Expanding the genetic spectrum of<i>ANOS1</i>mutations in patients with congenital hypogonadotropic hypogonadism

Gonçalves, Catarina I.; Fonseca, Fernando; Borges, Teresa; Cunha, Filipe; Lemos, Manuel C.

doi:10.1093/humrep/dew354

Cited by 26 publications

(25 citation statements)

References 28 publications

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“…In our study, we also found some patients in whom HH was combined with hearing impairment, renal agenesis and synkinesis. The sense of smell of 12 patients with KS was inconsistent with MRI analysis of the olfactory bulb, which has been reported previously . Mutations in the genes PROKR2 (17.6%) , FGFR1 (13.7%) , CHD7 (7.8%) and KAL1 (5.9%) were found to be common in the patients of this paediatric study, whereas FGFR1, CHD7, GNRHR and KAL1 were the most common genetic causes in a previous study of adult patients where the proportion each was no more than 10% .…”

Section: Discussioncontrasting

confidence: 85%

Clinical and genetic features of 64 young male paediatric patients with congenital hypogonadotropic hypogonadism

Wang

Gong

Qin

et al. 2017

Clinical Endocrinology

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SummaryContext: The diagnosis of congenital hypogonadotropic hypogonadism (CHH) in prepuberty has always been challenging. Here, we aimed at studying the clinical and genetic features of paediatric CHH, especially the phenotype of hypospadias and dual defects (patients showing hypothalamic and/or pituitary defects and testicular hypoplasia), so as to have a better understanding of CHH. Design:The clinical and genetic features of patients with CHH were analysed, and the relationships between hypospadias, dual defects and genetics were investigated. Patients:Patients who visited Beijing Children's Hospital and were positively diagnosed with CHH. Measurements:The collected data included sex hormones, MRI of the olfactory bulb, human chorionic gonadotrophin (hCG) test and genetic testing. We analysed clinical features and genetic results, especially hypospadias and dual defects, and compared the stimulated testosterone (T) levels in patients with and without cryptorchidism.Results: Sixty-four patients were positively diagnosed, and forty-seven (73.4%) had Kallmann syndrome (KS). Four patients (6.3%) had hypospadias, including 2 KS.Micropenis combined with cryptorchidism was the most common phenotype (39%).Approximately two-third of patients showed a poor response to hCG; 15 cases were diagnosed with dual defects, and there were no significant differences between those with and without cryptorchidism. Twenty-six cases (51%) of 51 patients were identified as having classical HH mutations, affecting 10 different genes, with oligogenic mutations in 5 cases (9.8%). The most common mutations were in PROKR2 (17.6%), FGFR1 (13.7%) and CHD7 (7.8%). The frequency of PROKR2 mutations was higher in dual HH when compared to other HH cases (6/15 vs 3/36, P = .021). Conclusions:Micropenis and/or cryptorchidism can serve as important signs for the diagnosis of HH in paediatrics, and the coexistence of hypospadias does not exclude the diagnosis of CHH, including KS or normosmic isolated HH (nHH). Testicular function may be impaired earlier than expected, and PROKR2 mutations need to be evaluated to identify presumed dual defects. K E Y W O R D Scongenital hypogonadotropic hypogonadism, dual HH, gene, hypospadias This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Section: Discussioncontrasting

confidence: 85%

Clinical and genetic features of 64 young male paediatric patients with congenital hypogonadotropic hypogonadism

Wang

Gong

Qin

et al. 2017

Clinical Endocrinology

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“…In familial forms, heterozygous women are always asymptomatic carriers (2,12,(69)(70)(71)(72). However, one series identified 10 women harboring variants.…”

Section: Kal1/anos1mentioning

confidence: 99%

“…Other signs associated with this genetic form, such as mirror movements (also called bimanual synkinesis) and renal agenesis, are frequent, but they do not always cosegregate with the mutation identified in a given family (69,70,(71)(72)(73)(74)(75)(76), for reasons that are still not clear. Other, rarer associated signs such as deafness (35)(36)(37)(38)(69)(70)(71)(72)(73)(74)(75)(76) and vas deferens agenesis, have been described in men with KAL1/ANOS1 mutations (69-74) but their inconsistent presence remains unexplained.…”

Section: Kal1/anos1mentioning

confidence: 99%

“…Other, rarer associated signs such as deafness (35)(36)(37)(38)(69)(70)(71)(72)(73)(74)(75)(76) and vas deferens agenesis, have been described in men with KAL1/ANOS1 mutations (69-74) but their inconsistent presence remains unexplained. Some patients with X-linked KS have large deletions in chromosome region Xp22.3, removing several adjacent genes.…”

Section: Kal1/anos1mentioning

confidence: 99%

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GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

Maione

Dwyer

Francou

et al. 2018

European Journal of Endocrinology

132

166

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Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women.However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation.These are genetic diseases that can be transmitted to patients' offspring. Importantly patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex, oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing, and is increasingly being used in medical practice. Thus it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission but also its role in incomplete penetrance and variable expresivity in a perspective of genetic counseling.

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“…Patients most often seek medical care with an initial complaint of delayed onset of puberty. Clinical diagnosis is made when delayed puberty presents accompanied by anosmia and after laboratory confirmation of low values of testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) (Gonçalves et al ., ).…”

Section: Introductionmentioning

confidence: 97%

A rare ANOS1 variant in siblings with Kallmann syndrome identified by whole exome sequencing

et al. 2017

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Kallmann syndrome is a rare genetic condition causing congenital hypogonadotropic hypogonadism. It presents with delayed puberty, anosmia, and infertility. Here, we set out to identify a causative DNA variant for Kallmann syndrome in two affected brothers of Hispanic ancestry. The male siblings presented with a clinical diagnosis of Kallmann syndrome (anosmia, delayed puberty, azoospermia, and undetectable luteinizing hormone and follicle stimulating hormone levels). Genetic variations were investigated by whole exome sequencing. Potentially pathogenic variants were filtered and prioritized followed by validation by Sanger sequencing in the two brothers and their mother. A pathogenic variant was identified in the ANOS1 gene on the X chromosome: c.1267C>T; both brothers were hemizygous, and their mother was heterozygous for the variant. The variant is a single nucleotide change that introduces a stop codon in exon 9 (p.R423*), likely producing a truncated variant of the protein. This variant has only been reported twice in the literature, in the setting of finding genetic causes for other conditions. This result supports the clinical value of whole exome sequencing for identification of genetic pathogenic variants. Genetic diagnosis is the essential first step for genetic counseling, preimplantation diagnosis, and research for a potential treatment.

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Expanding the genetic spectrum ofANOS1mutations in patients with congenital hypogonadotropic hypogonadism

Abstract: N/A.

Cited by 26 publications

References 28 publications

Clinical and genetic features of 64 young male paediatric patients with congenital hypogonadotropic hypogonadism

Clinical and genetic features of 64 young male paediatric patients with congenital hypogonadotropic hypogonadism

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

A rare ANOS1 variant in siblings with Kallmann syndrome identified by whole exome sequencing

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