Identification of gene variants in a cohort of hypogonadotropic hypogonadism: Diagnostic utility of custom NGS panel and WES in unravelling genetic complexity of the disease

Gach, Agnieszka; Pinkier, Iwona; Sałacińska, Kinga; Szarras‐Czapnik, Maria; Salachna, Dominik; Kucińska, Agata; Rybak-Krzyszkowska, Magda; Sakowicz, Agata

doi:10.1016/j.mce.2020.110968

Cited by 12 publications

(12 citation statements)

References 22 publications

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“…Moreover, these technical advancements in genetic testing have been accompanied by new challenges in sequence interpretation. 21) To date, mutations in more than 35 genes have been shown to be associated with CHH. However, mutations in many different genes can only explain approximately 40% of the causes of CHH, with the majority of CHH patients being genetically uncharacterized.…”

Section: Causes Of Congenital Hypogonadotropic Hypogonadismmentioning

confidence: 99%

“…The ability of next-generation sequencing to query the entire genome with increasing speed and accuracy is identifying a surprising number of rare sequence variants of unknown significance in both known and novel CHH genes. Moreover, these technical advancements in genetic testing have been accompanied by new challenges in sequence interpretation [ 21 ]. To date, mutations in more than 35 genes have been shown to be associated with CHH.…”

Section: Causes Of Congenital Hypogonadotropic Hypogonadismmentioning

confidence: 99%

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Treatment of congenital hypogonadotropic hypogonadism in male patients

Lee

Shim

Hwang

2022

Ann Pediatr Endocrinol Metab

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Congenital hypogonadotropic hypogonadism (CHH) is characterized by complete or partial failure of pubertal development because of inadequate secretion of gonadotropic hormones. CHH consists of hypogonadotropic hypogonadism with anosmia or hyposmia, Kallmann syndrome, and the normosmic variation normosmic idiopathic hypogonadotropic hypogonadism. CHH is one of the few treatable diseases of male infertility, although men with primary testicular dysfunction have irreversibly diminished spermatogenic capacity. The approach to CHH treatment is determined by goals such as developing virilization or inducing fertility. This review focuses on the current knowledge of therapeutic modalities for inducing puberty and fertility in men with CHH.

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Section: Causes Of Congenital Hypogonadotropic Hypogonadismmentioning

confidence: 99%

Section: Causes Of Congenital Hypogonadotropic Hypogonadismmentioning

confidence: 99%

Treatment of congenital hypogonadotropic hypogonadism in male patients

Lee

Shim

Hwang

2022

Ann Pediatr Endocrinol Metab

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“…3 To date, mutations in 61 genes have been reported to cause CHH that involved in GnRH neuron migration/axon guidance (ANOS1/HS6ST1/PROK2/PROKR2/ SEMA3A/SEMA3E/SEMA7A/NSMF/WDR11), GnRH neuron and gonadotroph differentiation and fate specification (FGFR1/CHD7/SOX2/NR0B1), GnRH neuron activation and networking (KISS1/KISS1R/TAC3/TACR3), GnRH secretion and action(GNRHR/GNRH1), CHH functional energy-deficit (LEP/LEPR), gonadotropin secretion or action (PCSK1/LHB/ FSHB), syndromes of CHH with cerebellar ataxia POLR3A/ POLR3B/OTUD4/RNF216), etc. [4][5][6]7 Monogenic inheritance was thought to account for most of the CHH cases. However, with the increasing application of whole exome sequencing (WES), it is now well known that oligogenic inheritance is more common than previously expected.…”

Section: Introductionmentioning

confidence: 99%

Genetic Profiles and Three-year Follow-up Study of Chinese Males with Congenital Hypogonadotropic Hypogonadism

