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中华医学遗传学杂志
四川大学
中华医学遗传学杂志

四川大学

张思仲

双月刊

1003-9406

cjmg@cma.org.cn

028-85501165

610041

四川省成都市人民南路三段17号(四川大学华西校区)

中华医学遗传学杂志/Journal Chinese Journal of Medical GeneticsCSCD北大核心CSTPCD
查看更多>>中华医学会主办，四川大学承办。本刊以报道我国医学遗传学、人类遗传学和相关领域的基础理论、技术方法等最新研究成果；以从事医学遗传学工作的各科临床医生、计划生育工作者、大专院校和科研单位有关人员为主要读者对象。设有述评、论著、技术与方法、综述、调查报告、遗传咨询、临床细胞遗传学、病例报告等栏目。 从1998年以来被美国《医学索引》（IM）、《化学文摘》（CA）、《工程索引》（EI）、ISI数据库的Biological Abstracts及BIOSIS Previews，波兰《哥白尼索引》（IC）,荷兰《医学文摘》（EM）和俄罗斯《文摘杂志》（AJ）等国际著名检索系统收录。
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    Alstr?m综合征一个家系的临床特征与遗传学分析

    白周现李高攀吴庆华孔祥东...
    1124-1127页
    查看更多>>摘要：目的 探讨1个Alström综合征家系的临床特征与遗传学病因。 方法 选取2021年2月于郑州大学第一附属医院就诊的1个Alström综合征家系(共5个成员)为研究对象。采集本研究Alström综合征家系的临床资料，抽取各成员的外周静脉血样，提取基因组DNA。应用全外显子组测序(WES)对大女儿与三儿子进行基因检测，应用Sanger测序进行家系验证，对候选变异进行致病性分析。 结果 大女儿(14岁)与三儿子(11岁)均患有先天性眼球震颤与弱视、发育迟缓及2型糖尿病。WES检测发现大女儿与三儿子均携带ALMS1基因c.3538A>T(p.Lys1180*)纯合变异，Sanger测序证实父亲、母亲与二女儿均携带ALMS1基因c.3538A>T(p.Lys1180*)杂合变异。根据《遗传变异分类标准与指南》与《原发性拷贝数变异解读与报告技术标准》，该变异被评定为致病性变异(PVS1+PM2_Supporting+PP4) 结论 ALSM1基因c.3538A>T(p.Lys1180*)纯合变异可能是本研究Alström综合征家系中大女儿与三儿子的遗传学致病原因，为其治疗提供参考依据。 Objective To explore the clinical characteristics and genetic etiology of a Chinese pedigree affected with Alström syndrome. Methods A pedigree with 5 members affected with Alström syndrome who had visited the First Affiliated Hospital of Zhengzhou University in February 2021 was selected as the study subject. Clinical data of the pedigree were collected, and peripheral venous blood samples were collected for the extraction of genomic DNA. Genetic testing was carried out for the eldest daughter and third son through whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing and bioinformatic analysis. Results The eldest daughter (14 years old) and the third son (11 years old) both had congenital nystagmus, amblyopia, growth retardation and type 2 diabetes. WES revealed that both had harbored homozygous c. 3538A>T (p.Lys1180*) variant of theALMS1 gene. Sanger sequencing confirmed that the father, mother, and second daughter were all heterozygous carriers. Based on the Guidelines for Genetic Variation and the Technical Standards for Interpretation and Reporting of Primary Copy Number Variations, the variant was predicted as pathogenic (PVS1+ PM2_Supporting+ PP4). Conclusion The homozygous c. 3538A>T (p.Lys1180*) variant of theALSM1 gene probably underlay the Alström syndrome in this pedigree, which has provided a reference for the clinical treatment.

