Next-generation sequencing for molecular diagnosis of autosomal recessive polycystic kidney disease

Edrees, Burhan; Athar, Mohammad; Al-Allaf, Faisal A.; Taher, Mohiuddin M.; Khan, Wazir Zada; Bouazzaoui, Abdellatif; Al-Harbi, Naffaa; Safar, R; Al-Edressi, Howaida; Alansary, Khawala; Anazi, Abulkareem; Altayeb, Naji; Ahmed, Muawia A.; Abduljaleel, Zainularifeen

doi:10.1016/j.gene.2016.07.021

Cited by 18 publications

(16 citation statements)

References 27 publications

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“…The missense change, p.(Arg1624Trp), was previously reported in patients from different ethnicities, including Caucasian Americans [24,25], Dutch [26], Czech Republicans [21], Slovenians [27], Saudi Arabians [24,28,29] and Kuwaitis [30]. The p.(Arg1624Trp) mutation has been described with late onset or older ARPKD presentations when present homozygously [24,28] and heterozygously in trans with other truncating or missense change [24,27].…”

Section: Discussionmentioning

confidence: 94%

Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

Alawi

Molinari

Salmi³

et al. 2020

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Background There is a high prevalence of rare genetic disorders in the Middle East, and their study provides unique clinical and genetic insights. Autosomal recessive polycystic kidney disease (ARPKD) is one of the leading causes of kidney and liver-associated morbidity and mortality in Oman. We describe the clinical and genetic profile of cohort of ARPKD patients.Methods We studied patients with a clinical diagnosis of ARPKD ( n =40) and their relatives [parents ( n =24) and unaffected siblings ( n =10)] from 32 apparently unrelated families, who were referred to the National Genetic Centre in Oman between January 2015 and December 2018. Genetic analysis of PKHD1 was performed through next generation sequencing (NGS) and Sanger sequencing.Results A clinical diagnosis of ARPKD was made prenatally in 8 patients, 21 were diagnosed during infancy (0-1 year), 9 during early childhood (2-8 years) and 2 at later ages (9-13 years). Clinical phenotypes included polycystic kidneys, hypertension, hepatic fibrosis and splenomegaly. 24 patients had documented chronic kidney disease. 24 out of the 32 families had a family history suggesting an autosomal recessive pattern of inherited kidney disease, and there was known consanguinity in 21 families (66%). A molecular genetic diagnosis with biallelic PKHD1 mutations was confirmed in 38 patients from 30 different families, giving a detection rate of 94%. Two unrelated patients remained genetically unsolved. In all of the solved cases, only four different PKHD1 missense pathogenic variants were identified: c.107C>T, p.(Thr36Met); c.406A>G, p.(Thr136Ala); c.4870C>T, p.(Arg1624Trp) and c.9370C>T, p.(His3124Tyr) located in exons 3, 6, 32 and 58, respectively. The c.406A>G, p.(Thr136Ala) missense mutation was detected homozygously in one family and heterozygously with a c.107C>T, p.(Thr36Met) allele in 5 other families. Overall, the most commonly detected pathogenic allele was c.107C>T; (Thr36Met), which was seen in 24 families.Conclusion Molecular genetic screening of PKHD1 in clinically suspected ARPKD cases produced a high diagnostic rate. The four PKHD1 missense variants identified suggest there may be common founder alleles in the Omani population. Cost effective targeted PCR analysis of these specific alleles can be a useful diagnostic tool for future cases of suspected ARPKD in Oman.

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Section: Discussionmentioning

confidence: 94%

Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

Alawi

Molinari

Salmi³

et al. 2020

Preprint

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“…Ion-torrent probably makes NGS an attractive approach additionally for clinical and diagnostic application, chiefly when simplest particular genes or specific sets of genes through to be analyzed, such as we investigated for ADPKD and ARPKD genes [18].…”

Section: Discussionmentioning

confidence: 99%

“…destabilizing or stabilizing the wild type protein fold [36], [37]. The validation of the identified variants in our previous study [18] due to amino acid substitution and its impact of the protein structure and function due to the stability changes were studied using computational simulation techniques. The six identified variants displaying clinical significance were studied further using computational methods and showed that the predicted protein with mutant variant structure will have influence on the protein function.…”

Section: Discussionmentioning

confidence: 99%

“…Library construction, target enrichment, template preparation and sequencing were performed as described in Edrees et al [18]. In brief, the DNA libraries and enrichment of targeted sequences of the genes (PKHD1, PKD1 and PKD2) were achieved using Ion Plus Fragment Library kit, Ion Xpress bar-code adapters 1–16 kit and TargetSeq customized panel (Life Technologies).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we have validated the disease-causing variants due to amino acid substitution [18] among ARPKD (PKHD1) and ADPKD (PKD1 and PKD2) genes based on the exons and flanking regions study in Saudi patients using Ion-PGM sequencing. This study show that based on the computational predictions an amino acid substitution may eventually affect the protein function due to the structural alteration causing stable changes in the involved domain.…”

Section: Introductionmentioning

confidence: 99%

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Functional alterations due to amino acid changes and evolutionary comparative analysis of ARPKD and ADPKD genes

et al. 2016

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A targeted customized sequencing of genes implicated in autosomal recessive polycystic kidney disease (ARPKD) phenotype was performed to identify candidate variants using the Ion torrent PGM next-generation sequencing. The results identified four potential pathogenic variants in PKHD1 gene [c.4870C > T, p.(Arg1624Trp), c.5725C > T, p.(Arg1909Trp), c.1736C > T, p.(Thr579Met) and c.10628T > G, p.(Leu3543Trp)] among 12 out of 18 samples. However, one variant c.4870C > T, p.(Arg1624Trp) was common among eight patients. Some patient samples also showed few variants in autosomal dominant polycystic kidney disease (ADPKD) disease causing genes PKD1 and PKD2 such as c.12433G > A, p.(Val4145Ile) and c.1445T > G, p.(Phe482Cys), respectively. All causative variants were validated by capillary sequencing and confirmed the presence of a novel homozygous variant c.10628T > G, p.(Leu3543Trp) in a male proband. We have recently published the results of these studies (Edrees et al., 2016). Here we report for the first time the effect of the common mutation p.(Arg1624Trp) found in eight samples on the protein structure and function due to the specific amino acid changes of PKHD1 protein using molecular dynamics simulations. The computational approaches provide tool predict the phenotypic effect of variant on the structure and function of the altered protein. The structural analysis with the common mutation p.(Arg1624Trp) in the native and mutant modeled protein were also studied for solvent accessibility, secondary structure and stabilizing residues to find out the stability of the protein between wild type and mutant forms. Furthermore, comparative genomics and evolutionary analyses of variants observed in PKHD1, PKD1, and PKD2 genes were also performed in some mammalian species including human to understand the complexity of genomes among closely related mammalian species. Taken together, the results revealed that the evolutionary comparative analyses and characterization of PKHD1, PKD1, and PKD2 genes among various related and unrelated mammalian species will provide important insights into their evolutionary process and understanding for further disease characterization and management.

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Polycystic Kidney Disease: Autosomal Recessive Type

Chen¹

2016

Atlas of Genetic Diagnosis and Counseling

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Next-generation sequencing for molecular diagnosis of autosomal recessive polycystic kidney disease

Cited by 18 publications

References 27 publications

Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

Functional alterations due to amino acid changes and evolutionary comparative analysis of ARPKD and ADPKD genes

Polycystic Kidney Disease: Autosomal Recessive Type

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