Abstract Book - 26th ESPU Congress, Joint Meeting with ICCS + SPU + AAP/SOU + AAPU + SFU

25 / 492

15:47 - 15:50
S2-5 (PP)
MOLECULAR BASIS OF NON-SYNDROMIC HYPOSPADIAS: SYSTEMATIC
MUTATION SCREENING AND GENOME-WIDE COPY-NUMBER ANALYSIS OF 63
PATIENTS
Masafumi KON1, Takeya KITTA1, Takahiko MITSUI1, Kaoru YOSHINO2, Katsuhiko UEOKA3, Kimihiko MORIYA1, Maki
FUKAMI4, Katsuya NONOMURA1 and Nobuo SHINOHARA1
1) Hokkaido University Graduate School of Medicine, Department of Renal and Genitourinary Surgery, Sapporo, JAPAN -
2) Aichi Children's Health and Medical Center, Department of Urology, Obu, JAPAN - 3) National Research Institute for
Child Health and Development, Department of Urology, Setagaya, JAPAN - 4) National Research Institute for Child
Health and Development, Department of Molecular Endocrinology, Setagaya, JAPAN
PURPOSE
Although non-syndromic hypospadias is a multifactorial disorder, this condition can also occur as a result of mutations in
single genes or submicroscopic copy-number variations (CNVs). A total of 25 genes have been implicated in the
development non-syndromic hypospadias. The aim of this study was to clarify the contribution of monogenic mutations
and cryptic CNVs in the etiology of non-syndromic hypospadias
MATERIAL AND METHODS
The study group consisted of 58 Japanese and five Vietnamese patients. We performed mutation screening for 25 known
causative/candidate/susceptibility genes using a next-generation sequencer. Functional consequences of nucleotide
alterations were assessed by in silico assays. The frequencies of SNPs in the patient group were compared with those in
the male general population. CNVs were analyzed by array-based comparative genomic hybridization and characterized
by fluorescence in situ hybridization.
RESULTS
Eight of 63 patients with anterior or posterior hypospadias carried putative pathogenic mutations in AR, BNC2, NR5A1,
SRD5A2 or HSD3B2. Two of the eight patients had mutations in multiple genes. We did not find any rare SNPs that were
abundant specifically in the patient group. One patient carried mosaic dicentric Y chromosome.
CONCLUSIONS
Our data indicate that mutations in known causative genes and submicroscopic CNVs account for more than 10% of
cases with non-syndromic hypospadias. Pathogenic defects appear to underlie both severe and mild hypospadias. In
contrast, known susceptibility SNPs seem to play only a minor role in the development of the disease. Most importantly,
this is the first study documenting the possible oligogenicity of non-syndromic hypospadias.