    眼球震颤弱视Alström综合征ALMS1基因

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    新发 EYA1基因杂合缺失变异所致鳃-耳综合征型耳聋一个家系的遗传学诊断

    李晶晶亢鸿飞孔祥东鞠翠钰...
    1128-1133页
    查看更多>>摘要：目的 探究1个鳃-耳综合征(BOS)型耳聋家系的基因变异类型，明确可能遗传学病因。 方法 选取2021年5月于郑州大学第一附属医院遗传与产前诊断中心就诊的1个BOS型耳聋家系为研究对象。采集本研究BOS型耳聋家系的临床资料，抽取先证者及其父母的外周血样，提取基因组DNA。应用全外显子组测序(WES)对先证者进行基因检测，应用多重连接探针扩增(MLPA)对测序结果进行家系验证，应用短串联重复序列(STR)分析技术对先证者及其父母进行亲缘关系鉴定，对候选变异进行致病性分析。 结果 先证者为6岁女性，临床主要表现为内耳畸形合并双侧鳃裂瘘管的先天性重度耳聋。WES检测发现先证者第8号染色体q13.3处存在2 466 kb的杂合缺失，该区域覆盖EYA1基因。MLPA检测证实先证者EYA1基因的全部18个外显子均存在杂合缺失，其父母未携带该基因缺失变异，提示为新发变异。STR分析支持先证者与其父母的生物学亲缘关系。根据美国医学遗传学与基因组学学会(ACMG)与ClinGen联合制订的相关指南，该变异被评级为致病性变异(PVS1+PS2+PM2_Supporting+PP4)。 结论 EYA1基因杂合缺失变异可能是本研究BOS型耳聋家系的遗传学病因，为临床诊断该家系提供参考依据。 Objective To explore the genetic basis for a Chinese pedigree affected with Branchio-Oto syndrome (BOS). Methods A pedigree with BOS which had presented at the Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University in May 2021 was selected as the study subject. Clinical data of the pedigree was collected. Peripheral blood samples of the proband and her parents were collected. Whole exome sequencing (WES) was carried out for the proband. Multiplex ligation-dependent probe amplification (MLPA) was used to verify the result of WES, short tandem repeat (STR) analysis was used to verify the relationship between the proband and her parents, and the pathogenicity of the candidate variant was analyzed. Results The proband, a 6-year-old girl, had manifested severe congenital deafness, along with inner ear malformation and bilateral branchial fistulae. WES revealed that she has harbored a heterozygous deletion of 2 466 kb at chromosome 8q13.3, which encompassed the EYA1 gene. MLPA confirmed that all of the 18 exons of the EYA1 gene were lost, and neither of her parents has carried the same deletion variant. STR analysis supported that both of her parents are biological parents. Based on the guidelines from the American College of Medical Genetics and Genomics, the deletion was classified as pathogenic (PVS1+ PS2+ PM2_Supporting+ PP4). Conclusion The heterozygous deletion of EYA1 gene probably underlay the pathogenicity of BOS in the proband, which has provided a basis for the clinical diagnosis.

    鳃-耳综合征耳聋EYA1基因新发变异基因诊断

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    X连锁无脑回畸形伴异常生殖器患儿1例的 ARX基因变异分析

    郭佳佳田远王慧娟王金光...
    1134-1139页
    查看更多>>摘要：目的 对1例X连锁无脑回畸形伴异常生殖器(XLAG)患儿进行ARX基因变异及临床表征分析，以明确其遗传学病因。 方法 将2021年5月郑州大学第三附属医院收治的1例XLAG患儿进行全外显子组高通量测序，对候选变异进行Sanger测序家系检测。根据美国医学遗传学与基因组学学会(ACMG)相关指南，针对测序数据利用Anno变异位点注释解读软件和XYGeneRanger变异位点检测软件进行分析。 结果 该家系患儿检出ARX基因c.945_948del半合子变异，为第2外显子的移码变异，可能导致蛋白截短。患儿母亲携带该杂合变异，父亲为野生型，变异既往未见报道。 结论 ARX基因c.945_948del变异与患儿XLAG的发生相关。上述发现丰富了ARX基因的变异谱，为患儿的诊断及遗传咨询提供了依据。 Objective To explore the clinical characteristics and genetic basis for a child with X-linked lissencephaly with abnormal genitalia (XLAG). Methods A child with XLAG who had presented at the Third Affiliated Hospital of Zhengzhou University in May 2021 was selected as the study subject. Peripheral blood samples of the child and his parents were collected and subjected to high-throughput sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the result was analyzed by using bioinformatic software. Results The child was found to have harbored a hemizygous c. 945_948del variant in exon 2 of the ARX gene, which as a frameshifting variant has resulted in a truncated protein. His mother was found to be heterozygous for the variant, whilst his father was of wild type. The variant was unreported previously. Conclusion The hemizygous c. 945_948del variant of the ARX gene probably underlay the XLAG in this patient. Above finding has provided a basis for the diagnosis and genetic counseling for this family.

