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GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism
Catarina I Gonçalves1, José M Aragüés2, Margarida Bastos3
1CICS-UBIHealth Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
Objective:
Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare disorder characterised by lack of pubertal development and infertility, due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH) and, unlike Kallmann syndrome, is associated with a normal sense of smell. Mutations in the GNRHR gene cause autosomal recessive nCHH. The aim of this study was to determine the prevalence of GNRHR mutations in a group of 40 patients with nCHH.
Design:
Cross-sectional study of 40 unrelated patients with nCHH.
Methods:
Patients were screened for mutations in the GNRHR gene by DNA sequencing.
Results:
GNRHR mutations were identified in five of 40 patients studied. Four patients had biallelic mutations (including a novel frameshift deletion p.Phe313Metfs*3, in two families) in agreement with autosomal recessive inheritance. One patient had a heterozygous GNRHR mutation associated with a heterozygous PROKR2 mutation, thus suggesting a possible role of synergistic heterozygosity in the pathogenesis of the disorder.
Conclusions:
This study further expands the spectrum of known genetic defects associated with nCHH. Although GNRHR mutations are usually biallelic and inherited in an autosomal recessive manner, the presence of a monoallelic mutation in a patient should raise the possibility of a digenic/oligogenic cause of nCHH.
Insights
Mutations in the GNRHR gene were found in 12.5% of patients with normosmic congenital hypogonadotropic hypogonadism (nCHH). This suggests GNRHR mutations are a cause of nCHH, sometimes involving multiple genes.
Area of Science:
- Genetics
- Endocrinology
- Reproductive Medicine
Background:
- Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare condition causing absent puberty and infertility due to GnRH pathway defects.
- Unlike Kallmann syndrome, nCHH patients have a normal sense of smell.
- Autosomal recessive mutations in the GNRHR gene are a known cause of nCHH.
Purpose of the Study:
- To investigate the prevalence of GNRHR gene mutations in a cohort of 40 patients diagnosed with nCHH.
- To identify novel mutations and understand inheritance patterns of GNRHR mutations in nCHH.
Main Methods:
- A cross-sectional study was conducted on 40 unrelated patients with nCHH.
- DNA sequencing was employed to screen the GNRHR gene for mutations in all participants.
Main Results:
- GNRHR mutations were detected in 5 out of 40 patients (12.5%).
- Four patients exhibited biallelic GNRHR mutations, consistent with autosomal recessive inheritance, including a novel frameshift deletion (p.Phe313Metfs*3).
- One patient presented with a heterozygous GNRHR mutation alongside a heterozygous PROKR2 mutation, indicating potential digenic inheritance.
Conclusions:
- This research expands the known genetic causes of nCHH.
- While typically biallelic and autosomal recessive, GNRHR mutations can be monoallelic, suggesting digenic or oligogenic mechanisms in nCHH pathogenesis.
- The findings highlight the genetic heterogeneity of nCHH and the importance of considering complex inheritance patterns.
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