Mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism

Zhou, Can; Niu, Yonghua; Xu, Hao; Li, Zongzhe; Wang, Tao; Yang, Weimin; Wang, Shaogang; Wang, Dao Wen; Liu, Jihong

doi:10.1016/j.fertnstert.2018.04.010

Cited by 40 publications

(45 citation statements)

References 55 publications

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“…Because features of CHARGE syndrome have been identified in some Kallman syndrome patients with pathogenic CHD7 variants, we decided to lump all of these conditions into "CHARGE syndrome" for curation purposes. [19][20][21][22] In addition, the HL GCEP only curated SLC26A4 for Pendred Syndrome, given the complexity and partial lack of clarity of a defining molecular basis for those patients who present without thyroid disease, which could better be considered a phenotype with variable expression. [23][24][25] Diseases that were split clearly differed in inheritance pattern, molecular mechanism, or phenotype.…”

Section: Discussionmentioning

confidence: 99%

ClinGen expert clinical validity curation of 164 hearing loss gene–disease pairs

DiStefano

Hemphill

Oza

et al. 2019

Genetics in Medicine

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Proper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene-disease relationships. The Clinical Genome Resource (ClinGen) has developed a semi-quantitative framework to assign clinical validity to gene-disease relationships. Methods: The ClinGen Hearing Loss Gene Curation Expert Panel (HL GCEP) uses this framework to perform evidence-based curations of genes present on testing panels from 17 clinical laboratories in the Genetic Testing Registry. The HL GCEP curated and reviewed 142 genes and 164 gene-disease pairs, including 105 nonsyndromic and 59 syndromic forms of hearing loss. Results: The final outcome included 82 Definitive (50%), 12 Strong (7%), 25 Moderate (15%), 32 Limited (20%), 10 Disputed (6%), and 3 Refuted (2%) classifications. The summary of each curation is date stamped with the HL GCEP approval, is live, and will be kept up-to-date on the ClinGen website (https://search.clinicalgenome.org/kb/gene-validity). Conclusion: This gene curation approach serves to optimize the clinical sensitivity of genetic testing while reducing the rate of uncertain or ambiguous test results caused by the interrogation of genes with insufficient evidence of a disease link.

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Section: Discussionmentioning

confidence: 99%

ClinGen expert clinical validity curation of 164 hearing loss gene–disease pairs

DiStefano

Hemphill

Oza

et al. 2019

Genetics in Medicine

View full text Add to dashboard Cite

show abstract

“…Because features of CHARGE syndrome have been identified in some Kallman syndrome patients with pathogenic CHD7 variants, we decided to lump all of these conditions into "CHARGE syndrome" for curation purposes. [19][20][21][22] In addition, the HL GCEP only curated SLC26A4 for Pendred Syndrome, given the lack of any defining molecular basis for those patients who present without thyroid disease, which could better be considered a phenotype with variable expression. 23,24 Diseases that were split clearly differed in inheritance pattern, molecular mechanism, or phenotype.…”

Section: Discussionmentioning

confidence: 99%

ClinGen Expert Clinical Validity Curation of 164 Hearing Loss Gene-Disease Pairs

DiStefano

Hemphill

Oza

et al. 2019

Preprint

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PurposeProper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene-disease relationships. The Clinical Genome Resource (ClinGen) has developed a semi-quantitative framework to assign clinical validity to gene-disease relationships.MethodsThe ClinGen Hearing Loss Gene Curation Expert Panel (HL GCEP) uses this framework to perform evidence-based curations of genes present on testing panels from 17 clinical laboratories in the Genetic Testing Registry. The HL GCEP curated and reviewed 142 genes and 164 gene-disease pairs, including 105 nonsyndromic and 59 syndromic forms of hearing loss.ResultsThe final outcome included 82 Definitive (50%), 12 Strong (7%), 25 Moderate (15%), 32 Limited (20%), 10 Disputed (6%), and 3 Refuted (2%) classifications. The summary of each curation is date stamped with the HL GCEP approval, is live, and will be kept up-to-date on the ClinGen website (https://search.clinicalgenome.org/kb/gene-validity).ConclusionThis gene curation approach serves to optimize the clinical sensitivity of genetic testing while reducing the rate of uncertain or ambiguous test results caused by the interrogation of genes with insufficient evidence of a disease link.