    ARX基因基因变异无脑回畸形异常生殖器

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    PIGT基因变异所致MCAHS3型患儿1例的遗传学分析及产前诊断

    华英杨莉孙绍霞李玉芬...
    1140-1145页
    查看更多>>摘要：目的 探讨1例多发先天性畸形-肌张力低下-癫痫综合征3型(MCAHS3)患儿的临床特点及遗传学病因，为其母腹中胎儿提供产前诊断依据。 方法 选取2022年7月27日因"反复抽搐4年余"就诊于临沂市人民医院的1例女性MCAHS3患儿为研究对象，收集患儿的临床资料，抽取患儿及父母外周血样，提取基因组DNA进行家系全外显子组测序(WES)，采用Sanger测序对候选变异进行验证。并对其妊娠18周母亲进行羊水穿刺，提取胎儿DNA进行产前诊断。应用生物信息学软件分析构建蛋白模型变异位点的致病性。 结果 患儿为4岁女性，频繁癫痫发作，面容特殊，肌张力低下，重度发育迟缓。基因检测提示患儿PIGT基因上存在母源的c.1126del(p.H376Tfs*56)和父源的c.1285G>C(p.E429Q)复合杂合变异。根据美国医学遗传学与基因组学学会(ACMG)变异评级相关指南，位点c.1126del(p.H376Tfs*56)为致病性变异(PVS1+PM2_Supporting+PM4)，位点c.1285G>C(p.E429Q)为可能致病性变异(PM2_Supporting +PM3+PM4)。同时胎儿携带PIGT基因c.1126del(p.H376Tfs*56)和c.1285G>C(p.E429Q)复合杂合变异，考虑胎儿患病可能性大，引产胎儿。 结论 PIGT基因c.1126del(p.H376Tfs*56)和c.1285G>C(p.E429Q)位点复合杂合变异考虑为MCAHS3患儿的遗传学病因，经产前诊断避免了此类患儿的出生。 Objective To explore the clinical features and genetic etiology of a child with Multiple congenital malformations-hypotonia-epilepsy syndrome type 3 (MCAHS3) and provide prenatal diagnosis for her parents. Methods A female child who had presented at Linyi People′s Hospital on 27 July 2022 for recurrent convulsions for over 4 years was selected as the study subject. Clinical data of the child were collected. Peripheral blood samples were taken from the child and her parents and subjected for whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out on amniotic fluid sample at 18 weeks′ gestation. Bioinformatic software was used to analyze the pathogenicity of the protein model for the variant loci. Results The child was a 4-year-old female with frequent seizures, peculiar facial appearance, hypotonia and severe developmental delay. Genetic analysis revealed that she has harbored compound heterozygous variants of the PIGT gene, namely c. 1126del (p.H376Tfs*56) and c. 1285G>C (p.E429Q), which were respectively inherited from her mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics, the c. 1126del (p.H376Tfs*56) variant was predicted to be pathogenic (PVS1+ PM2_Supporting+ PM4), and c. 1285G>C (p.E429Q) variant was predicted to be likely pathogenic (PM2_Supporting+ PM3+ PM4). Prenatal diagnosis suggested that the fetus also harbored the same compound heterozygous variants, and the pregnancy was terminated with induced labor. Conclusion The c. 1126del (p.H376Tfs*56) and c. 1285G>C (p.E429Q) compound heterozygous variants of thePIGT gene probably underlay the MCAHS3 in this patient, and prenatal diagnosis has prevented birth of further affected child in this family.

    产前诊断PIGT基因多发先天性畸形肌张力低下癫痫

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    非典型智力障碍伴射精障碍患者1例的 ARID1B基因变异分析