Zhang

Gao

et al. 2021

The Journal of Sexual Medicine

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Background: The correlation between long-term treatment outcomes with genotypes in congenital hypogonadotropic hypogonadism (CHH) males is rarely reported. Aim: To investigate the correlations among genotypes, phenotypes, and treatment outcomes for CHH male patients. Methods: Whole exome sequencing was performed for 73 Chinese CHH males from one academic center. Patients self-selected one of the 4 treatments: pulsatile Gonadorelin pump (PGP), cyclical gonadotropins therapy (CGT), human menopausal gonadotropin monotherapy, or testosterone replacement treatment. Clinical assessments were performed every 3 months for 3 years. Outcomes: The pathogenicity of variants was determined. Baseline clinical features, spermatogenesis outcomes were analysed. Results: 62 variants were identified in 51 patients (69.9%), 17 of which were novel. Among these mutations, variants on FGFR1, PROKR2, CHD7, ANOS1 and NSMF gene were 16.1%, 16.1%, 11.3%, 8.1% and 8.1% respectively. 11 patients followed the oligogenic pattern (21.6%). All CHD7 patients had hearing impairment or structural deformities of external/inner ear, and were diagnosed as CHARGE syndrome. 24.7% of CHH patients manifested with ear/hearing anomalies. KS patients had higher rates of cryptorchidism history and ear/hearing anomalies than normosmic CHH subjects. Male patients with PROKR2 mutations showed relatively better testicular development, less dental deformity when compared with FGFR1 mutations. About 30% normosmic patients defined by simple olfactory assessment showed olfactory nerve center (ONC) dysplasia under nasal sinus MRI examination. Among the CHH males treated with CGT or PGP, 70.2% reached spermatogenesis within 3 years of treatment. Clinical Implications: No direct correlation was observed between certain responsible genes and spermatogenic outcomes. When CHH patients were identified with CHD7 variants, ear/hearing evaluation should be carefully performed. The precise assessment of ONC development was advised for normosmic CHH subjects.Strengths & Limitations: This study provided informative long-term treatment data of CHH male patients screened with whole exome sequencing. The limitations included small number of subgroups with multifaceted gene variants, clinical heterogeneity, and uncontrolled sperm-inducing treatment method. The seventeen novel mutations worth experimental validation in the future. Conclusion:The clinical severity is partially related with specific gene variants, and detailed individualized data and outcomes were provided. Ear/hearing anomalies were closely connected with CHD7 variants, and were common problems for CHH patients. Simple olfactory assessment underestimated the true olfactory deficit. L. Zhang, Y. Gao, Q. Du, et al. Genetic Profiles and Three-year Follow-up Study of Chinese Males With Congenital Hypogonadotropic Hypogonadism. J Sex Med 2021;XX:XXX−XXX.

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“…As of today, 46 genes have been associated with IHH (Topaloglu, 2017;Cangiano et al, 2020). The molecular alterations identified in these genes account for 40% of all IHH cases (Gach et al, 2020), thus suggesting that half of the IHH causal genes remain unknown. Molecular alterations have been identified for several neuropeptides or their corresponding receptors, which are involved in the physiology of the gonadotropic axis: GNRHR/GNRH1, KISS1R/GPR54, TAC3/TACR3, and PROK2/PROKR2 (Brioude et al, 2010;Topaloglu and Kotan, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…IHH may be inherited in an X-linked recessive, autosomal dominant, or autosomal recessive modes of inheritance. IHH has been predominantly detected in sporadic cases (Quaynor et al, 2011;Gach et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Oligogenic Inheritance Underlying Incomplete Penetrance of PROKR2 Mutations in Hypogonadotropic Hypogonadism

et al. 2021

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The role of the prokineticin 2 pathway in human reproduction, olfactory bulb morphogenesis, and gonadotropin-releasing hormone secretion is well established. Recent studies have highlighted the implication of di/oligogenic inheritance in this disorder. In the present study, we aimed to identify the genetic mechanisms that could explain incomplete penetrance in hypogonadotropic hypogonadism (HH). This study involved two unrelated Tunisian patients with HH, which was triggered by identifying a homozygous p.(Pro290Ser) mutation in the PROKR2 gene in a girl (HH1) with Kallmann syndrome (KS). The functional effect of this variant has previously been well demonstrated. Unexpectedly, her unaffected father (HH1P) and brother (HH1F) also carried this genetic variation at a homozygous state. In the second family, we identified a heterozygous p.(Lys205del) mutation in PROKR2, both in a male patient with normosmic idiopathic IHH (HH12) and his asymptomatic mother. Whole-exome sequencing in the three HH1 family members allowed the identification of additional variants in the prioritized genes. We then carried out digenic combination predictions using the oligogenic resource for variant analysis (ORVAL) software. For HH1, we found the highest number of disease-causing variant pairs. Notably, a CCDC141 variant (c.2803C > T) was involved in 18 pathogenic digenic combinations. The CCDC141 variant acts in an autosomal recessive inheritance mode, based on the digenic effect prediction data. For the second patient (HH12), prediction by ORVAL allowed the identification of an interesting pathogenic digenic combination between DUSP6 and SEMA7A genes, predicted as “dual molecular diagnosis.” The SEMA7A variant p.(Glu436Lys) is novel and predicted as a VUS by Varsome. Sanger validation revealed the absence of this variant in the healthy mother. We hypothesize that disease expression in HH12 could be induced by the digenic transmission of the SEMA7A and DUSP6 variants or a monogenic inheritance involving only the SEMA7A VUS if further functional assays allow its reclassification into pathogenic. Our findings confirm that homozygous loss-of-function genetic variations are insufficient to cause KS, and that oligogenism is most likely the main transmission mode involved in Congenital Hypogonadotropic Hypogonadism.

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Identification of gene variants in a cohort of hypogonadotropic hypogonadism: Diagnostic utility of custom NGS panel and WES in unravelling genetic complexity of the disease

Cited by 12 publications

References 22 publications

Treatment of congenital hypogonadotropic hypogonadism in male patients

Treatment of congenital hypogonadotropic hypogonadism in male patients

Genetic Profiles and Three-year Follow-up Study of Chinese Males with Congenital Hypogonadotropic Hypogonadism

Oligogenic Inheritance Underlying Incomplete Penetrance of PROKR2 Mutations in Hypogonadotropic Hypogonadism

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