Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism(IHH)and an oligogenic etiology has been suggested.However,the associated genes may account for only approximately 50%cases.In addition,a gen...Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism(IHH)and an oligogenic etiology has been suggested.However,the associated genes may account for only approximately 50%cases.In addition,a genomic systematic pedigree analysis is still lacking.Here,we conducted whole exome sequencing(WES)on 18 unrelated men affected by IHH and their corresponding parents.Notably,one reported and 10 novel variants in eight known IHH causative genes(AXL,CCDC141,CHD7,DMXL2,FGFR1,PNPLA6,POLR3A,and PR0KR2),nine variants in nine recently reported candidate genes(DCAF17,DCC,EGF,IGSF10,NOTCH1,PDE3A,RELN,SLIT2,and TRAPPC9),and four variants in four novel candidate genes for IHH(CCDC88C,CDON,GADL1,and SPRED3)were identified in 77.8%(14/18)of IHH cases.Among them,eight(8/18,44.4%)cases carried more than one variant in IHH-related genes,supporting the oligogenic model.Interestingly,we found that those variants tended to be maternally inherited(maternal with n=17 vs paternal with n=7;P=0.028).Our further retrospective investigation of published reports replicated the maternal bias(maternal with n=46 i^s paternal with n=28;P=0.024).Our study extended a variant spectrum for IHH and provided the first evidence that women are probably more tolerant to variants of IHH-related genes than men.展开更多
Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disorder with phenotypic and genetic heterogeneity.Recent studies have suggested an oligogenic basis of ALS,in which the co-occurrence of two or more gene...Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disorder with phenotypic and genetic heterogeneity.Recent studies have suggested an oligogenic basis of ALS,in which the co-occurrence of two or more genetic variants has additive or synergistic deleterious effects.To assess the contribution of possible oligogenic inheritance,we profiled a panel of 43 relevant genes in 57 sporadic ALS(sALS)patients and eight familial ALS(fALS)patients from five pedigrees in east China.We filtered rare variants using the combination of the Exome Aggregation Consortium,the 1000 Genomes and the HuaBiao Project.We analyzed patients with multiple rare variants in 43 known ALS causative genes and the genotype–phenotype cor-relation.Overall,we detected 30 rare variants in 16 different genes and found that 16 of the sALS patients and all the fALS patients examined harbored at least one variant in the investigated genes,among which two sALS and four fALS patients harbored two or more variants.Of note,the sALS patients with one or more variants in ALS genes had worse survival than the patients with no variants.Typically,in one fALS pedigree with three variants,the family member with three variants(Superoxide dismutase 1(SOD1)p.V48A,Optineurin(OPTN)p.A433V and TANK binding kinase 1(TBK1)p.R573H)exhibited much more severe disease phenotype than the member carrying one variant(TBK1 p.R573H).Our findings suggest that rare variants could exert a negative prognostic effect,thereby supporting the oligogenic inheritance of ALS.展开更多
Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid...Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic-pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, high-throughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder.展开更多
基金the National Key Research and Development Program of China(2016YFC0905100)National Natural Science Foundation of China(31625015 and 31521003)+2 种基金Shanghai Medical Center of Key Programs for Female Reproductive Diseases(2017ZZ01016)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)Shanghai Municipal Commission for Science and Technology(19QA1407500).
文摘Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism(IHH)and an oligogenic etiology has been suggested.However,the associated genes may account for only approximately 50%cases.In addition,a genomic systematic pedigree analysis is still lacking.Here,we conducted whole exome sequencing(WES)on 18 unrelated men affected by IHH and their corresponding parents.Notably,one reported and 10 novel variants in eight known IHH causative genes(AXL,CCDC141,CHD7,DMXL2,FGFR1,PNPLA6,POLR3A,and PR0KR2),nine variants in nine recently reported candidate genes(DCAF17,DCC,EGF,IGSF10,NOTCH1,PDE3A,RELN,SLIT2,and TRAPPC9),and four variants in four novel candidate genes for IHH(CCDC88C,CDON,GADL1,and SPRED3)were identified in 77.8%(14/18)of IHH cases.Among them,eight(8/18,44.4%)cases carried more than one variant in IHH-related genes,supporting the oligogenic model.Interestingly,we found that those variants tended to be maternally inherited(maternal with n=17 vs paternal with n=7;P=0.028).Our further retrospective investigation of published reports replicated the maternal bias(maternal with n=46 i^s paternal with n=28;P=0.024).Our study extended a variant spectrum for IHH and provided the first evidence that women are probably more tolerant to variants of IHH-related genes than men.
基金This work was supported by 2020 Central Transfer Payment Medical Siege Institutions Capacity Building Project(National and Provincial Multi-scientific Cooperation Diagnosis and Treatment of Major Diseases Capacity Building Project)Shanghai Fudan University Education Development Foundation and State Key Laboratory of Genetic Engineering,Human Phenome Institute,Zhangjiang Fudan International Innovation Center,Fudan UniversityShanghai Municipal Science and Technology Major Project 2017HZDZX01.
文摘Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disorder with phenotypic and genetic heterogeneity.Recent studies have suggested an oligogenic basis of ALS,in which the co-occurrence of two or more genetic variants has additive or synergistic deleterious effects.To assess the contribution of possible oligogenic inheritance,we profiled a panel of 43 relevant genes in 57 sporadic ALS(sALS)patients and eight familial ALS(fALS)patients from five pedigrees in east China.We filtered rare variants using the combination of the Exome Aggregation Consortium,the 1000 Genomes and the HuaBiao Project.We analyzed patients with multiple rare variants in 43 known ALS causative genes and the genotype–phenotype cor-relation.Overall,we detected 30 rare variants in 16 different genes and found that 16 of the sALS patients and all the fALS patients examined harbored at least one variant in the investigated genes,among which two sALS and four fALS patients harbored two or more variants.Of note,the sALS patients with one or more variants in ALS genes had worse survival than the patients with no variants.Typically,in one fALS pedigree with three variants,the family member with three variants(Superoxide dismutase 1(SOD1)p.V48A,Optineurin(OPTN)p.A433V and TANK binding kinase 1(TBK1)p.R573H)exhibited much more severe disease phenotype than the member carrying one variant(TBK1 p.R573H).Our findings suggest that rare variants could exert a negative prognostic effect,thereby supporting the oligogenic inheritance of ALS.
基金Athanasia Stoupa received a research grant from the European Society for Paediatric Endocrinology (ESPE). Aurore Carré, Dulanjalee Kariyawasam, and Michel Polak received funding from Sandoz SAS and Merck Serono France, the French Society of Endocrinology and Paediatric Diabetology (SFEDP), and the French National Research Agency (ANR-21-CE14-0055-01-MITHY-PLA) .
文摘Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic-pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, high-throughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder.
