PKHD1 mutations are generally considered to cause autosomal recessive polycystic kidney disease(ARPKD).ARPKD is a rare disorder and one o f the most severe conditions leading to end-stage renal disease in childhood.Wi...PKHD1 mutations are generally considered to cause autosomal recessive polycystic kidney disease(ARPKD).ARPKD is a rare disorder and one o f the most severe conditions leading to end-stage renal disease in childhood.With the biallelic deletion mutation,patients have difficulty in surviving the perinatal period,resulting in perinatal or neonatal death.This study retrospectively analyzed patient characteristics,imaging characteristics,laboratory examinations and family surveys from 7 Chinese children with different PKHD1 gene mutations diagnosed by high-throughput sequencing from January 2014 to February 2018.O f the 7 children,there were 3 males and 4 females.Eight missense mutations,two frameshift mutations,two deletion mutations,and two intronic slicing mutations were identified.Six of the mutations have not previously been identified.In the literature search,we identified a total of 29 Chinese children with PKHD1 mutations.The missense mutation c.2507T>C in exon 24 was found in one patient in our study,and five patients with liver fibrosis but normal renal function were reported in the literature.The missense mutation c.5935G>A in exon 37 was found in two patients in our study and three cases in the literature.Four patients had renal failure at an age as young as 1 year of those five patients with the missense mutation c.5935G>A in exon 37.It was concluded that:(1)Kidney length more than 2-3 SDs above the mean and early-onset hypertension might be associated with PKHDI-associated ARPICD;(2)The more enlarged the kidney size is,the lower the renal function is likely to be;(3)c.5935G>A may be a hot spot that leads to early renal failure in Chinese children with PKHD1 mutations;(4)c.2507T>C may be a hot-spot mutation associated with hepatic lesions in Chinese children with PKHD1.展开更多
目的探讨常染色体隐性遗传多囊肾病(ARPKD)患儿(新生儿、婴幼儿及青少年)PKHD1基因变异的临床表型及基因型。方法选择2021年1月1日至2022年6月30日,因"胎儿期肾脏增大,要求进一步检查""尿痛伴发热2 d""尿频伴...目的探讨常染色体隐性遗传多囊肾病(ARPKD)患儿(新生儿、婴幼儿及青少年)PKHD1基因变异的临床表型及基因型。方法选择2021年1月1日至2022年6月30日,因"胎儿期肾脏增大,要求进一步检查""尿痛伴发热2 d""尿频伴尿痛"于西安市儿童医院就诊,并在本院确诊的3例ARPKD患儿(先证者)[患儿1(生后25 d龄男童)、患儿2(4岁女童)、患儿3(13岁女童)]为研究对象。采用回顾性分析法,对这3例患儿PKHD1基因变异的临床表型、实验室检查结果进行分析,采取全外显子组测序(WES)及Sanger测序进行致病突变基因位点分析和家系验证。根据美国医学遗传学与基因组学学会(ACMG)的《序列变异解释的标准和指南(Standards and Guidelines for the Interpretation of Sequence Variants:A Joint Consensus Recommendation)》(以下简称为ACMG指南),综合评估PKHD1基因变异的致病性。本研究遵循的程序符合西安市儿童医院伦理委员会规定,并通过该伦理委员会审查、批准(审批文号:伦20220059)。结果①3例患儿PKHD1基因变异临床表型及相关辅助检查结果:均存在双肾增大伴双肾多发囊肿(无肝、肾功能异常,无血尿及蛋白尿)。患儿2、3伴肝纤维化、肝内胆管扩张,患儿1合并高血压。②患儿及其家系成员PKHD1基因检测结果:患儿1为c.11223T>G(p.Y3741*)和c.4682G>A(p.C1561Y)复合杂合变异,分别遗传自其母亲与父亲;患儿2为c.9007T>C(p.S3003P)和c.5935G>A(p.G1979R)复合杂合变异,分别遗传自其父亲与母亲,而2位双胞胎弟弟为c.9007T>C杂合变异;患儿3为c.11542G>C(p.V3848L)和c.5935G>A(p.G1979R)复合杂合变异,分别遗传自其父亲与母亲,与胞姐携带相同变异,而其胞弟为c.5935G>A杂合变异。③根据ACMG指南判断3例患儿上述5种PKHD1基因变异致病性:c.4682G>A(p.G1979R)和c.5935G>A(p.G1979R)为临床意义不明性变异与致病性变异;c.11223T>G(p.Y3741*)、c.9007T>C(p.S3003P)和c.11542G>C(p.V3848L)分别为无义、错义、错义变异,根据ACMG指南分别被判断为可能致病性变异、可能致病性变异与临床意义不明性变异。结论本研究3例患儿均为PKHD1基因变异所致ARPKD患儿。该病患儿临床表型多变,并且多数与其他囊性肾病患儿临床表型相似,对疑似该病患儿应尽早采取基因检测进行诊断,这对患儿预后及家系遗传咨询具有重要意义。展开更多
