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Background <p>Congenital hypogonadotropic hypogonadism (CHH) is a heterogeneous disorder resulting from defective secretion or action of gonadotropin-releasing hormone (GnRH). The <i>NDNF</i> gene, which encodes a secreted neurotrophic factor essential for GnRH neuron migration and survival, has been linked to the development of CHH. This study aims to present novel compound heterozygous variants of the <i>NDNF</i> gene and investigate the genotype-phenotype correlation.</p> Methods and results <p>This study involved two infertile sisters with symptoms of CHH. DNA extraction, whole-exome sequencing, and segregation analyses were performed. Expression analysis was performed using qRT-PCR. In silico tools were also used to evaluate the pathogenesis of the variants. Clinical evaluation revealed classical features of CHH, such as low gonadotropins and sex steroids. Both affected individuals were compound heterozygous for the c.628&#xa0;C &gt; T (p.Q210*) and c.653&#xa0;A &gt; G (p.E218G) variants. The heterozygous c.653&#xa0;A &gt; G and c.628&#xa0;C &gt; T variants were identified in the parents of the patients. Each of these variants exhibited different phenotypic severity in the heterozygous state compared to the compound heterozygous state. Indeed, none of them, unlike their parents, had any history of pregnancy. The c.628&#xa0;C &gt; T variant also escapes mRNA degradation.</p> Conclusion <p>This research first provides additional evidence for the role of <i>NDNF</i> in the etiology of CHH and then demonstrates the severe impact of novel compound heterozygous variants (c.628&#xa0;C &gt; T, c.653&#xa0;A &gt; G) on infertility. It seems logical that most monoallelic <i>NDNF</i> variants have a better chance of treatment and fertility than the same variants in the biallelic state.</p>

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Novel compound heterozygous NDNF variants in congenital hypogonadotropic hypogonadism: insights into genotype-phenotype correlation and infertility

  • 期刊论文

  • 发表日期：

    2025年8月11日

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  • Behzad Haj Mohammad Hassani,
  • Niloofar Ghasemi,
  • Kianoosh Malekzadeh

摘要

Background

Congenital hypogonadotropic hypogonadism (CHH) is a heterogeneous disorder resulting from defective secretion or action of gonadotropin-releasing hormone (GnRH). The NDNF gene, which encodes a secreted neurotrophic factor essential for GnRH neuron migration and survival, has been linked to the development of CHH. This study aims to present novel compound heterozygous variants of the NDNF gene and investigate the genotype-phenotype correlation.

Methods and results

This study involved two infertile sisters with symptoms of CHH. DNA extraction, whole-exome sequencing, and segregation analyses were performed. Expression analysis was performed using qRT-PCR. In silico tools were also used to evaluate the pathogenesis of the variants. Clinical evaluation revealed classical features of CHH, such as low gonadotropins and sex steroids. Both affected individuals were compound heterozygous for the c.628 C > T (p.Q210*) and c.653 A > G (p.E218G) variants. The heterozygous c.653 A > G and c.628 C > T variants were identified in the parents of the patients. Each of these variants exhibited different phenotypic severity in the heterozygous state compared to the compound heterozygous state. Indeed, none of them, unlike their parents, had any history of pregnancy. The c.628 C > T variant also escapes mRNA degradation.

Conclusion

This research first provides additional evidence for the role of NDNF in the etiology of CHH and then demonstrates the severe impact of novel compound heterozygous variants (c.628 C > T, c.653 A > G) on infertility. It seems logical that most monoallelic NDNF variants have a better chance of treatment and fertility than the same variants in the biallelic state.