Regional genotypic variations in normosmic congenital hypogonadotropic hypogonadism: our experience and systematic review

Patil, Virendra; Lila, Anurag; Shah, Nalini; Arya, Sneha; Ekbote, Alka V.; Sarathi, Vijaya; Shah, Ravikumar; Jadhav, Swati; Memon, Saba Samad; Bandgar, Tushar

doi:10.1007/s11102-022-01209-z

Cited by 4 publications

(12 citation statements)

References 16 publications

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“… 9 , 11 , 30 , 31 Of these, FGFR1 and MKRN3 variants are the most common causes of hypogonadotropic hypogonadism and CPP, respectively. 9 , 32 , 33 , 34 Variants in KISS1R , TACR3 , PROKR2 , and GNRHR were shown to lead to hypogonadotropic hypogonadism as an autosomal dominant, recessive, or oligogenic disorder (Table 2 ). 9 , 30 Thus, hypogonadotropic hypogonadism represents a typical oligogenic disorder.…”

Section: Pubertal Disordersmentioning

confidence: 99%

“… 9 , 30 Reportedly, the frequency of PROKR2 variants in patients with hypogonadotropic hypogonadism is particularly high in China, Japan, and Taiwan. 33 Of these, the p.W178S variant is regarded as a founder mutation in China. 33 Furthermore, loss‐of‐function variants of PROK2 encoding the PROKR2 ligand cause hypogonadotropic hypogonadism in autosomal dominant, recessive, and oligogenic manners.…”

Section: Genetic Variants Of Gpcrs Associated With Pubertal Disordersmentioning

confidence: 99%

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Genetic variants of G‐protein coupled receptors associated with pubertal disorders

Suzuki

Miyado

Kuroki

et al. 2023

Reprod Medicine & Biology

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BackgroundThe human hypothalamic–pituitary‐gonadal (HPG) axis is the regulatory center for pubertal development. This axis involves six G‐protein coupled receptors (GPCRs) encoded by KISS1R, TACR3, PROKR2, GNRHR, LHCGR, and FSHR.MethodsPrevious studies have identified several rare variants of the six GPCR genes in patients with pubertal disorders. In vitro assays and animal studies have provided information on the function of wild‐type and variant GPCRs.Main FindingsOf the six GPCRs, those encoded by KISS1R and TACR3 are likely to reside at the top of the HPG axis. Several loss‐of‐function variants in the six genes were shown to cause late/absent puberty. In particular, variants in KISS1R, TACR3, PROKR2, and GNRHR lead to hypogonadotropic hypogonadism in autosomal dominant, recessive, and oligogenic manners. Furthermore, a few gain‐of‐function variants of KISS1R, PROKR2, and LHCGR have been implicated in precocious puberty. The human HPG axis may contain additional GPCRs.ConclusionThe six GPCRs in the HPG axis govern pubertal development through fine‐tuning of hormone secretion. Rare sequence variants in these genes jointly account for a certain percentage of genetic causes of pubertal disorders. Still, much remains to be clarified about the molecular network involving the six GPCRs.

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Section: Pubertal Disordersmentioning

confidence: 99%

Section: Genetic Variants Of Gpcrs Associated With Pubertal Disordersmentioning

confidence: 99%

Genetic variants of G‐protein coupled receptors associated with pubertal disorders

Suzuki

Miyado

Kuroki

et al. 2023

Reprod Medicine & Biology

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“…The CHH diagnosis and subclassification methodology are similar to a recently published study from our center. 5 For probands ≥ 18 years, CHH was diagnosed if proband had clinical symptoms and signs of hypogonadism with low or normal gonadotropins along with serum testosterone < 100 ng/dl in males and serum estradiol < 20 pg/ml in females, normal levels of other pituitary hormones; and wherever available normal pituitary magnetic resonance imaging (MRI); and absence of systemic illness. In MRI, olfactory bulb volume was assessed and classified as normal or hypoplastic/aplastic.…”

Section: Patients (Our Cohort)mentioning

confidence: 99%

“…Our center data based on Sanger sequencing 4 of five genes revealed a limited genetic yield of 12.6% for KS and 19.6% for nCHH, which increased to 35.3% for nCHH using NGS analyzing 29 known CHH genes. 5 Our systematic review of NGS-based studies in nCHH demonstrated a geographical variation in commonly affected genes. 5 This paper reports the molecular diagnostic yield using NGS and phenotype-genotype spectrum for our center's KS cohort.…”

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confidence: 94%

“…5 Our systematic review of NGS-based studies in nCHH demonstrated a geographical variation in commonly affected genes. 5 This paper reports the molecular diagnostic yield using NGS and phenotype-genotype spectrum for our center's KS cohort. Additionally, a systematic review of published studies analyzing multiple CHH genes using NGS in KS cohorts was performed.…”

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confidence: 94%

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Genetic spectrum of Kallmann syndrome: Single‐center experience and systematic review

Patil

Lila

Shah

et al. 2022

Clinical Endocrinology

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Objective: To study phenotype-genotype data of Asian−Indian Kallmann syndrome (KS) from our center and systematically review the studies analyzing multiple congenital hypogonadotropic hypogonadism (CHH) genes in KS cohorts using nextgeneration sequencing.Design, Patients, Measurement: Five hundred twenty-two KS probands (our center n = 78, published studies n = 444) were included in this systematic review. Molecular diagnosis was considered if the likely pathogenic/pathogenic variant in known CHH gene/s was reported in the appropriate allelic state. Varsome prediction tool (following American College of Medical Genetics standards) was used to analyze the variants.Result: For our center, the molecular diagnosis was seen in 20.5% of probands and was seen more often with severe than partial reproductive phenotype (28.3% vs. 4%, p = .0013). Our center data adds eight novel variants. The molecular diagnosis was seen in 31% as per the systematic review and analysis. It ranged from 16.6% to 72.2% at different centers. The affected genes were FGFR1 (9.8%), ANOS1 (7.5%), PROKR2 (6.1%), CHD7 (5.4%), oligogenic (2.1%), and others <1% each (FGF8, SOX10, PROK2, SEMA3A, IL17RD, and GNRHR). FGFR1 and ANOS1 were the commonly affected genes globally, whereas PROKR2 was commonest in studies from China and CHD7 from Japan, South Korea and Poland. Conclusion(s):This systematic review highlights that the genetic yield is 31% in KS probands, with distinct regional variations. The association of severe reproductive phenotype with the higher genetic yield needs further validation.

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Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort

Carriço,

Gonçalves,

Al-Naama

et al. 2024

Human Reproduction Open

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STUDY QUESTION What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. WHAT IS KNOWN ALREADY CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. STUDY DESIGN, SIZE, DURATION Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. PARTICIPANTS/MATERIALS, SETTING, METHODS The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). MAIN RESULTS AND THE ROLE OF CHANCE A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. WIDER IMPLICATIONS OF THE FINDINGS This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine—a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.

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Regional genotypic variations in normosmic congenital hypogonadotropic hypogonadism: our experience and systematic review

Cited by 4 publications

References 16 publications

Genetic variants of G‐protein coupled receptors associated with pubertal disorders

Genetic variants of G‐protein coupled receptors associated with pubertal disorders

Genetic spectrum of Kallmann syndrome: Single‐center experience and systematic review

Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort

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