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“…Regarding phenotype-genotype correlation some authors reported inconclusive results and little co-segregation by analyzing pedigrees in their cohorts (Aoyama et al 2017;Zhou et al 2018), probably due to the complex genetic background of CHH. However, differences in genetic profile among populations are indicated in Chinese and Japanese cohorts (Aoyama et al 2017;Zhou et al 2018). Zhou et al reported that in Chinese population, cryptorchidism was the most common accompanying feature in addition to CHH, but no single gene in their panel showed association with this abnormality (Zhou et al 2018).…”

Section: Pathogenicity Of the Identified Variants Genotypephenotype mentioning

confidence: 99%

“…However, there is no consented gene list that should be offered for patients providing an accurate diagnosis for the majority of cases. After publication of the expert consensus 7 CHH gene panel testing studies were reported (Table 2) (Quaynor et al 2016;Aoyama et al 2017;Wang et al 2017;Cassatella et al 2018;Zhou et al 2018;Amato et al 2019;Kim et al 2019). In these studies, 25-261 genes were included as susceptibility genes of CHH.…”

Section: Testing Strategiesmentioning

confidence: 99%

“…However, differences in genetic profile among populations are indicated in Chinese and Japanese cohorts (Aoyama et al 2017;Zhou et al 2018). Zhou et al reported that in Chinese population, cryptorchidism was the most common accompanying feature in addition to CHH, but no single gene in their panel showed association with this abnormality (Zhou et al 2018). Wang et al reported that the frequency of PROKR2 mutations was higher in dual CHH patients (showing hypothalamic and/or pituitary defects with testicular hypoplasia) when compared to other CHH cases.…”

Section: Pathogenicity Of the Identified Variants Genotypephenotype mentioning

confidence: 99%

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Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice

et al. 2020

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Congenital hypogonadotropic hypogonadism (CHH) is a clinically and genetically heterogeneous congenital disease. Symptoms cover a wide spectrum from mild forms to complex phenotypes due to gonadotropin-releasing hormone (GnRH) deficiency. To date, more than 40 genes have been identified as pathogenic cause of CHH. These genes could be grouped into two major categories: genes controlling development and GnRH neuron migration and genes being responsible for neuroendocrine regulation and GnRH neuron function. High-throughput, next-generation sequencing (NGS) allows to analyze numerous gene sequences at the same time. Nowadays, whole exome or whole genome datasets could be investigated in clinical genetic diagnostics due to their favorable cost-benefit. The increasing genetic data generated by NGS reveal novel candidate genes and gene variants with unknown significance (VUSs). To provide clinically valuable genetic results, complex clinical and bioinformatics work are needed. The multifaceted genetics of CHH, the variable mode of inheritance, the incomplete penetrance, variable expressivity and oligogenic characteristics further complicate the interpretation of the genetic variants detected. The objective of this work, apart from reviewing the currently known genes associated with CHH, was to summarize the advantages and disadvantages of the NGS-based platforms and through the authors' own practice to guide through the whole workflow starting from gene panel design, performance analysis and result interpretation. Based on our results, a genetic diagnosis was clearly identified in 21% of cases tested (8/38). Congenital hypogonadotropic hypogonadism (CHH) Congenital hypogonadotropic hypogonadism (CHH) as a clinically heterogeneous entity Congenital hypogonadotropic hypogonadism (CHH) is a genetic condition characterized by incomplete or absent puberty and infertility due to central (tertiary or hypothalamic) hypogonadism caused by gonadotropic hormonereleasing hormone (GnRH) deficiency. Three clinical forms are distinguished by the European consensus: (1) GnRH deficiency with defective sense of smell (Kallmann syndrome, KS), (2) isolated GnRH deficiency (normosmic CHH) and the third form when KS/CHH is part of a complex genetic syndrome (Boehm et al. 2015). CHH has an incidence of 1:125,000 in female and 1:30,000 in males indicating the male predominance (Stamou and Georgopoulos 2018). CHH has a heterogeneous clinical appearance, and lately the constitutional delay of growth and puberty (CDGP), the adultonset hypogonadotropic hypogonadism and the hypothalamic amenorrhea are also considered as a milder end of the Electronic supplementary material The online version of this article (

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Mutation profiles and clinical characteristics of Chinese males with isolated hypogonadotropic hypogonadism

Cited by 40 publications

References 55 publications

ClinGen expert clinical validity curation of 164 hearing loss gene–disease pairs

ClinGen expert clinical validity curation of 164 hearing loss gene–disease pairs

ClinGen Expert Clinical Validity Curation of 164 Hearing Loss Gene-Disease Pairs

Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice

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