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Clinical and genetic characteristics of autosomal recessive polycystic kidney disease in Oman.

ABSTRACT: 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 if not previously known was performed using targeted exon PCR of known disease alleles 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. Twenty-four patients had documented chronic kidney disease (median age 3?years). Twenty-four 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 known in 18 patients and newly identified in 20 other patients, totalling 38 patients from 30 different families. Two unrelated patients remained genetically unsolved. The different PKHD1 missense pathogenic variants were: 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. CONCLUSIONS:Molecular genetic screening of PKHD1 in clinically suspected ARPKD cases produced a high diagnostic rate. The limited number of PKHD1 missense variants identified in ARPKD cases suggests these 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.

SUBMITTER: Al Alawi I

PROVIDER: S-EPMC7429752 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Clinical and genetic characteristics of autosomal recessive polycystic kidney disease in Oman.

Al Alawi Intisar I Molinari Elisa E Al Salmi Issa I Al Rahbi Fatma F Al Mawali Adhra A Sayer John A JA

BMC nephrology 20200814 1

<h4>Background</h4>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.<h4>Methods</h4>We studied patients with a clinical diagnosis of ARPKD (n = 40) and their relatives (parents (n = 24) and una ...[more]

PMID: 32799815

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Project description:Background and objectivesAutosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The longest open reading frame comprises 66 exons encoding polyductin or fibrocystin, a type I transmembrane protein with 4074 amino acids. Functional investigations are considerably hampered by its large size and lack of expression in tissues that are usually available for analysis such as lymphocytes or fibroblasts.Design, setting, participants, & measurementsAllegedly strong and clear-cut genotype-phenotype correlations for the type of PKHD1 mutation could be established. Thus far, practically all patients with two truncating mutations showed perinatal or neonatal demise and at least one hypomorphic missense mutation is thought to be indispensable for survival. Mutation analysis of >500 ARPKD families was performed by conventional and next-generation sequencing techniques.ResultsThis study presents four unrelated patients with ARPKD with a nonlethal, moderate clinical course despite the burden of two PKHD1 mutations expected to lead to premature termination of translation. In line with parental consanguinity, all mutations occurred in the homozygous state and segregated with the disorder in these families. To try to unravel the mechanisms that underlie this obvious contradiction, these patients were further analyzed in detail by utilizing different methods. In all cases, complex transcriptional alterations were detected. Alternative splicing patterns might disrupt a critical stoichiometric and temporal balance between different protein products and may play a crucial role in defining the phenotype of these patients.ConclusionsAlthough these findings represent rare events, they are of importance for genetic counseling and illustrate that some caution is warranted in the interpretation of mutations and their clinical significance. The authors hypothesize that expression of a minimal amount of functional protein is needed for survival of the neonatal period in ARPKD.

Dataset Information

Clinical and genetic characteristics of autosomal recessive polycystic kidney disease in Oman.

Publications

Clinical and genetic characteristics of autosomal recessive polycystic kidney disease in Oman.

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