Mutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadism
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Updated: May 3, 2026
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Published on: August 25, 2019
Johanna Känsäkoski1, Rainer Fagerholm2, Eeva-Maria Laitinen3
11] Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland [2] Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
Background:
Congenital hypogonadotropic hypogonadism (HH), a rare disorder characterized by absent, partial, or delayed puberty, can be caused by the lack or deficient number of hypothalamic gonadotropin-releasing hormone (GnRH) neurons. SEMA3A was recently implicated in the etiology of the disorder, and Sema7A-deficient mice have a reduced number of GnRH neurons in their brains.
Methods:
SEMA3A and SEMA7A were screened by Sanger sequencing in altogether 50 Finnish HH patients (34 with Kallmann syndrome (KS; HH with hyposmia/anosmia) and 16 with normosmic HH (nHH)). In 20 patients, mutation(s) had already been found in genes known to be implicated in congenital HH.
Results:
Three heterozygous variants (c.458A>G (p.Asn153Ser), c.1253A>G (p.Asn418Ser), and c.1303G>A (p.Val435Ile)) were found in SEMA3A in three KS patients, two of which also had a mutation in FGFR1. Two rare heterozygous variants (c.442C>T (p.Arg148Trp) and c.1421G>A (p.Arg474Gln)) in SEMA7A were found in one male nHH patient with a previously identified KISS1R nonsense variant and one male KS patient with a previously identified mutation in KAL1, respectively.
Conclusion:
Our results suggest that heterozygous missense variants in SEMA3A and SEMA7A may modify the phenotype of KS but most likely are not alone sufficient to cause the disorder.
Insights
Genetic variants in SEMA3A and SEMA7A may influence Kallmann syndrome (KS) and normosmic hypogonadotropic hypogonadism (nHH) phenotypes. However, these SEMA gene variants are unlikely to be the sole cause of congenital hypogonadotropic hypogonadism (HH).
Area of Science:
- Genetics
- Endocrinology
- Neuroscience
Background:
- Congenital hypogonadotropic hypogonadism (HH) is a rare disorder affecting puberty onset, often due to insufficient gonadotropin-releasing hormone (GnRH) neurons.
- SEMA3A has been recently linked to HH, and Sema7A-deficient mice exhibit fewer GnRH neurons.
Purpose of the Study:
- To investigate the role of SEMA3A and SEMA7A gene variants in the etiology of congenital hypogonadotropic hypogonadism (HH).
- To determine if variants in SEMA3A and SEMA7A contribute to the phenotype of Kallmann syndrome (KS) and normosmic HH (nHH).
Main Methods:
- Sanger sequencing was used to screen SEMA3A and SEMA7A in 50 Finnish HH patients (34 KS, 16 nHH).
- Genetic analysis included patients with known mutations in other congenital HH-associated genes.
Main Results:
- Three heterozygous SEMA3A variants were identified in three KS patients, two of whom also had FGFR1 mutations.
- Two rare heterozygous SEMA7A variants were found in one nHH patient (with a KISS1R variant) and one KS patient (with a KAL1 mutation).
Conclusions:
- Heterozygous missense variants in SEMA3A and SEMA7A may contribute to modifying the phenotype of KS.
- These SEMA gene variants are unlikely to be the sole causative factor for congenital hypogonadotropic hypogonadism (HH).
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