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Genome-Wide Copy Number Analysis and Systematic Mutation Screening in 58 Patients with Hypogonadotropic Hypogonadism

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Genome-Wide Copy Number Analysis and Systematic Mutation Screening in 58 Patients with Hypogonadotropic Hypogonadism ORIGINAL ARTICLES: GENETICS Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism Yoko Izumi, M.D.,a,b Erina Suzuki, M.A.,a Susumu Kanzaki, M.D.,c Shuichi Yatsuga, M.D.,d Saori Kinjo, M.D.,e Maki Igarashi, Ph.D.,a Tetsuo Maruyama, M.D.,b Shinichiro Sano, M.D.,a Reiko Horikawa, M.D.,f Naoko Sato, M.D.,a Kazuhiko Nakabayashi, Ph.D.,g Kenichiro Hata, M.D.,g Akihiro Umezawa, M.D.,h Tsutomu Ogata, M.D.,a,i Yasunori Yoshimura, M.D.,b and Maki Fukami, M.D.a a Department of Molecular Endocrinology, National Research Institute for Child Health and Development; b Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo; c Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Tottori; d Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka; e Department of Pediatrics, Okinawa Chubu Hospital, Okinawa; f Division of Endocrinology and Metabolism, National Center for Child Health and Development; g Department of Maternal-Fetal Biology and h Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo; and i Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan Objective: To clarify the molecular basis of hypogonadotropic hypogonadism (HH). Design: Genome-wide copy number analysis by array-based comparative genomic hybridization and systematic mutation screening of 29 known causative genes by next-generation sequencing, followed by in silico functional assessment and messenger RNA/DNA analyses of the mutants/variants. Setting: Research institute. Patient(s): Fifty-eight patients with isolated HH (IHH), combined pituitary hormone deficiency (CPHD), and syndromic HH. Intervention(s): None. Main Outcome Measure(s): Frequency and character of molecular abnormalities. Result(s): Pathogenic defects were identified in 14 patients with various types of HH, although oligogenicity was not evident in this patient group. As rare abnormalities, we identified a submicroscopic deletion involving FGFR1 and an SOX3 polyalanine deletion in patients with IHH, and a WDR11 splice site mutation in a patient with CPHD. No disease-associated polymorphism was detected in the 58 patients. Conclusion(s): The present study provides further evidence that mutations and deletions in the known causative genes play a relatively minor role in the etiology of HH and that submicroscopic rearrangements encompassing FGFR1 can lead to IHH as a sole recognizable clinical feature. Furthermore, the results indicate for the first time that polyalanine deletions in SOX3 and mutations in WDR11 consti- tute rare genetic causes of IHH and CPHD, respectively. (Fertil SterilÒ 2014;102:1130–6. Ó2014 by American Society for Reproductive Medicine.) Use your smartphone Key Words: FGFR1, genomic rearrangements, gonadotropin deficiency, mutation, SOX3, to scan this QR code WDR11 and connect to the discussion forum for Discuss: You can discuss this article with its authors and with other ASRM members at http:// this article now.* fertstertforum.com/izumiy-hypogonadotropic-hypogonadism-molecular-analysis- * Download a free QR code scanner by searching for “QR screening/ scanner” in your smartphone’s app store or app marketplace. Received April 4, 2014; revised May 28, 2014; accepted June 11, 2014; published online July 23, 2014. Y.I. has nothing to disclose. E.S. has nothing to disclose. S. Kanzaki has nothing to disclose. S.Y. has nothing to disclose. S. Kinjo has nothing to disclose. M.I. has nothing to disclose. T.M. has nothing to disclose. S.S. has nothing to disclose. R.H. has nothing to disclose. N.S. has nothing to disclose. K.N. has nothing to disclose. K.H. has nothing to disclose. A.U. has nothing to disclose. T.O. has nothing to disclose. Y.Y. has nothing to disclose. M.F. has nothing to disclose. Supported by the Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology; from the Japan Society for the Promotion of Science (grant 22132004-A01, Tokyo, Japan); by the grants from the Ministry of Health, Labor and Welfare, from National Center for Child Health and Development (grant 23A-1, 24-7, Tokyo, Japan); and from Takeda foundation. Reprint requests: Maki Fukami, M.D., Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2–10–1 Ohkura, Setagaya, Tokyo 157-8535, Japan (E-mail: [email protected]). Fertility and Sterility® Vol. 102, No. 4, October 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.06.017 1130 VOL. 102 NO. 4 / OCTOBER 2014 Fertility and Sterility® ypogonadotropic hypogonadism (HH) is a clinically DNA was extracted from peripheral