Clinical Assessment,mutation Detection And Genetics Analysis In Seven Kallmann Syndrome Pedigrees

Context:Kallmann Syndrome (KS), a form of idiopathic hypogonadotropic hypogonadism(IHH), is an endocrine condition characterized by developmental abnormalities of thereproductive system and abnormal olfaction. The etiology of KS is divided intospontaneous and hereditary.Twenty genes have been associated with IHH, but thegenetics are complex and genotype–phenotype relationships are not fully understood.Objective:Here, we screened for genetic mutations in seven KS pedigrees and attempted tocorrelate our findings with the observed clinical symptoms.Design and participants:The development of secondary sexual characteristic, olfactory phenotype and otherclinical phenotypes were observed in the patient of the seven Chinese KS pedigrees. Wealso sequenced the exons and intron–exon boundaries of19of the20IHH-related genes(KAL-1、FGFR1、FGF8、PROKR2、PROK2、NELF、WDR11、HS6ST1、KISS1R、KISS1、TAC3、TACR3、LEPR、LEP、PCSK1、GNRHR、GNRH1、SEMA3A、NDN) in these pedigrees. Detected mutations were also tested for in70sporadic KScases and200Chinese healthy controls.Results:In Pedigrees1,2, and7, the secondary sex characteristics were poorly developedand the patients’ sense of smell was severely or completely lost; these were variable inthe other pedigrees. We detected a genetic mutation in five of the seven pedigrees:homozygous KAL1p.R191ter (Pedigree1); homozygous KAL1p.C13ter (Pedigree2; anovel mutation); heterozygous FGFR1p.R250W (Pedigree3); and homozygousPROKR2p.Y113H (Pedigrees4and5). No genetic change was detected in Pedigrees6and7. Among the70sporadic cases, we detected one homozygous and oneheterozygous PROKR2p.Y113H mutation. This mutation was also detected heterozygously in2/200normal controls and its pathogenicity is therefore questionable.Conclusion:1. We detected a genetic mutation in five of our seven pedigrees, including thenovel nonsense mutation KAL1p.C13ter.2. The genetics and genotype–phenotype relationships in KS are complicated.Classical monogenic inheritance can be affected by factors such as skewedX-inactivation, delayed dominance and microdeletions. Digenic and oligogenicinheritance are becoming increasingly considered and furthermore, the genetic effectsmay be modified by environmental and epigenetic factors. This study detected all thegenes (except CHD7) associated with KS and nIHH, however, no digenic or oligogenicpattern was found. So it is presumably that other mutation genes maybe the not-yetdiscovered genes.