Background Autosomal recessive polycystic kidney disease （ARPKD） is a rare inherited disease, which is a disorder with multiple organ involvement, mainly the kidney and liver. It is caused by mutations in the PKHD1 ...Background Autosomal recessive polycystic kidney disease （ARPKD） is a rare inherited disease, which is a disorder with multiple organ involvement, mainly the kidney and liver. It is caused by mutations in the PKHD1 gene. Here, we reported the clinical characteristics of a case with ARPKD and analyze the genetic features of this patient as well as of his father using targeted exome sequencing and Sanger sequencing. Methods Genomic DNA was extracted from peripheral blood leukocytes obtained from a patient with ARPKD. The mutations were identified using exome sequencing and confirmed by Sanger sequencing. Results The patient was diagnosed as ARPKD based on ultrasonography and abdominal computed tomography which showed polycystic changes, multiple calcinosis of both kidneys, and multiple dilated bile ducts of the liver. Compound heterozygous PKHD1 gene mutations A979G and G5935A, which lead to substitution of an asparagine for an aspartate at amino acid 327 （N327D） and a glycine for an arginine at amino acid 1979 （G1979R） respectively, were identified using targeted exome sequencing and confirmed by Sanger sequencing for the patient. In addition, the father of the patient was identified to be a carrier of heterozygous A979G mutation of this gene. Conclusions We identified that the compound heterozygous PKHD1 gene mutations are the molecular basis of the patient with ARPKD. Targeted exome sequencing is suitable for genetic diagnosis of single-gene inherited diseases like ARPKD in which the pathogenic gene is a large.展开更多
基金This project was supported by the National Natural Science Foundation of China(No.81873596).
文摘PKHD1 mutations are generally considered to cause autosomal recessive polycystic kidney disease(ARPKD).ARPKD is a rare disorder and one o f the most severe conditions leading to end-stage renal disease in childhood.With the biallelic deletion mutation,patients have difficulty in surviving the perinatal period,resulting in perinatal or neonatal death.This study retrospectively analyzed patient characteristics,imaging characteristics,laboratory examinations and family surveys from 7 Chinese children with different PKHD1 gene mutations diagnosed by high-throughput sequencing from January 2014 to February 2018.O f the 7 children,there were 3 males and 4 females.Eight missense mutations,two frameshift mutations,two deletion mutations,and two intronic slicing mutations were identified.Six of the mutations have not previously been identified.In the literature search,we identified a total of 29 Chinese children with PKHD1 mutations.The missense mutation c.2507T>C in exon 24 was found in one patient in our study,and five patients with liver fibrosis but normal renal function were reported in the literature.The missense mutation c.5935G>A in exon 37 was found in two patients in our study and three cases in the literature.Four patients had renal failure at an age as young as 1 year of those five patients with the missense mutation c.5935G>A in exon 37.It was concluded that:(1)Kidney length more than 2-3 SDs above the mean and early-onset hypertension might be associated with PKHDI-associated ARPICD;(2)The more enlarged the kidney size is,the lower the renal function is likely to be;(3)c.5935G>A may be a hot spot that leads to early renal failure in Chinese children with PKHD1 mutations;(4)c.2507T>C may be a hot-spot mutation associated with hepatic lesions in Chinese children with PKHD1.
