Intragenic duplication in the PKHD1 gene in autosomal recessive polycystic kidney disease.
BACKGROUND
In the present study, we report on a couple who underwent prenatal genetic diagnosis for autosomal recessive polycystic kidney disease (ARPKD).


METHODS
This healthy couple had previously had a healthy boy but had experienced two consecutive neonatal deaths due to respiratory distress resulting from pulmonary hypoplasia caused by oligohydramnios. The woman consulted our facility after she realized she was pregnant again. We promptly performed a carrier test for the PKHD1 gene by target exome sequencing of samples from the couple. A pathogenic mutation was identified only in the paternal allele (c.9008C>T, p.S3003F). The mutation was confirmed by Sanger sequencing of the DNA from formalin-fixed, paraffin-embedded, kidney tissue of the second neonate patient and was not found in the healthy sibling. We then performed haplotype analyses using microsatellite markers scattered throughout the PKHD1 gene. DNA from the amniocentesis was determined to belong to a carrier, and the couple decided to continue with the pregnancy, obtaining a healthy newborn. Subsequent detailed examination of the exome data suggested higher read depth at exons 45 and 46. Multiplex ligation-dependent probe amplification allowed identification of duplication of these two exons. This case suggests the potential usefulness of target exome sequencing in the prenatal diagnosis of the PKHD1 gene in ARPKD.


CONCLUSIONS
This is the first report of intragenic duplication in the PKHD1 gene in ARPKD.
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. mjun@fujita-hu.ac.jp.|Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. mjun@fujita-hu.ac.jp.
Jun
J
Miyazaki
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. mayuko0718jp@nifty.com.|Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. mayuko0718jp@nifty.com.
Mayuko
M
Ito
Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. nharuki@fujita-hu.ac.jp.
Haruki
H
Nishizawa
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. takema@fujita-hu.ac.jp.
Takema
T
Kato
Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. yukito@fujita-hu.ac.jp.
Yukito
Y
Minami
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. hinagaki@fujita-hu.ac.jp.|Genome and Transcriptome Analysis Center, Fujita Health University, Aichi, Japan. hinagaki@fujita-hu.ac.jp.
Hidehito
H
Inagaki
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. otamae@fujita-hu.ac.jp.|Department of Genetic Counseling, Fujita Health University Hospital, Aichi, Japan. otamae@fujita-hu.ac.jp.
Tamae
T
Ohye
Department of Pediatrics, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. m-miata@jc4.so-net.ne.jp.
Masafumi
M
Miyata
Department of Pediatrics, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. mizujin@fujita-hu.ac.jp.
Hiroko
H
Boda
Department of Diagnostic Pathology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. ykiri@fujita-hu.ac.jp.
Yuka
Y
Kiriyama
Department of Diagnostic Pathology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. mkuro@fujita-hu.ac.jp.
Makoto
M
Kuroda
Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. kurisen@zg7.so-net.ne.jp.
Takao
T
Sekiya
Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. kura@fujita-hu.ac.jp.|Genome and Transcriptome Analysis Center, Fujita Health University, Aichi, Japan. kura@fujita-hu.ac.jp.|Department of Genetic Counseling, Fujita Health University Hospital, Aichi, Japan. kura@fujita-hu.ac.jp.
Hiroki
H
Kurahashi
Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. fujiit44@gmail.com.
Takuma
T
Fujii
D000649:Amniocentesis / Q000379:methods; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D017044:Polycystic Kidney, Autosomal Recessive / Q000175:diagnosis* / Q000235:genetics*; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
C451750:PKHD1 protein, human; D011956:Receptors, Cell Surface