Study On The Genetic Diagnosis Of Congenital Hypogonadotropic Hypogonadism In Male

Objective: Congenital hypogonadotropic hypogonadism(CHH)is a type of endocrine disease caused by the synthesis,secretion,and dysfunction of gonadotropin-releasing hormone(Gn RH);and when associated with anosmia or hyposmia,CHH is termed Kallmann syndrome(KS).The first part systematically elaborates the genetic etiology,clinical manifestation,diagnosis and differential diagnosis,treatment and reversal of CHH,and genetic testing and genetic counseling,providing a good theoretical basis for the study of CHH.In the second part,we analyzed the clinical features(including reproductive-related phenotype and non-reproductive phenotype-related phenotypes)and the changes of endocrine hormone levels in 76 CHH male patients,aiming to provide an important reference for clinical diagnosis.In the third part,two KS families were studied,the causes of family diseases were identified from the perspective of genetics and the genotype-phenotype correspondence was discussed.At the same time,the basis for clinical treatment and genetic counseling of patients was established.Methods: In the first part,we collected,reviewed and sorted out the CHH literature from the Pubmed database and reviewed the etiology,diagnosis and treatment of CHH.In the second part,76 clinical patients with CHH were collected for detailed clinical examination and assessment.SPSS 20.0 software was used for statistical analysis of the assessment data,and the chi-square test was used for differential verification.In the third part,the peripheral blood of patients and their family members was collected from two KS family members.The whole exome sequencing technology captures exon regions of patients and high-throughput sequencing data were screened,filtered,and analyzed.Patients may be causative of mutations;and the mutation site is verified by polymerase chain reaction amplification,Sanger sequencing,and bioinformatics analysis.Results: First,the study of 76 male CHH probands found that CHH patients had a high incidence of reproductive-related phenotypes of small penis(16/76),while the accompanying non-reproductive phenotypes were mostly found in KS,mainly including: hearing impairment(5/76),high myopia(2/76),hypoplastic iris(3/76),congenital lip/patella(3/76),and renal dysplasia(2/76).Secondly,a genetic diagnosis study of a KS family led to the analysis of FGFR1 gene mutations(c.1810 G>A,p.604 Q>X)which is highly likely to be the cause of the disease in this family.The mutation was verified to co-segregate with the disease in the family;bioinformatic analysis showed that the amino acid encoded by the mutation site was highly conserved among different species;this mutation was not found in the SNP database and 200 normal controls,excluding mutant polymorphisms.Finally,analysis of WES data from probands in KS famiy with deafness and iris heterogeneity suggests that the SOX10 gene mutation(c.1287 del G,p.G429 G fs*73)may be a causative mutation..It was verified that the mutation was co-segregated from the disease in the family.Bioinformatic analysis revealed that after the mutation of the SOX10 gene(c.1287 del G,p.G429 G fs*73),the encoded amino acid sequence was clearly disordered and terminated prematurely,resulting in a truncated protein.Conclusion: The statistics of the study found that clinical CHH is often accompanied by a variety of non-reproductive phenotypes,which provides an important reference for clinical doctors in clinical diagnosis.On the other hand,from the genetic point of view,the pathogenic genes of the two KS families were identified,FGFR1 gene mutations and SOX10 gene mutations;not only enriched gene mutation spectrum,favorable for genotype-phenotype correspondence,but also for the clinical treatment and genetic counseling provide an important basis.