Mutational analysis of the CYP1B1 gene in Pakistani primary congenital glaucoma patients: Identification of four known and a novel causative variant at the 3′ splice acceptor site of intron 2

Abstract

Funding informationQuaid-i-Azam University Primary congenital glaucoma (PCG) causes blindness in early age. It has an autosomal recessive pattern of inheritance, hence is more prevalent in populations with frequent consanguineous marriages that occur in the Pakistani population. Mutations in the CYP1B1 gene are commonly associated with PCG. The aim of the present study was to identify genetic mutations in the CYP1B1 gene in PCG cases belonging to 38 Pakistani families. DNA was extracted using blood samples collected from all enrolled patients, their available unaffected family members and controls. Direct sequencing of the CYP1B1 gene revealed a novel 3' splice acceptor site causative variant segregating in an autosomal recessive manner in a large consanguineous family with four PCG-affected individuals. The novel variant was not detected in 93 ethnically matched controls.Furthermore, four already reported mutations, including p.G61E, p.R355X, p.R368H, and p. R390H were also detected in patients belonging to nine different families. All identified causative variants were evaluated by computational programs, that is, SIFT, PolyPhen-2, and Muta-tionTaster. Pathogenicity of the novel splice site variant identified in this study was analyzed by Human Splicing Finder and MaxEntScan. Ten out of 38 families with PCG had the disease due to CYP1B1 mutations, suggesting CYP1B1 was contributing to PCG in these Pakistani patients.Identification of this novel 3' splice acceptor site variant in intron 2 is the first report for the CYP1B1 gene contributing to genetic heterogeneity of disease. K E Y W O R D S autosomal recessive, CYP1B1, primary congenital glaucoma, splice site variant

Mutation screening of the CYP1B1 gene reveals thirteen novel disease-causing variants in consanguineous Pakistani families causing primary congenital glaucoma

“…; p. Ser476Pro is 44% prevalent in India, p.Arg469Trp, p.Arg368His, p.Arg390His, p.Gly61Glu and p.Glu173Arg are 70% prevalent in Iran, p.Gly61Glu, p. Arg390His and p.Glu229Lys are [15]. Previous studies from Pakistan had reported p.Arg390His mutation to be implicated in more than 50% of analyzed PCG cases [6,20,38,39]; however, in present study, we did not identify this mutation in any of the analyzed case. A possible explanation of non-detection of p.Arg390His mutation in our study cohort could be the differences in ethnicities of analyzed subjects.…”

“…Up till now almost 270 mutations are reported in CYP1B1 gene including missense, small deletions, indels, gross deletions and regulatory mutations [19]. Studies have revealed several genetic mutations causing PCG from Pakistani population, but this data is still too limited as compared to high prevalence of this disorder in our population due to consanguinity [6,10,15,20]. In an ongoing effort of mutation screening of CYP1B1 gene in PCG cases belonging to consanguineous Pakistani families, we enrolled and screened twenty-five families for CYP1B1 variants.…”

Analysis of Wilson disease mutations in copper binding domain of ATP7B gene

“…Among enrolled cases 95% cases belonged to inbred families with 82.5% being products of first cousin unions ( Table 2 ). This observation is attributed to high degree of consanguinity, a main determinant of the high incidence of recessive disorders in our population [ 16 , 17 ]. Furthermore, 5% cases were not belonging to consanguineous parents which show presence of minor allele in general population with possibility of compound heterozygous variations predisposing to clinical manifestation [ 18 ].…”

FANCA and contribution of studies from Asian populations to the understanding of fanca mediated Fanconi anemia

“…As FANCA is reported to be responsible for about 60%-70% cases of FA (SELENTI et al, 2015) and FA is inherited as autosomal recessive disorder. All autosomal recessive diseases are highly prevalent in inbred populations (FIRASAT et al, 2017;AFZAL et al, 2019) therefore Asian populations where consanguinity is customary have higher incidence FA. All the articles published till March, 2019 were assessed from www.ncbi.nlm.nih.gov/pubmed to extract data regarding mutations of FANCA gene including type of mutation, location of mutation, amino acid/protein change, population from where reported and study protocol.…”