    石润茜徐盈张建芳常媛媛...
    1146-1149页
    查看更多>>摘要：目的 探讨1例非典型智力障碍伴射精障碍患者的临床特征与遗传学病因。 方法 选取2021年11月18日于空军军医大学第一附属医院就诊的1例非典型智力障碍伴射精障碍患者为研究对象。采集患者相关临床资料，抽取患者及其父母外周静脉血样，应用全外显子组测序(WES)对患者进行基因检测，采用Sanger测序进行家系验证，并对候选变异进行致病性分析。 结果 本研究患者为26岁男性，临床表现为非典型智力障碍伴射精障碍。WES检测结果提示，患者携带ARID1B基因c.5776C>T(p.Arg1926X)杂合变异。经Sanger测序验证，患者父母均未携带该变异，提示该变异为新发变异。ARID1B基因c.5776C>T(p.Arg1926X)变异在1000 Genomes、ExAC、gnomAD及ClinVar等数据库中已见报道；dbSNP数据库检索结果显示，该变异在正常人群中的携带频率为0.000 4%；Mutation Taster、CADD及MutPred等在线软件预测结果显示，该变异为有害性变异；Clustal Omega在线软件分析结果显示，该变异位点编码氨基酸在不同物种间高度保守；PyMOL软件分析结果显示，该变异可能影响编码蛋白功能；根据美国医学遗传学与基因组学学会(ACMG)与ClinGen联合制订的相关指南与标准，该变异被判定为致病性变异。 结论 ARID1B基因c.5776C>T(p.Arg1926X)变异可能是本研究患者智力障碍伴射精障碍的遗传学病因，拓宽了ARID1B基因的变异谱与表型谱，为患者的治疗提供了参考依据。 Objective To explore the clinical characteristics and genetic etiology of a patient with mental retardation and ejaculatory dysfunction. Methods A patient with mental retardation and ejaculatory dysfunction who was admitted to the First Affiliated Hospital of Air Force Military Medical University on November 18, 2021 was selected as the study subject. Clinical data of the patient were collected. Peripheral venous blood samples were collected from the patient and his parents. Whole exome sequencing (WES) was carried out for the patient, and the candidate variant was verified by Sanger sequencing and bioinformatic analysis. Results The patient, a 26-year-old male, had manifested atypical mental retardation and ejaculatory dysfunction. WES revealed that he has harbored a heterozygous variant of the ARID1B gene, namely c. 5776C>T (p.Arg1926X). Sanger sequencing verified that neither of his parents has carried the same variant. The variant has been recorded in the 1000 Genomes, ExAC, gnomAD and ClinVar databases. A search of the dbSNP database suggested that the variant has a population frequency of 0.000 4%. The variant was predicted as deleterious by online software including Mutation Taster, CADD, and MutPred. Analysis with Cluster Omega online software suggested that the amino acid encoded by the variant site was highly conserved among various species. Analysis with PyMOL software suggested that the variant may affect the function of the encoded protein. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and ClinGen, the variant was predicted to be pathogenic. Conclusion The c. 5776C>T (p.Arg1926X) variant of theARID1B gene probably underlay the mental retardation and ejaculatory dysfunction in this patient. Above finding has broadened the spectrum of the ARID1B gene variants and provided reference for the diagnosis and treatment of the patient.

    精神发育迟滞射精障碍非典型ARID1B基因

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    COL4A4基因复合杂合变异所致Alport综合征患者1例的遗传学分析

    杨冰冰刘风勋邹兰兰薛小玲...
    1150-1154页
    查看更多>>摘要：目的 分析1例Alport综合征患者的临床表型及遗传学特征。 方法 选取2020年11月至郑州大学第一附属医院肾内科就诊的1例Alport综合征患者为研究对象。收集患者的临床资料。应用高通量测序对患者进行COL4A3、COL4A4、COL4A5基因检测，针对候选致病变异进行Sanger测序家系验证。 结果 患者主要临床表现为血尿、蛋白尿、听力下降，听觉相关检查提示双耳对称性耳蜗性感音神经性耳聋，肾穿刺病理活检结果为轻度系膜增生性肾小球肾炎。基因检测发现患者携带COL4A4基因c.940G>A(p.Gly314Ser)和c.3773G>A(p.Gly1258Asp)复合杂合变异，分别为父源性和母源性变异，呈常染色体隐性遗传。该变异既往未见报道，根据美国医学遗传学与基因组学学会相关指南均评估为致病性变异。 结论 COL4A4基因c.940G>A(p.Gly314Ser)和c.3773G>A(p.Gly1258Asp)变异可能为该Alport综合征患者的遗传学病因。上述发现丰富了COL4A4基因的变异谱。 Objective To analyze the clinical phenotype and genetic characteristics of a patient with Alport syndrome. Methods A patient with Alport syndrome who had visited the First Affiliated Hospital of Zhengzhou University in November 2020 was selected as the study subject. Clinical data of the patient were collected. High-throughput sequencing was carried out to detect potential variant of the COL4A3, COL4A4 and COL4A5 genes, and Sanger sequencing was carried out for verification of candidate variants in the family. Results The main clinical manifestations of the patient included hematuria, proteinuria, and impaired hearing. Audiometric testing suggested symmetrical cochlear sensory neural hearing loss on both sides. Renal biopsy revealed mild mesangial proliferative glomerulonephritis. Genetic testing revealed that the patient has harbored compound heterozygous variants of the COL4A4 gene, namely c. 940G>A (p.Gly314Ser) and c. 3773G>A (p.Gly1258Asp), which were respectively inherited from her father and mother. Neither variant has been reported before, and were predicted to be pathogenic based on the guidelines from the American College of Medical Genetics and Genomics. Conclusion The c. 940G>A (p.Gly314Ser) and c. 3773G>A (p.Gly1258Asp) compound heterozygous variants of theCOL4A4 gene probably underlay the Alport syndrome in this patient. Above finding has enriched the mutational spectrum of the COL4A4 gene.

