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Novel Mutation in the PKHD1 Gene Diagnosed Prenatally in a Fetus with Autosomal Recessive Polycystic Kidney Disease.

ABSTRACT: We report a 29-year-old gravida 2, para 0100, who presented at 19 weeks and 4 days of gestation for ultrasound to assess fetal anatomy. Routine midtrimester fetal anatomy ultrasound revealed enlarged, hyperechoic fetal kidneys and normal amniotic fluid index. Follow-up ultrasound at 23 weeks and 5 days revealed persistently enlarged, hyperechoic fetal kidneys. Progressive oligohydramnios was not evident until 29 weeks of gestation, with anhydramnios noted by 35 weeks of gestation. Amniocentesis was performed for karyotype and to search for mutations in the PKHD1 for the presumptive diagnosis of autosomal recessive polycystic kidney disease (ARPKD). In our patient, a maternally inherited, previously reported pathogenic missense mutation in the PKHD1 gene, c.10444C>T, was identified. A second, previously unreported de novo mutation, c.5909-2delA, was also identified. This mutation affects the canonical splice site and is most likely pathogenic. Our case highlights PKHD1 allelic heterogeneity and the importance of genetic testing in the prenatal setting where many other genetic etiologies can phenocopy ARPKD.

SUBMITTER: Thakur P

PROVIDER: S-EPMC4120792 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Fatal outcome of autosomal recessive polycystic kidney disease in neonates with recessive PKHD1 mutations.

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Project description:Autosomal recessive polycystic kidney disease (ARPKD) is an early-onset form of polycystic kidney disease that often leads to devastating outcomes for patients. ARPKD is caused by mutations in the PKHD1 gene, an extensive gene that encodes for the ciliary protein fibrocystin/polyductin. Next-generation sequencing is presently the best option for molecular diagnosis of ARPKD. Our aim was to set up the first study of ARPKD patients from the Czech Republic, to determine the composition of their mutations and genotype-phenotype correlations, along with establishment of next-generation sequencing of the PKHD1 gene that could be used for the diagnosis of ARPKD patients.Mutational analysis of the PKHD1 gene was performed in 24 families using the amplicon-based next-generation sequencing (NGS) technique. In patients without 2 causal mutations identified by NGS, subsequent MLPA analysis of the PKHD1 gene was carried out.Two underlying mutations were detected in 54% of families (n = 13), one mutation in 13% of families (n = 3), and in 33% of families (n = 8) no mutation could be detected. Overall, seventeen different mutations (5 novel) were detected, including deletion of one exon. The detection rate in our study reached 60% in the entire cohort of patients; but 90% in the group of patients who fulfilled all clinical criteria of ARPKD, and 42% in the group of patients with unknown kidney pathology. The most frequent mutation was T36M, accounting for nearly 21% of all identified mutations.Next-generation sequencing of the PKHD1 gene is a very useful method of molecular diagnosis in patients with a full clinical picture of ARPKD, and it has a high detection rate. Furthermore, its relatively low costs and rapidity allow the molecular genetic analysis of patients without the full clinical criteria of ARPKD, who might also have mutations in the PKHD1 gene.

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Birth of a healthy infant following preimplantation PKHD1 haplotyping for autosomal recessive polycystic kidney disease using multiple displacement amplification.

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