title: An Ashkenazi founder mutation in the PKHD1 gene.
abstract: Autosomal recessive polycystic kidney disease (ARPKD) is usually detected late in pregnancies in embryos with large echogenic kidneys accompanied by oligohydramnios. Hundreds of private pathogenic variants have been identified in the large PKHD1 gene in various populations. Yet, because of the large size of the gene, segregation analysis of microsatellite polymorphic markers residing in the PKDH1 locus has commonly been utilized for prenatal diagnosis. Keeping in mind the limitations of this strategy, we utilized it for testing 7 families with affected fetuses or newborns, of which in 5 at least one parent was Ashkenazi, and identified that the same haplotype was shared by the majority of the Ashkenazi parents (7/9). This led us to suspect that they carry the same founder mutation. Whole Exome analysis of DNA from a fetus of one of the families detected an already known pathogenic variant c.3761_3762delCCinsG, an indel variant resulting in frameshift (p.Ala1254GlyfsX49). This variant was detected in 9 parents (5 families), of them 7 individuals were Ashkenazi and one Moroccan Jew who shared the same haplotype, and one Ashkenazi, who carried the same variant on a recombinant haplotype. Screening for this variant in 364 Ashkenazi individuals detected 2 carriers. These findings suggest that although c.3761_3762delCCinsG is considered one of the frequent variants detected in unrelated individuals, and was thought to have occurred independently on various haplotypes, it is in fact a founder mutation in the Ashkenazi population.
authors.affiliation: Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Adina
authors.initials: A
authors.lastname: Quint
authors.affiliation: Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Sagi
authors.affiliation: Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Shai
authors.initials: S
authors.lastname: Carmi
authors.affiliation: Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Daum
authors.affiliation: Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Macarov
authors.affiliation: Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ziva
authors.initials: Z
authors.lastname: Ben Neriah
authors.affiliation: Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Vardiela
authors.initials: V
authors.lastname: Meiner
authors.affiliation: Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address: lereris@hadassah.org.il.
authors.forename: Israela
authors.initials: I
authors.lastname: Lerer
mesh_terms: D004252:DNA Mutational Analysis; D005260:Female; D005333:Fetus / Q000473:pathology; D016368:Frameshift Mutation; D005820:Genetic Testing; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney / Q000196:embryology / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats; D017044:Polycystic Kidney, Autosomal Recessive / Q000175:diagnosis* / Q000196:embryology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: C451750:PKHD1 protein, human; D011956:Receptors, Cell Surface
keywords: ARPKD; Ashkenazi; Founder mutation; PKHD1; c.3761_3762delCCinsG