A novel follicle-stimulating hormone receptor mutation causing primary ovarian failure: a fertility application of whole exome sequencing

Vilain, Éric; Goldstein, E.; Lipson, Allen; Ngun, Tuck C; Eskin, Ascia; Gosschalk, Jason E.; Roach, Lara; Vashist, Neerja; Barseghyan, Hayk; Lee, Eric; Arboleda, Valerie A.; Vaiman, Daniel; Yüksel, Zafer; Fellous, Marc

doi:10.1093/humrep/dew025

Cited by 80 publications

(60 citation statements)

References 53 publications

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“…Furthermore, the wild-type residue is very conserved and located near a highly conserved position in the TMD as observed in previously described mutations [Doherty et al, 2002;Katari et al, 2015;Bramble et al, 2016].…”

Section: Discussionsupporting

confidence: 60%

“…Recently, 2 novel FSHR mutations in 2 unrelated POF cohorts were identified using WES. Both mutations (c.1253T>G;p.Ile418Ser and c.1222G>T;p.Asp408Tyr) are also located in exon 10 in the highly conserved second TMD [Katari et al, 2015;Bramble et al, 2016]. Moreover, a nearby pathogenic variant (c.1255G>A;p.Ala419Thr) was detected in a Finnish female with primary amenorrhea.…”

Section: Discussionmentioning

confidence: 99%

“…Our novel c.1298C>A;p.Ala433Asp homozygous FSHR variant was also detected by massively parallel exome sequencing as well as the variants c.1253T>G; p.Ile418Ser and c.1222G>T;p.Asp408Tyr recently identified [Katari et al, 2015;Bramble et al, 2016]. WES deeply screens all coding regions and allows for the identification of mutations in patients with rare genetic disorders.…”

Section: Discussionmentioning

confidence: 99%

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A Novel Homozygous Missense FSHR Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family

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Lerário

Funari

et al. 2017

Sex Dev

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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.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Novel Homozygous Missense FSHR Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family

França

Lerário

Funari

et al. 2017

Sex Dev

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“…The analysis of a few cohorts of 46,XX POI patients by means of high throughput techniques, such as comparative genomic hybridization array (array-CGH) and SNP array, has led to the identification of CNVs affecting several X-linked and autosomal loci with a possible role in female fertility (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Similarly, the recent application of whole-exome sequencing (WES) to a few POI multigenerational familial cases has succeeded in revealing rare single nucleotide variants affecting genes implicated in ovarian function (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). As already reported in other complex diseases characterized by a great genetic heterogeneity, it is likely that patients with POI may harbor multiple genetic variants.…”

Section: The Heterogeneous Manifestations and Multifactorial Origin Omentioning

confidence: 99%

Genetics of primary ovarian insufficiency

et al. 2016

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Primary ovarian insufficiency (POI) is characterized by a loss of ovarian function before the age of 40 and account for one major cause of female infertility. POI relevance is continuously growing because of the increasing number of women desiring conception beyond 30 years of age, when POI prevalence is >1%. POI is highly heterogeneous and can present with ovarian dysgenesis and primary amenorrhea, or with secondary amenorrhea, and it can be associated with other congenital or acquired abnormalities. In most cases POI remains classified as idiopathic. However, the age of menopause is an inheritable trait and POI has a strong genetic component. This is confirmed by the existence of several candidate genes, experimental and natural models. The variable expressivity of POI defect may indicate that, this disease may frequently be considered as a multifactorial or oligogenic defect. The most common genetic contributors to POI are the X chromosome‐linked defects. Here, we review the principal X‐linked and autosomal genes involved in syndromic and non‐syndromic forms of POI with the expectation that this list will soon be upgraded, thus allowing the possibility to predict the risk of an early age at menopause in families with POI.

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“…Rare mutations in the FSH receptor ( FSHR , autosomal recessive), BMP15 (X-linked), NR5A1 (autosomal dominant), and STAG3 explain a few of the cases. 10–12 …”

Section: Disorders Of Sex Development Phenotypic and Genotypic Spectrummentioning

confidence: 99%

Genetics of Disorders of Sex Development

Sandberg¹,

Délot

Fox³

et al. 2017

Endocrinology and Metabolism Clinics of North America

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The Disorders of Sex Development (DSD) Consensus Conference, held in Chicago in 2005, identified several domains of care where improvement was needed.1 In particular, it called for the establishment of an infrastructure for collaborative interdisciplinary clinical practice and research, with the goal of integrating scientific understanding of DSD with real-time standardization and improvement in clinical practice. The DSD-Translational Research Network (DSD-TRN) was created in response, the first such North American infrastructure, a network of 4 (now expanded to 10) research and clinical sites and a central registry, with the collaboration of Accord Alliance, a nonprofit convener of diverse DSD stakeholders. To address the variability within and across medical, surgical, and behavioral health aspects of care, the DSD-TRN is dedicated to the standardization of diagnostic and treatment protocols in order to enhance clinical and scientific discovery, as well as quality of life outcomes for patients and their families. A critical aspect of this standardization of practice is a commitment to an early and comprehensive diagnostic process (including genetic), associated with extensive standardized phenotyping and psychosocial screening and support of patients and families. A recent review of the state of clinical, biochemical, genetic, and psychosocial evaluations of the newborn or adolescent with DSD, 10 years after the consensus statement, continued to highlight the need for a thorough diagnostic process that sets in motion informed discussions with parents (and newly diagnosed adolescent patients) regarding treatment options.2 Developmental pathways of sex determination and differentiation impacted in isolated and syndromic DSD conditions were recently reviewed.3–5 This article will briefly review the main categories of genetic causes of DSD and the diagnostic revolution promised by the advent of new genomic technology, and will present the DSD-TRN guidelines for genetic diagnosis, features of the registry for future research, and a peek into some early registry data.

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A novel follicle-stimulating hormone receptor mutation causing primary ovarian failure: a fertility application of whole exome sequencing

Abstract: E.V. is partially funded by the DSD Translational Research Network (NICHD 1R01HD068138). M.S.B. is funded by the Neuroendocrinology, Sex Differences and Reproduction training grant (NICHD 5T32HD007228). The authors have no competing interests to disclose.

Cited by 80 publications

References 53 publications

A Novel Homozygous Missense <b><i>FSHR</i></b> Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family

A Novel Homozygous Missense <b><i>FSHR</i></b> Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family

Genetics of primary ovarian insufficiency

Genetics of Disorders of Sex Development

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