目的:先天性低促性腺激素性性腺功能减退症(congenital hypogonadotropic hypogonadism,CHH)是一种罕见的先天性疾病,由于下丘脑促性腺激素释放激素的合成、分泌或信号转导缺陷引起先天性性腺发育不良。CHH以青春期发育延迟或缺乏、性...目的:先天性低促性腺激素性性腺功能减退症(congenital hypogonadotropic hypogonadism,CHH)是一种罕见的先天性疾病,由于下丘脑促性腺激素释放激素的合成、分泌或信号转导缺陷引起先天性性腺发育不良。CHH以青春期发育延迟或缺乏、性激素及促性腺激素水平低下为主要表现,同时可能伴有其他临床表型。一部分CHH患者伴有嗅觉丧失或低下,被称为卡尔曼综合征(Kallmann syndrome,KS)。ANOS1基因是第一个被发现的CHH致病基因,位于X染色体上,其突变可导致X-连锁隐性遗传的CHH。本研究拟通过分析CHH患者中ANOS1的基因突变图谱以及临床表型和基因型的关系,为CHH的遗传学诊断奠定基础。方法:利用全外显子组测序(whole exome sequencing,WES)的方法筛选来自中国的165名男性CHH患者中ANOS1基因的罕见变异(rare sequencing variants,RSVs)。利用Polyphen2、Mutation tastaster、SIFT和CADD(Combined Annotation Dependent Depletion)4种常见的生物信息学工具预测编码区变异的功能,基于神经网络的剪接位点预测(Splice Site Prediction by Neural Network,NNSPLICE)软件对检测到的内含子区的RSVs进行注释,并利用美国医学遗传学和基因组学学院(American College of Medical Genetics and Genomics,ACMG)遗传变异分类标准与指南判断ANOS1 RSVs是否具有致病性。初步建立中国人群CHH患者ANOS1的遗传突变谱,通过收集部分患者详细的临床资料,建立临床表型和基因型的相关性。结果:WES分析显示165名CHH患者中17例患者发生了ANOS1突变,突变频率为10.3%。在17名CHH患者中共检测到13个ANOS1 RSVs,包括5个无义突变(p.T76X、p.R191X、p.W257X、p.R262X和p.W589X),2个剪切位点突变(c.318+3A>C和c.1063-1G>C)和6个错义突变(p.N402S、p.N155D、p.P504L、p.C157R、p.Q635P及p.V560I)。在17名携带ANOS1 RSVs的患者中,很多同时伴有其他临床表型,其中最常见的为隐睾(10/17),其次是单侧肾脏发育不全(3/17),牙齿�展开更多
BACKGROUND Kallmann syndrome(KS)is a hypogonadotropic hypogonadism accompanied by anosmia or hyposmia.It is associated with the low secretion of gonadotropins which can lead to other abnormal endocrine metabolism diso...BACKGROUND Kallmann syndrome(KS)is a hypogonadotropic hypogonadism accompanied by anosmia or hyposmia.It is associated with the low secretion of gonadotropins which can lead to other abnormal endocrine metabolism disorders such as diabetes.Through genetic and molecular biological methods,more than 10 KS pathogenic genes have been found.AIM To identify the existing mutation sites of KS with diabetes and reveal the relationship between genotype and phenotype.METHODS We studied KS pathogenesis through high-throughput exome sequencing on four diabetes’patients with KS for screening the potential pathogenic sites and exploring the genotype-phenotype correlation.Clinical data and peripheral blood samples were collected from the patients.White blood cells were separated and genomic DNA was extracted.High-throughput sequencing of all exons in the candidate pathogenic genes of probands was performed,and the results obtained were analyzed.RESULTS Sequencing revealed mutations in the KLB p.T313M,ANOS1 p.C172F,and IGSF10 gene(p.Lys1819Arg and p.Arg1035Thr)at different sites,which may have been associated with disease onset.CONCLUSION The diagnosis of KS is challenging,especially in early puberty,and the clinical manifestations reflect physical delays in development and puberty.Timely diagnosis and treatment can induce puberty,thereby improving sexual,bone,metabolic and mental health.展开更多
