title: Perinatal hypophosphatasia caused by uniparental isodisomy.
abstract: Hypophosphatasia (HPP) is an inherited disorder characterized by defective bone mineralization caused by mutations in the alkaline phosphatase gene (ALPL). Clinically, the disease spans a great continuum of disease severity and six forms can be distinguished according to the age of onset. The most severe is the autosomal recessive perinatal form, a major prenatal skeletal dysplasia in Japan. The ALPL mutation c.1559delT causes perinatal HPP and occurs frequently in the Japanese. Most patients with perinatal HPP in Japan are homozygous for c.1559delT, and their parents are usually heterozygous with no evidence of consanguinity. Here we identified a fetus with perinatal HPP resulting from an unusual mechanism known as paternal uniparental isodisomy (UPD) of chromosome 1. Sequence analysis of ALPL in the patient revealed the presence of the homozygous mutation c.1559delT. We suspected UPD because the father and mother were heterozygous and wild type, respectively. Analysis of polymorphic microsatellite markers spanning chromosome 1 and whole-genome arrays revealed a uniparental inheritance from the father and excluded deletions or de novo mutations. This is the first description of perinatal HPP caused by UPD. This report also emphasizes the low recurrence risk of a non-Mendelian inheritance pattern in UPD and the value of determining parental genotypes with homozygous mutations in a patient to confirm whether the condition is caused by UPD or not, even when the mutation is detected as a hot spot, as described in the literature.
authors: Division of Clinical Genetics, Nippon Medical School Hospital, Tokyo, Japan; Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan. Electronic address: aw3703@nms.ac.jp.
authors: Atsushi
authors: A
authors: Watanabe
authors: Aomori Prefectural Central Hospital, Aomori, Japan.
authors: Shuhei
authors: S
authors: Satoh
authors: Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Fujita
authors: Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
authors: Banyar Than
authors: BT
authors: Naing
authors: Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
authors: Hideo
authors: H
authors: Orimo
authors: Division of Clinical Genetics, Nippon Medical School Hospital, Tokyo, Japan; Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
authors: Takashi
authors: T
authors: Shimada
mesh_terms: D000328:Adult; D000469:Alkaline Phosphatase / Q000235:genetics; D001483:Base Sequence; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007014:Hypophosphatasia / Q000150:complications* / Q000000981:diagnostic imaging / Q000201:enzymology; D007231:Infant, Newborn; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D011859:Radiography; D014463:Ultrasonography; D024182:Uniparental Disomy / Q000235:genetics*
chemical_list: D000469:Alkaline Phosphatase
keywords: Hypophosphatasia (HPP); Liver/bone/kidney alkaline phosphatase gene (ALPL); Loss of heterozygosity (LOH); Perinatal HPP; Uniparental isodisomy (UPD)