leukocytes of the patients. H and genetically heterogeneous condition that occurs We examined copy number alterations in the entire genome as an isolated hormonal defect (isolated HH, IHH) or using an array-based catalog comparative genomic hybridi- in combination with other pituitary hormone deficiencies zation (4 Â 180 k format, catalog number G4449A; Agilent (combined pituitary hormone deficiency, CPHD) (1). Hypogo- Technologies). In the present study, we focused on copy num- nadotropic hypogonadism can also take place as a component ber changes involving the known causative genes and those of congenital syndromes such as Kallmann syndrome (KS), involving genomic intervals more than 1.5 Mb, which have septo-optic dysplasia, and CHARGE syndrome (1–4). a higher probability of being associated with disease pheno- Hypogonadotropic hypogonadism affects men and women, types (27). To exclude benign copy number variants, we although the prevalence is significantly higher in men than referred to the database of genomic variants (http://projects. in women (5). Monoallelic, biallelic, and oligogenic tcag.ca/variation/). mutations in more than 15 genes including FGFR1, PROKR2, KAL1, and CHD7 have been identified in patients Mutation Analysis with HH (1, 6–11). In addition, missense mutations in WDR11 and polyalanine deletions in SOX3 have recently Mutation analysis was carried out for the coding regions of 29 been described as rare causes of IHH/KS and CPHD, known HH causative genes, namely, CHD7, FGF8, FGFR1, respectively (12–16). Because of the highly heterogeneous FSHB, GNRH1, GNRHR, HESX1, HS6ST1, KAL1, KISS1, genetic basis of HH, there have been few reports of KISS1R, LEP, LEPR, LHB, LHX3, LHX4, NELF, NR0B1, systematic mutation analyses in patients with this condition OTX2, POU1F1, PROK2, PROKR2, PROP1, SEMA3A, SOX2, (9–11, 17). Furthermore, genome-wide copy number analyses SOX3, TAC3, TACR3, and WDR11 (8, 28–30). Sequences have rarely been performed for patients with HH, although were determined by the Haloplex system (Agilent submicroscopic deletions involving KAL1, FGFR1, GNRH1, Technologies) on a MiSeq sequencer (Illumina). The average and KISS1R have been identified in a small number of read depth in target regions was 322.9. Nucleotide changes patients (17–25). Thus, the current understanding of the were identified using the Surecall system (Agilent etiology of HH remains fragmentary. Technologies) and SAMtools v0.1.17 software (http:// Recent advances in molecular technology including samtools.sourceforge.net/). In the present study, we focused array-based comparative genomic hybridization and next- on nonsynonymous substitutions and splice site mutations. generation sequencing have enabled researchers to perform Single nucleotide polymorphisms (SNPs) of allele frequency genome-wide copy number analysis and high-throughput >1.0% in the Japanese general population (dbSNP, http:// mutation screening for multiple samples. Here, using compar- www.ncbi.nlm.nih.gov/) and nucleotide changes identified ative genomic hybridization and next-generation sequencing, in our control samples (unaffected Japanese individuals, we analyzed samples from 58 patients with various types of n ¼ 16) were excluded from further study. Nucleotide HH. Our results provide novel information about the molecular substitutions identified by next-generation sequencing were abnormalities underlying this condition. confirmed by Sanger sequencing. Primer sequences are avail- able upon request. MATERIALS AND METHODS The functional consequences of missense substitutions were predicted by in silico analysis using PolyPhen-2 (http:// Patients genetics.bwh.harvard.edu/pph2/). We classified frameshift We studied 58 unrelated Japanese patients with HH (34 male and nonsense mutations as damaging mutations. We referred and 24 female subjects, aged 0–56 years). The patient group to previous articles and the human gene mutation database included patients 1–10 and 35–45 with normosmic IHH (http://www.hgmd.cf.ac.uk/ac/index.php) to identify muta- (nIHH), patients 11–25 and 46–51 with KS, patients 26–28 tions that have been associated with HH. For one patient and 52 with CPHD, patients 29 and 53–55 with CHARGE syn- with a nucleotide change in the consensus sequence at a drome, and patients 30 and 31 with septo-optic dysplasia. splice acceptor site of WDR11, we performed reverse Patients 32–34 and 56–58 were IHH patients who did not un- transcription-polymerase chain reaction (PCR) analysis using dergo quantitative assessment of olfactory function; these pa- lymphoblastoid messenger RNA and a primer pair, 50- tients should have either nIHH or KS. Clinical data of the GGGCTGGCAAGGTTTAATTG-30 and 50-GCTTGGATGGGGA
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