Hypergonadotropic hypogonadism (HH) is defined by increased gonadotropin levels in men and women. Primary ovarian failure (POF) is a form of female infertility characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40 years. Although several genes have been associated with POF, its causative genes remain to be identified. Here, we used whole-exome sequencing (WES) to study a consanguineous family with a 46,XX girl and a 46,XY man affected by HH. All exons of both siblings and their parents were captured and massively sequenced by WES, and the candidate variant was confirmed by Sanger sequencing. A novel c.1298C>A;p.Ala433Asp missense variant of the follicle-stimulating hormone receptor (FSHR) gene was found in both affected siblings in a homozygous state and in their parents in a heterozygous state. This FSHR variant is not present in available databases (1000 Genomes and NHLBI/EVS) and Brazilian exome controls. Moreover, it is highly conserved and predicted as deleterious in all prediction sites analyzed. In conclusion, the novel homozygous FSHR variant observed in 2 siblings with HH can expand the spectrum of FSHR mutations in humans.

Achermann JC, Domenice S, Bachega TA, Nishi MY, Mendonca BB: Disorders of sex development: effect of molecular diagnostics. Nat Rev Endocrinol 8:478-488 (2015).
Aittomäki K, Dieguez Lucena J, Pakarinen P, Sistonen P, Tapanainen J, et al: Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82:959-968 (1995).
AlAsiri S, Basit S, Wood-Trageser MA, Yatsenko SA, et al: Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Invest 125:258-262 (2015).
Alvarez-Castro JM, Yang RC: Multiallelic models of genetic effects and variance decomposition in non-equilibrium populations. Genetic 139:1119-1134 (2011).
Bramble MS, Goldstein EH, Lipson A, Ngun T, Eskin A, et al: A novel follicle-stimulating hormone receptor mutation causing primary ovarian failure: a fertility application of whole exome sequencing. Hum Reprod 31:905-914 (2016).
Caburet S, Arboleda VA, Llano E, Overbeek PA, Barbero JL, et al: Mutant cohesin in premature ovarian failure. N Engl J Med 370:943-949 (2014).
Desai SS, Roy BS, Mahale SD: Mutations and polymorphisms in FSH receptor: functional implications in human reproduction. Reproduction 146:235-248 (2013).
Dierich A, Sairam R, Monaco L, Fimia GM, Gansmuller A, et al: Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance. Proc Natl Acad Sci USA 95:13612-13617 (1998).
Doherty E, Pakarinen P, Tiitinen A, Kiilavuori A, Huhtaniemi I, et al: A novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure. J Clin Endocrinol Metab 87:1151-1155 (2002).
Garrison A, Marth, G: Haplotype-based variant detection from short-read sequencing, http://arxiv.org/abs/1207.3907 (2012).
Jiang X, Dias JA, He X: Structural biology of glycoprotein hormones and their receptors: insights to signaling. Mol Cell Endocrinol 382:424-451 (2014).
Katari S, Wood-Trageser MA, Jiang H, Kalynchuk E, Muzumdar R, et al: Novel inactivating mutation of the FSH receptor in two siblings of Indian origin with premature ovarian failure. J Clin Endocrinol Metab 100:2154-2157 (2015).
Kumar TR, Wang Y, Lu N, Matzuk MM: Follicule stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat Genet 15:201-204 (1997).
Latronico AC, Arnhold IJ: Inactivating mutations of the human luteinizing hormone receptor in both sexes. Semin Reprod Med 30:382-386 (2012).
Li H, Durbin R: Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26:589-595 (2010).
Persani L, Rossetti R, Cacciatore C: Genes involved in human premature ovarian failure. J Mol Endocrinol 45:257-279 (2010).
Rabbani B, Tekin M, Mahdieh N: The promise of whole-exome sequencing in medical genetics. J Hum Genet 59:5-15 (2014).
Santos MG, Machado AZ, Martins CN, Domenice S, Costa EM, et al: Homozygous inactivating mutation in NANOS3 in two sisters with primary ovarian insufficiency. Biomed Res Int 2014:787465 (2014).
Shelling AN: Premature ovarian failure. Reprod Rev 140:633-641 (2010).
Simoni M, Gromoll J, Nieschlag E: The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology and pathophysiology. Endocr Rev 18:739-773 (1997).
Tischler G, Leonard S: Biobambam: tools for read pair collation based algorithms on BAM files. Source Code Biol Med 9:13 (2014).
Tucker EJ, Grover SR, Bachelot A, Touraine P, Sinclair AH: Premature ovarian insufficiency: new perspectives on genetic cause and phenotypic spectrum. Endocr Rev 37:609-635 (2016).
Venselaar H, te Beek TAH, Kuipers RKP, Hekkelman ML, Vriend G: Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics 11:548 (2010).
Wang K, Li M, Hakonarson H: ANNOVAR: functional annotation of genetic variants from high- throughput sequencing data. Nucleic Acids Res 38:e164 (2010).
Wood-Trageser MA, Gurbuz F, Yatsenko SA, Jeffries EP, Kotan LD, et al: MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability. Am J Hum Genet 95:754-762 (2014).
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.