ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000007.13) (NC_000007.14)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
22416012 Young et al. (2012) report a family with Kallmann syndrome: a proband and two relatives, with a heterozygous deletion of 213 kb at locus 7q21.11. The deletion includes 11 of 17 exons of SEMA3A and was first identified by genomic microarray and confirmed by RT-qPCR. Sequencing of the SEMA3A exons and intron-exon junctions to assess whether a second mutation was present, was negative. All patients presented with the phenotype. Two of the patients were male and were found to present with hypogonadism and hyposmia. One patient was female and presented with primary amenorrhea, absent breast development, and anosmia. In this family, the Kallmann phenotype was transmitted in an autosomal dominant manner, which suggests that haploinsufficiency of SEMA3A is sufficient to cause the Kallmann phenotype. However, they do not rule out the possibility of a second genetic event that was not revealed by their study.

Haploinsufficiency phenotype comments:

Although SEMA3A deletion has been linked to Kallman syndrome, the inheritance pattern is unclear. Therefore the current haploinsufficiency score is 1. Additional studies with proposed alternative mechanisms of pathogenicity are summarized below. PMID: 22927827 Hanchate et al. (2012) screened 386 patients with a clinical diagnosis of Kallmann syndrome for mutations in SEMA3A by Sanger sequencing (coding exons and flanking splice sites); some of these patients also carried a molecular diagnosis, with mutation in a known Kallmann syndrome-associated gene. In 24 of these patients they identified 7 missense mutations and 1 small frameshifting deletion. Functional in vitro studies revealed that these mutations resulted in either impaired secretion (consistent with loss of function) or reduced signaling activity of the secreted protein. None of the patients studied were found to carry a second mutation/deletion in SEMA3A. They conclude that the Kallmann syndrome phenotype requires the combination of a mutation/deletion in both SEMA3A and another gene, consistent with an oligogenic pattern of inheritance. PMID: 24124006 Hofmann et al. (2013) report an individual with bi-allelic alteration of SEMA3A: a deletion of 150 kb that includes the first exon, a coding exon, and a second in-frame mutation in SEMA3A at aa316. The deletion was confirmed to be inherited from an apparently healthy father; however, no additional mutation testing was done. The patient presented with minor facial dysmorphism, skeletal anomalies, and short stature. SEMA3A relative expression was decreased in the patient compared to normal controls. Neither patient showed clinical findings consistent with Kallmann syndrome. The authors conclude that biallelic SEMA3A defects cause a novel short stature syndrome without the typical Kallmann syndrome phenotypic findings.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No literature found.