ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.