    Alport综合征COL4A4基因常染色体隐性遗传

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    局灶节段性肾小球硬化和神经发育综合征患儿1例的遗传学分析

    孙旭辉辛敏田京梅张影影...
    1155-1159页
    查看更多>>摘要：目的 分析1例局灶节段性肾小球硬化和神经发育综合征(FSGSNEDS)患儿的遗传学特征。 方法 选取2019年9月15日于胜利油田中心医院儿科就诊的1例FSGSNEDS患儿为研究对象。收集患儿的临床资料，应用家系全外显子组测序(trio-WES)、Sanger测序、染色体核型分析和拷贝数变异测序(CNV-seq)对患儿及其父母进行遗传学分析。 结果 患儿为3岁男性，主要临床表现为发育迟缓、肾病综合征和癫痫。Trio-WES以及Sanger测序结果显示患儿携带TRIM8基因c.1375C>T(p.Q459*)杂合变异，其父母该位点为野生型。根据美国医学遗传学与基因组学学会(ACMG)相关指南评估为致病性变异。患儿及其父母的染色体核型及CNV-seq结果未见异常。 结论 患儿被确诊为FSGSNEDS，TRIM8基因c.1375C>T变异可能是其遗传学病因。 Objective To explore the genetic characteristics of a child with Focal segmental glomerulosclerosis and neurodevelopmental syndrome (FSGSNEDS). Methods A child with FSGSNEDS who had visited Shengli Oilfield Central Hospital on September 15, 2019 was selected as the study subject. Clinical data of the child was collected, and trio-whole exome sequencing (trio-WES), Sanger sequencing, chromosomal karyotyping analysis, and copy number variation sequencing (CNV-seq) were used to analyze the child and his parents. Results The child, a 3-year-old boy, had manifested developmental delay, nephrotic syndrome, and epilepsy. Trio-WES and Sanger sequencing showed that he has carried a heterozygous c. 1375C>T (p.Q459*) variant of theTRIM8 gene, for which both his parents were of the wild type. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic. No abnormality was found in the chromosomal karyotyping and CNV-seq results of the child and his parents. Conclusion The child was diagnosed with FSGSNEDS, for which the c. 1375C>T variant of theTRIM8 gene may be accountable.

    肾病综合征TRIM8基因发育迟缓基因检测

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    CRB1基因新变异致早发视网膜色素变性患者1例的分析

