USH2A gene variants cause Keratoconus and Usher syndrome phenotypes in Pakistani families

Ahmed, Asif Naveed; Tahir, Raheel; Khan, Niamat; Ahmad, Mushtaq; Dawood, Muhammad; Basit, Abdul; Yasin, Muhammad; Nowshid, Maha; Marwan, Muhammad; Sultan, Komal; Saleha, Shamim

doi:10.1186/s12886-021-01957-9

Cited by 9 publications

(5 citation statements)

References 48 publications

(57 reference statements)

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“…In summary, eight alleles were eligible to be classified as benign/likely benign consistently by the ACMG standards, ClinVar classification system, and by majority of the online in-silico predictors. These eight benign/likely benign missense alleles are further detailed in Table 3 , and include SEMA4A (p.Arg713Gln) [ 72 ], USH2A (p.Ser2445Phe) [ 73 ], RPGRIP1 (p.Ala547Ser) [ 74 ], RP1 (p.Thr373Ile) [ 75 ], ZNF513 (p.Cys339Arg) [ 7 ], ALMS1 (p.Lys1748Glu) [ 76 ], RAX2 (p.Gly125Glu) [ 77 ], and EYS (p.Thr2777Ser) [ 78 ].…”

Section: Resultsmentioning

confidence: 99%

A systematic review of inherited retinal dystrophies in Pakistan: updates from 1999 to April 2023

Munir,

Afsar,

Rehman

2024

BMC Ophthalmol

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Background Inherited retinal degenerations (IRDs) are a group of rare genetic conditions affecting retina of the eye that range in prevalence from 1 in 2000 to 1 in 4000 people globally. This review is based on a retrospective analysis of research articles reporting IRDs associated genetic findings in Pakistani families between 1999 and April 2023. Methods Articles were retrieved through survey of online sources, notably, PubMed, Google Scholar, and Web of Science. Following a stringent selection criterion, a total of 126 research articles and conference abstracts were considered. All reported variants were cross-checked and validated for their correct genomic nomenclature using different online resources/databases, and their pathogenicity scores were explained as per ACMG guidelines. Results A total of 277 unique sequence variants in 87 distinct genes, previously known to cause IRDs, were uncovered. In around 70% cases, parents of the index patient were consanguineously married, and approximately 88.81% of the detected variants were found in a homozygous state. Overall, more than 95% of the IRDs cases were recessively inherited. Missense variants were predominant (41.88%), followed by Indels/frameshift (26.35%), nonsense (19.13%), splice site (12.27%) and synonymous change (0.36%). Non-syndromic IRDs were significantly higher than syndromic IRDs (77.32% vs. 22.68%). Retinitis pigmentosa (RP) was the most frequently observed IRD followed by Leber’s congenital amaurosis (LCA). Altogether, mutations in PDE6A gene was the leading cause of IRDs in Pakistani families followed by mutations in TULP1 gene. Conclusion In summary, Pakistani families are notable in expressing recessively inherited monogenic disorders including IRDs likely due to the highest prevalence of consanguinity in the country that leads to expression of rare pathogenic variants in homozygous state.

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Section: Resultsmentioning

confidence: 99%

A systematic review of inherited retinal dystrophies in Pakistan: updates from 1999 to April 2023

Munir,

Afsar,

Rehman

2024

BMC Ophthalmol

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“…In this study, causative variants in TULP1 , PDE6C , RHO , MERTK and MYO7A genes were identified in all the 4 Pakistani families displayed either non-syndromic RP or USH phenotypes using WES approach. Studies have previously reported variants in CRB1 , PDE6A , PDE6B , RP1 , TULP1, CLRN1, MERTK and CNGA1 causing non-syndromic RP and variants in MYO7A , USH2A , CDH23 , USH1H , PCDH15 genes causing USH in families of Pakistani origin [ 8 , 21 – 28 ]. Importantly, delineating genetic basis of RP and USH in this study and in previous studies provides essential information for molecular diagnosis as well as for genetic counselling of extended families in order to reduce burden of these diseases in Pakistani population.…”

