakistani family

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0276 ◽

2019 ◽

Vol 32 (12) ◽

pp. 1385-1389

Author(s):

Aman Ullah ◽

Ranjha Khan ◽

Muhammad Naeem

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Dominant ◽

Missense Variant ◽

Periodic Paralysis ◽

Pakistani Family ◽

Autosomal Dominant Disorder ◽

Whole Exome ◽

The Family ◽

Blood Potassium

Abstract Background Familial hypokalemic periodi9c paralysis (hypoKPP) is a rare autosomal dominant disorder characterized by episodic paralytic attacks caused by fall in blood potassium. CACNA1S, SCN4A or KCNJ2 variants can cause hypoKPP. Case presentation We investigated a Pakistani family affected with autosomal dominant familial hypoKPP through whole exome sequencing (WES). A heterozygous KCNJ2 missense variant c.919A > G was found segregating with the disease phenotype in the family. Conclusions The KCNJ2 missense variant is the likely cause of the disorder in the affected family. The finding should help improve antenatal screening and genetic counselling of this family.

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