    易茗陶大昌杨元刘运强...
    1160-1164页
    查看更多>>摘要：目的 对1例早发视网膜色素变性(RP)患者进行遗传学分析。 方法 选取2022年3月10日于四川大学华西医院就诊的1例患者作为研究对象。通过全外显子组测序(WES)对患者及其父母进行变异筛查，对候选变异进行Sanger测序家系验证以及致病性分析。 结果 患者双眼视野严重损失，眼底检查显示骨针状色素沉着、视网膜小动脉衰减和视盘苍白。WES检测显示患者CRB1基因存在c.2969T>C(p.Leu990Ser)和c.1816T>C(p.Cys606Arg)复合杂合错义变异，分别遗传自其父母。CRB1基因c.1816T>C(p.Cys606Arg)纯合变异既往曾在一个视网膜色素变性家系中被检出，而c.2969T>C(p.Leu990Ser)变异则未见报道。根据美国医学遗传学与基因组学学会(ACMG)相关指南，二者均被评级为可能致病变异。 结论 CRB1基因c.2969T>C(p.Leu990Ser)和c.1816T>C(p.Cys606Arg)复合杂合变异可能是本研究患者发生早发性视网膜色素变性的遗传学病因。上述发现拓展了CRB1基因的变异谱。 Objective To explore the genetic basis for a patient with early-onset retinitis pigmentosa (RP). Methods A patient who had presented at the West China Hospital of Sichuan University on March 10, 2022 was selected as the study subject. The patient and his parents were subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing and in silico analysis. Results The patient has featured substantial loss of binocular vision field. Funduscopy revealed characteristic bone spicule-type pigment deposits, as well as attenuated retinal arterioles and pale-appearing optic discs. WES revealed that he has harbored compound missense variants of a RP-associated CRB1 gene, including c. 2969T>C (p.Leu990Ser) and c. 1816T>C (p.Cys606Arg), which were respectively inherited from his father and mother. Homozygous c. 1816T>C (p.Cys606Arg) variant has been identified among RP patients, whilst the c. 2969T>C (p.Leu990Ser) variant was unreported previously. Both variants were predicted as likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Conclusion The novel compound heterozygous variants of the CRB1 gene probably underlay the early-onset RP in this patient. Above finding has enriched the mutational spectrum of the CRB1 gene.

    视网膜色素变性CRB1基因全外显子组测序

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    致心律失常性右室心肌病患儿1例的 PKP2基因变异分析

    黄娟郭晓峰吉炜鞠翠钰...
    1165-1170页
    查看更多>>摘要：目的 探讨1例致心律失常性右室心肌病(ARVC)患儿的临床特征与遗传学病因。 方法 选取2022年8月23日于福建省儿童医院就诊的1例ARVC患儿作为研究对象。采集患儿的相关临床资料，抽取患儿及其父母的外周静脉血样，应用全外显子组测序(WES)对患儿进行基因检测，采用Sanger测序进行家系验证，并对候选变异进行致病性分析。 结果 本研究患儿为6岁男性，临床表现为全身浮肿、全心扩大、室间隔及室壁运动普遍性减弱、左心室舒张及收缩功能减低、右心室收缩功能减低。WES检测结果提示患儿携带PKP2基因c.119_122del(p.Leu40Argfs Ter 71)杂合移码变异与c.1978G>A(p.Gly660Arg)杂合错义变异。经Sanger测序验证，上述变异分别遗传自患儿父亲与母亲。PKP2基因c.119_122del变异在1000 Genomes、gnomAD及ExAC等数据库中未见收录；经SWISS-MODEL与PyMOL在线软件分析可能导致PKP2蛋白截短；根据美国医学遗传学与基因组学学会(ACMG)与ClinGen联合制订的相关指南，该变异被判定为可能致病性变异。PKP2基因c.1978G>A变异在1000 Genomes、gnomAD及ExAC等数据库中未见收录；应用REVEL、SIFT、CADD、MutationTaster及PolyPhen-2等在线软件预测为有害变异；经T-coffee与ESPriptv3.0在线服务器分析，该变异位点编码氨基酸在不同物种中高度保守；经SWISS-MODEL与PyMOL在线服务器分析，该变异可能影响蛋白功能；根据ACMG与ClinGen联合制订的相关指南，该变异被判定为可能致病性变异。 结论 PKP2基因c.119_122del(p.Leu40Argfs Ter 71)杂合移码变异与c.1978G>A(p.Gly660Arg)杂合错义变异可能是本研究ARVC患儿的遗传学病因。上述发现拓宽了PKP2基因的变异谱，为ARVC患者的诊断提供了依据。 Objective To explore the clinical and genetic characteristics of a child with Arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods A 6-year-old boy with ARVC who had visited Fujian Provincial Children′s Hospital on August 23, 2022 was selected as the study subject. Relevant clinical data were collected, and peripheral venous blood samples were collected from the child and his parents for genetic testing through whole exome sequencing (WES). Sanger sequencing was carried out for family verification, and pathogenicity analysis was conducted for the candidate variants. Results The child had exhibited clinical symptoms including systemic edema, generalized heart enlargement, universal reduction of interventricular septum and ventricular wall movement, reduced left ventricular diastolic and systolic function, and reduced right ventricular systolic function. WES revealed that the child has harbored compound heterozygous variants of the PKP2 gene, namely c. 119_122del (p.Leu40ArgfsTer71) and c. 1978G>A (p.Gly660Arg), which were verified by Sanger sequencing to be respectively inherited from his father and mother. The c. 119_122del variant has not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to lead to truncation of the PKP2 protein by SWISS-MODEL and PyMOL online software and classified as likely pathogenic based on the guidelines jointly developed by the American College of Medical Genetics and Genomics (ACMG) and ClinGen. The c. 1978G>A variant has also not been recorded in the 1000 Genomes, gnomAD and ExAC databases, and was predicted to be deleterious by online software including REVEL, SIFT, CADD, Mutation Taster, and PolyPhen-2. The amino acid encoded by the variant site was highly conserved among various species by analysis using T-coffee and ESPriptv3.0 online servers. The variant may affect the protein function by SWISS-MODEL and PyMOL online server analysis, and was classified as likely pathogenic based on the guidelines jointly developed by the ACMG and ClinGen. Conclusion The compound heterozygous variants of c. 119_122del (p.Leu40ArgfsTer71) and c. 1978G>A (p.Gly660Arg) of thePKP2 gene probably underlay the ARVC in this child. Above finding has broadened the spectrum of PKP2 gene variants and provided a reference for the diagnosis and genetic counseling.

