Mutation Screening for 117 Patients with Kallmann Syndrome.

Introduction: Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism (HH) and olfactory dysfunction. Although , a causative gene for Waardenburg syndrome (WS) and peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease (PCWH) has previously been implicated in KS, the clinical significance of variants as the cause of KS remains uncertain.

Patients And Methods: A total of 117 patients with KS underwent mutation screening of and 14 other causative genes for KS/HH. Rare variants were subjected to in silico and in vitro analyses. We also examined clinical data of the patients and their parents with variants.

Results: Sequence analysis identified 2 heterozygous variants of (c.1225G > T, p.Gly409* and c.475C > T, p.Arg159Trp) in patients 1-3, as well as in the parents of patients 1 and 3. The variants were assessed as pathogenic/likely pathogenic, according to the American College of Medical Genomics guidelines. Both variants lacked in vitro transactivating activity for the promoter and exerted no dominant-negative effects. Patients 1-3 carried no pathogenic variants in other genes examined. The patients presented with typical KS, while such features were absent in the parents of patients 1 and 3. None of the 5 variant-positive individuals exhibited hypopigmentation, while 1 and 2 individuals exhibited complete and partial hearing loss, respectively.

Conclusion: These results provide evidence that haploinsufficiency accounts for a small percentage of KS cases. haploinsufficiency is likely to be associated with a broad phenotypic spectrum, which includes KS without other clinical features of WS/PCWH.