Section: Discussionmentioning

confidence: 99%

“…It is generally considered that about 70-80% of all RP cases are non-syndromic, where eyes are exclusively affected [ 3 ]. However, the most common syndromic form of RP is Usher syndrome (USH), characterized by sensorineural hearing loss, RP, and, in some cases, vestibular dysfunction [ 4 ]. USH is the most frequent cause of deaf-blindness and affects more than 50% of both deaf and blind individuals in different populations [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…In general, MYO7A is the most frequent cause of USH type1 accounting for approximately 50% of cases [ 19 , 20 ]. Although, studies have reported variants in CRB1 , PDE6A , PDE6B , RP1 , TULP1, CLRN1, MERTK and CNGA1 causing non-syndromic RP and MYO7A , USH2A , CDH23 , USH1H , PCDH15 genes are responsible for USH phenotypes in families of Pakistani origin [ 8 , 21 – 28 ]. Among these genes, the most causative USH genes are MYO7A and CDH23 having relative abundance of 42.9% and 28.6% respectively [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Unravelling the genetic basis of retinal dystrophies in Pakistani consanguineous families

et al. 2023

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Background Retinitis Pigmentosa (RP) is a clinically and genetically progressive retinal dystrophy associated with severe visual impairments and sometimes blindness, the most common syndromic form of which is Usher syndrome (USH). This study aimed to further increase understanding of the spectrum of RP in the Khyber Pakhtunkhwa region of Pakistan. Methodology Four consanguineous families of Pashtun ethnic group were investigated which were referred by the local collaborating ophthalmologists. In total 42 individuals in four families were recruited and investigated using whole exome and dideoxy sequencing. Among them, 20 were affected individuals including 6 in both family 1 and 2, 5 in family 3 and 3 in family 4. Result Pathogenic gene variants were identified in all four families, including two in cone dystrophy and RP genes in the same family (PDE6C; c.480delG, p.Asn161ThrfsTer33 and TULP1; c.238 C > T, p.Gln80Ter) with double-homozygous individuals presenting with more severe disease. Other pathogenic variants were identified in MERTK (c.2194C > T, p.Arg732Ter), RHO (c.448G > A, p.Glu150Lys) associated with non-syndromic RP, and MYO7A (c.487G > A, p.Gly163Arg) associated with USH. In addition, the reported variants were of clinical significance as the PDE6C variant was detected novel, whereas TULP1, MERTK, and MYO7A variants were detected rare and first time found segregating with retinal dystrophies in Pakistani consanguineous families. Conclusions This study increases knowledge of the genetic basis of retinal dystrophies in families from Pakistan providing information important for genetic testing and diagnostic provision particularly from the Khyber Pakhtunkhwa region.

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“…USH2A variants display a wide phenotypic spectrum, therefore, most prevalent USH2A variants phenotype-genotype correlation may contribute to genetic counselling. It also improves the prognosis of affected individuals, and provides guideline for patient-speci c treatment [12]. USH2A (c.8559-2 A > G) variant site located in the structural domain of protein FN3 and causes an exon 43 jump, affecting protein function.…”

Section: Discussionmentioning

confidence: 99%

Novel frameshift Variant c.3056delA of the DHX38 Gene in a Chinese Family With Retinitis Pigmentosa

Zhu

Liu

et al. 2023

Preprint

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Background Retinitis pigmentosa (RP) is the most common inherited retinal degeneration. Our purpose was to describe disease-causing variants in a Chinese patient with RP. We described the clinical features and identify a novel (p.Lys1019fs) variant in DHX38.Case presentation A 47-year-old Chinese man complained of persistent visual impairment. To clarify the diagnosis, the clinical symptoms were observed and analysed in combination with comprehensive ophthalmologic examinations and genetic analysis. Abnormal fundus manifestations were found, including thinning of retinal arteriovenous vessels, obscure reflection in macular fovea, and scattered osteocyte-like pigment in the retina. We identified two mutations of USH2A gene (c.2802T > G and c.8559-2A > G ) and one novel mutation of DHX38 gene (c.3056delA) in the proband. The parents with visual loss were heterozygous carriers. The compound heterozygous mutations in USH2A are the underlying cause of this case. And the novel variant results in the mutation of amino acid 1019 from lysine to arginine and bring a new reading frame, the 37th codon followed by the mutation site turn to be a stop codon, resulting in a premature protein truncation.Conclusions The study identified two compound heterozygous USH2A variants (c.2802T > G and c.8559-2A > G) and one novel DHX38 variants (c.3056delA) in an RP patient. It is conducive to a clearer understanding of genotype-phenotype correlation in the non-syndromic RP patients. Our study expands the spectrum of DHX38 variants in RP as well.

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USH2A gene variants cause Keratoconus and Usher syndrome phenotypes in Pakistani families

Cited by 9 publications

References 48 publications

A systematic review of inherited retinal dystrophies in Pakistan: updates from 1999 to April 2023

A systematic review of inherited retinal dystrophies in Pakistan: updates from 1999 to April 2023

Unravelling the genetic basis of retinal dystrophies in Pakistani consanguineous families

Novel frameshift Variant c.3056delA of the DHX38 Gene in a Chinese Family With Retinitis Pigmentosa

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