基金supported by the National Natural Science Foundation(81770780)the Natural Science Foundation of Hunan Province(2020JJ4901),China。
文摘目的:先天性低促性腺激素性性腺功能减退症(congenital hypogonadotropic hypogonadism,CHH)是一种罕见的先天性疾病,由于下丘脑促性腺激素释放激素的合成、分泌或信号转导缺陷引起先天性性腺发育不良。CHH以青春期发育延迟或缺乏、性激素及促性腺激素水平低下为主要表现,同时可能伴有其他临床表型。一部分CHH患者伴有嗅觉丧失或低下,被称为卡尔曼综合征(Kallmann syndrome,KS)。ANOS1基因是第一个被发现的CHH致病基因,位于X染色体上,其突变可导致X-连锁隐性遗传的CHH。本研究拟通过分析CHH患者中ANOS1的基因突变图谱以及临床表型和基因型的关系,为CHH的遗传学诊断奠定基础。方法:利用全外显子组测序(whole exome sequencing,WES)的方法筛选来自中国的165名男性CHH患者中ANOS1基因的罕见变异(rare sequencing variants,RSVs)。利用Polyphen2、Mutation tastaster、SIFT和CADD(Combined Annotation Dependent Depletion)4种常见的生物信息学工具预测编码区变异的功能,基于神经网络的剪接位点预测(Splice Site Prediction by Neural Network,NNSPLICE)软件对检测到的内含子区的RSVs进行注释,并利用美国医学遗传学和基因组学学院(American College of Medical Genetics and Genomics,ACMG)遗传变异分类标准与指南判断ANOS1 RSVs是否具有致病性。初步建立中国人群CHH患者ANOS1的遗传突变谱,通过收集部分患者详细的临床资料,建立临床表型和基因型的相关性。结果:WES分析显示165名CHH患者中17例患者发生了ANOS1突变,突变频率为10.3%。在17名CHH患者中共检测到13个ANOS1 RSVs,包括5个无义突变(p.T76X、p.R191X、p.W257X、p.R262X和p.W589X),2个剪切位点突变(c.318+3A>C和c.1063-1G>C)和6个错义突变(p.N402S、p.N155D、p.P504L、p.C157R、p.Q635P及p.V560I)。在17名携带ANOS1 RSVs的患者中,很多同时伴有其他临床表型,其中最常见的为隐睾(10/17),其次是单侧肾脏发育不全(3/17),牙齿�
文摘BACKGROUND Kallmann syndrome(KS)is a hypogonadotropic hypogonadism accompanied by anosmia or hyposmia.It is associated with the low secretion of gonadotropins which can lead to other abnormal endocrine metabolism disorders such as diabetes.Through genetic and molecular biological methods,more than 10 KS pathogenic genes have been found.AIM To identify the existing mutation sites of KS with diabetes and reveal the relationship between genotype and phenotype.METHODS We studied KS pathogenesis through high-throughput exome sequencing on four diabetes’patients with KS for screening the potential pathogenic sites and exploring the genotype-phenotype correlation.Clinical data and peripheral blood samples were collected from the patients.White blood cells were separated and genomic DNA was extracted.High-throughput sequencing of all exons in the candidate pathogenic genes of probands was performed,and the results obtained were analyzed.RESULTS Sequencing revealed mutations in the KLB p.T313M,ANOS1 p.C172F,and IGSF10 gene(p.Lys1819Arg and p.Arg1035Thr)at different sites,which may have been associated with disease onset.CONCLUSION The diagnosis of KS is challenging,especially in early puberty,and the clinical manifestations reflect physical delays in development and puberty.Timely diagnosis and treatment can induce puberty,thereby improving sexual,bone,metabolic and mental health.