文摘目的探讨常染色体隐性遗传多囊肾病(ARPKD)患儿(新生儿、婴幼儿及青少年)PKHD1基因变异的临床表型及基因型。方法选择2021年1月1日至2022年6月30日,因"胎儿期肾脏增大,要求进一步检查""尿痛伴发热2 d""尿频伴尿痛"于西安市儿童医院就诊,并在本院确诊的3例ARPKD患儿(先证者)[患儿1(生后25 d龄男童)、患儿2(4岁女童)、患儿3(13岁女童)]为研究对象。采用回顾性分析法,对这3例患儿PKHD1基因变异的临床表型、实验室检查结果进行分析,采取全外显子组测序(WES)及Sanger测序进行致病突变基因位点分析和家系验证。根据美国医学遗传学与基因组学学会(ACMG)的《序列变异解释的标准和指南(Standards and Guidelines for the Interpretation of Sequence Variants:A Joint Consensus Recommendation)》(以下简称为ACMG指南),综合评估PKHD1基因变异的致病性。本研究遵循的程序符合西安市儿童医院伦理委员会规定,并通过该伦理委员会审查、批准(审批文号:伦20220059)。结果①3例患儿PKHD1基因变异临床表型及相关辅助检查结果:均存在双肾增大伴双肾多发囊肿(无肝、肾功能异常,无血尿及蛋白尿)。患儿2、3伴肝纤维化、肝内胆管扩张,患儿1合并高血压。②患儿及其家系成员PKHD1基因检测结果:患儿1为c.11223T>G(p.Y3741*)和c.4682G>A(p.C1561Y)复合杂合变异,分别遗传自其母亲与父亲;患儿2为c.9007T>C(p.S3003P)和c.5935G>A(p.G1979R)复合杂合变异,分别遗传自其父亲与母亲,而2位双胞胎弟弟为c.9007T>C杂合变异;患儿3为c.11542G>C(p.V3848L)和c.5935G>A(p.G1979R)复合杂合变异,分别遗传自其父亲与母亲,与胞姐携带相同变异,而其胞弟为c.5935G>A杂合变异。③根据ACMG指南判断3例患儿上述5种PKHD1基因变异致病性:c.4682G>A(p.G1979R)和c.5935G>A(p.G1979R)为临床意义不明性变异与致病性变异;c.11223T>G(p.Y3741*)、c.9007T>C(p.S3003P)和c.11542G>C(p.V3848L)分别为无义、错义、错义变异,根据ACMG指南分别被判断为可能致病性变异、可能致病性变异与临床意义不明性变异。结论本研究3例患儿均为PKHD1基因变异所致ARPKD患儿。该病患儿临床表型多变,并且多数与其他囊性肾病患儿临床表型相似,对疑似该病患儿应尽早采取基因检测进行诊断,这对患儿预后及家系遗传咨询具有重要意义。
文摘Background Autosomal recessive polycystic kidney disease （ARPKD） is a rare inherited disease, which is a disorder with multiple organ involvement, mainly the kidney and liver. It is caused by mutations in the PKHD1 gene. Here, we reported the clinical characteristics of a case with ARPKD and analyze the genetic features of this patient as well as of his father using targeted exome sequencing and Sanger sequencing. Methods Genomic DNA was extracted from peripheral blood leukocytes obtained from a patient with ARPKD. The mutations were identified using exome sequencing and confirmed by Sanger sequencing. Results The patient was diagnosed as ARPKD based on ultrasonography and abdominal computed tomography which showed polycystic changes, multiple calcinosis of both kidneys, and multiple dilated bile ducts of the liver. Compound heterozygous PKHD1 gene mutations A979G and G5935A, which lead to substitution of an asparagine for an aspartate at amino acid 327 （N327D） and a glycine for an arginine at amino acid 1979 （G1979R） respectively, were identified using targeted exome sequencing and confirmed by Sanger sequencing for the patient. In addition, the father of the patient was identified to be a carrier of heterozygous A979G mutation of this gene. Conclusions We identified that the compound heterozygous PKHD1 gene mutations are the molecular basis of the patient with ARPKD. Targeted exome sequencing is suitable for genetic diagnosis of single-gene inherited diseases like ARPKD in which the pathogenic gene is a large.