    致心律失常性右室心肌病PKP2基因基因变异

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    FOXF1基因变异致肺泡毛细血管发育不良并肺静脉错位患儿1例的诊治及基因分析

    张伟峰刘志勇林伟儒张丰丰...
    1171-1175页
    查看更多>>摘要：目的 探讨1例严重肺动脉高压、呼吸衰竭新生儿的诊治过程及遗传特征。 方法 以2021年3月于泉州市妇幼保健院·儿童医院收治的1例患儿作为研究对象。收集患儿的围产期情况、临床表现、实验室及影像学检查结果以及诊治资料。对患儿进行全外显子组测序，对检出的候选变异进行Sanger测序家系验证。 结果 患儿为女性，出生后不久出现进展性呼吸衰竭与顽固性肺动脉高压，机械通气、血管活性药物、吸入一氧化氮等常规治疗无效，经体外膜肺氧合治疗撤机后再发持续性肺动脉高压，家属放弃治疗后死亡。全外显子组测序发现其携带FOXF1基因c.682_683insGCGGCGGC(p.G234Rfs*148)新发杂合变异，根据美国医学遗传学与基因组学学会(ACMG)相关指南评级为致病性变异，证据项为PVS1_Strong+PM2_Supporting+PS2。根据其临床特征及基因检测结果，诊断患儿为肺泡毛细血管发育不良伴肺静脉错位(ACD/MPV)。 结论 FOXF1基因c.682_683insGCGGCGGC(p.G234Rfs*148)的发现丰富了FOXF1基因的变异谱，为其临床诊治和遗传咨询提供了依据。 Objective To explore the diagnosis, treatment and genetic characteristics of a neonate with severe pulmonary hypertension and respiratory failure. Methods Perinatal history, clinical manifestations, laboratory finding and diagnosis and treatment data of the child were collected. Whole exome sequencing was carried out for the child, and Sanger sequencing was used to verify the candidate variants. Results The female neonate has developed progressive respiratory failure and refractory pulmonary hypertension shortly after birth. Conventional treatment such as mechanical ventilation, vasoactive drugs, and inhaled nitric oxide were ineffective. She has developed sustained pulmonary hypertension after weaning from extracorporeal membrane oxygenation therapy, and had died after the treatment had ceased. Whole exome sequencing revealed that she has harbored a heterozygous de novo variant of c. 682_683insGCGGCGGC (p.G234Rfs*148) of the FOXF1 gene, which was predicted as pathogenic based on guidelines from the American College of Medical Genetics and Genomics (ACMG), with evidence items of PVS1_Strong+ PM2_Supporting+ PS2. Based on her clinical manifestations and result of genetic testing, the child was diagnosed with alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV). Conclusion Discovery of the c. 682_683insGCGGCGGC (p.G234 Rfs*148) variant of the FOXF1 gene has expanded the mutational spectrum of the FOXF1 gene, which has facilitated implementation of specific treatment and provided a basis for clinical diagnosis and genetic counseling.

    肺泡毛细血管发育不良并肺静脉错位FOXF1基因肺动脉高压体外膜肺氧合新生儿

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