罕见鸟氨酸氨基甲酰转移酶缺乏症合并MECP2重复综合征一个家系的基因变异分析及产前诊断

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中文摘要：目的分析1例鸟氨酸氨基甲酰转移酶缺乏症(OTCD)合并MECP2重复综合征家系的基因变异特征，并为该家系提供产前诊断。方法回顾性分析2017年12月19日就诊于甘肃省妇幼保健院新生儿重症监护中心的1例患儿(先证者)及其家系成员的临床资料。高通量测序结合多重连接探针扩增(MLPA)技术对患儿进行致病性变异分析。短串联重复序列(STR)连锁分析、MLPA以及拷贝数变异测序(CNV-seq)对胎儿进行产前诊断。结果先证者为出生3 d的女婴，测序发现其携带OTC基因第7 ～ 9外显子杂合缺失。根据美国医学遗传学与基因组学会变异相关指南，该变异被评级为可能致病性变异(PVS1＋PM2_Supporting＋PP4)，与其急性脑病发作合并代谢异常(血氨显著升高、血瓜氨酸降低、尿乳清酸增高)的临床表现相符，确诊其为OTCD。产前诊断未发现胎儿携带与先证者相同的OTC基因缺失变异，但存在Xq28区重复，涵盖MECP2重复综合征的全部区域，且SRY(＋)，母亲及先证者均证实携带该重复。结合先证者存在X染色体失活的可能性，考虑先证者同时罹患OTCD与MECP2重复综合征，而胎儿为MECP2重复综合征男性患者。结论基因检测明确了OTCD合并MECP2重复综合征家系的致病变异，可为患者家庭的精准治疗、遗传咨询及再次生育提供依据。 Objective To explore the genetic basis for a Chinese pedigree affected with co-morbid Ornithine carbamoyl transferase deficiency (OTCD) and MECP2 duplication syndrome. Methods A proband who was admitted to the Neonatal Intensive Care Unit of Gansu Provincial Maternal and Child Health Care Hospital on December 19, 2017 was selected as the study subject. High-throughput sequencing and multiplex ligation-dependent probe amplification (MLPA) were carried out for her pedigree, and short tandem repeat-based linkage analysis and chromosome copy number variation sequencing (CNV-seq) were used for the prenatal diagnosis. Results The proband, a 3-day-old female, was found to harbor heterozygous deletion of exons 7-9 of the OTC gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PVS1+ PM2_Supporting+ PP4). The proband was diagnosed with OTCD, which was in keeping with her acute encephalopathy and metabolic abnormalities (manifesting as hyperammonemia, decreased blood citrulline, and increased urine orotic acid). Prenatal diagnosis was carried out for the subsequent pregnancy. The fetus did not harbor the exons 7-9 deletion of the OTC gene, but was found to carry a duplication in Xq28 region (which encompassed the whole region of MECP2 duplication syndrome) and was positive for the SRY sequence. The same duplication was also found in the proband and her mother. Considering the possible existence of X-chromosome inactivation, the proband was diagnosed with two X-linked recessive disorders including OTCD and MECP2 duplication syndrome, and the fetus was determined as a male affected with the MECP2 duplication syndrome. Conclusion Discoveries of the pathogenic variants underlying the OTCD and MECP2 duplication syndrome have enabled clinical intervention, treatment, genetic counseling and prenatal diagnosis for this pedigree.

外文标题：Genetic analysis and prenatal diagnosis for a Chinese pedigree affected with co-morbid Ornithine carbamoyl transferase deficiency and MECP2 duplication syndrome

外文摘要：Objective To explore the genetic basis for a Chinese pedigree affected with co-morbid Ornithine carbamoyl transferase deficiency (OTCD) and MECP2 duplication syndrome. Methods A proband who was admitted to the Neonatal Intensive Care Unit of Gansu Provincial Maternal and Child Health Care Hospital on December 19, 2017 was selected as the study subject. High-throughput sequencing and multiplex ligation-dependent probe amplification (MLPA) were carried out for her pedigree, and short tandem repeat-based linkage analysis and chromosome copy number variation sequencing (CNV-seq) were used for the prenatal diagnosis. Results The proband, a 3-day-old female, was found to harbor heterozygous deletion of exons 7-9 of the OTC gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PVS1+ PM2_Supporting+ PP4). The proband was diagnosed with OTCD, which was in keeping with her acute encephalopathy and metabolic abnormalities (manifesting as hyperammonemia, decreased blood citrulline, and increased urine orotic acid). Prenatal diagnosis was carried out for the subsequent pregnancy. The fetus did not harbor the exons 7-9 deletion of the OTC gene, but was found to carry a duplication in Xq28 region (which encompassed the whole region of MECP2 duplication syndrome) and was positive for the SRY sequence. The same duplication was also found in the proband and her mother. Considering the possible existence of X-chromosome inactivation, the proband was diagnosed with two X-linked recessive disorders including OTCD and MECP2 duplication syndrome, and the fetus was determined as a male affected with the MECP2 duplication syndrome. Conclusion Discoveries of the pathogenic variants underlying the OTCD and MECP2 duplication syndrome have enabled clinical intervention, treatment, genetic counseling and prenatal diagnosis for this pedigree.

外文关键词：

HyperammonemiaOrnithine carbamoyltransferase deficiencyOTC genePrenatal diagnosisCopy number variationMECP2 duplication syndrome

作者：

张庆华、郝胜菊、惠玲、郑雷、王兴、冯暄、刘芙蓉、陈雪、周秉博、王玉佩、张钏、许芯

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作者单位：

甘肃省妇幼保健院（甘肃省中心医院）医学遗传中心，兰州　730050

关键词：

高氨血症鸟氨酸氨基甲酰转移酶缺乏症 OTC基因产前诊断拷贝数变异 MECP2重复综合征

基金：

甘肃省出生缺陷与罕见病临床医学研究中心项目兰州市人才创新创业项目兰州市科技计划甘肃省科技计划

项目编号：

21JR7RA6802018-RC-952021-1-18222YF7FA094

出版年：

2024

DOI：

10.3760/cma.j.cn511374-20221110-00780

中华医学遗传学杂志

中华医学会

中华医学遗传学杂志

CSTPCD

影响因子：0.562

ISSN：1003-9406

年,卷(期)：2024.41(3)

参考文献量13