Abstract：
OBJECTIVE: With the availability of Next Generation Sequencing (NGS) diagnosis of genetic disorders has improved significantly. Its use is also applicable to ascertain diagnosis and management in a perinatal setting. The study aims to detect the genetic aetiology of various congenital structural and functional defects using NGS technology in the reproductive cohort at a tertiary centre. The secondary objective is to address challenges in the interpretation of variants.
METHODS: This was a retrospective study of couples who underwent exome sequencing (Mono-testing proband only or Duo-testing parents only or Trio-testing proband and parents) for suspected single gene disorders between years 2020-2022 at a tertiary care perinatal center in the South India. American College of Medical Genetics (ACMG) guidelines were followed to classify the pathogenicity of the variants identified by exome sequencing.
RESULTS: The overall diagnostic yield as defined by pathogenic/likely pathogenic variants obtained was (23/43) 53.4 %. The individual subsets have the following diagnostic yield viz., Mono 5/6 (83 %); Carrier 16/32 (50 %); Trio 2/5 (40 %). Diagnostic yield was significantly higher in consanguineous couples. However, miscarriage history, and organ system involvement did not have a significant effect on the diagnostic yield. Prenatal diagnosis was offered for seven patients based on the exome result. One fetus was confirmed with a compound heterozygous pathogenic variant.
CONCLUSIONS: Diagnostic yield of exome sequencing in our cohort was 53 %. The detection of pathogenic variants was maximum in those cases undergoing Mono exome sequencing. In places where there is a high prevalence of consanguinity and endogamy, NGS may be offered as first line test in the context of prenatal diagnosis.
METHODS: This was a retrospective study of couples who underwent exome sequencing (Mono-testing proband only or Duo-testing parents only or Trio-testing proband and parents) for suspected single gene disorders between years 2020-2022 at a tertiary care perinatal center in the South India. American College of Medical Genetics (ACMG) guidelines were followed to classify the pathogenicity of the variants identified by exome sequencing.
RESULTS: The overall diagnostic yield as defined by pathogenic/likely pathogenic variants obtained was (23/43) 53.4 %. The individual subsets have the following diagnostic yield viz., Mono 5/6 (83 %); Carrier 16/32 (50 %); Trio 2/5 (40 %). Diagnostic yield was significantly higher in consanguineous couples. However, miscarriage history, and organ system involvement did not have a significant effect on the diagnostic yield. Prenatal diagnosis was offered for seven patients based on the exome result. One fetus was confirmed with a compound heterozygous pathogenic variant.
CONCLUSIONS: Diagnostic yield of exome sequencing in our cohort was 53 %. The detection of pathogenic variants was maximum in those cases undergoing Mono exome sequencing. In places where there is a high prevalence of consanguinity and endogamy, NGS may be offered as first line test in the context of prenatal diagnosis.
摘要：
目的：随着下一代测序（NGS）的普及，遗传性疾病的诊断得到了显着改善。它的使用也适用于确定围产期环境中的诊断和管理。该研究旨在使用NGS技术在三级中心的生殖队列中检测各种先天性结构和功能缺陷的遗传病因。次要目标是应对变体解释中的挑战。
方法：这是一项回顾性研究，对在2020年至2022年之间在印度南部三级护理围产期中心进行了疑似单基因疾病的夫妇进行了外显子组测序（仅对先证者进行单测试或仅对父母进行双测试或对先证者和父母进行三测试）。遵循美国医学遗传学学会(ACMG)指南对通过外显子组测序鉴定的变体的致病性进行分类。
结果：通过获得的致病性/可能的致病性变体定义的总体诊断产率为（23/43）53.4％。各个子集具有以下诊断产量。,单5/6（83%）；承运人16/32（50%）；三重奏2/5（40%）。近亲夫妇的诊断率明显更高。然而,流产史,器官系统受累对诊断率没有显着影响。根据外显子组结果为7例患者提供产前诊断。一个胎儿被证实具有复合杂合致病变体。
结论：我们队列中外显子组测序的诊断率为53%。在进行单外显子组测序的那些情况下，致病性变体的检测最大。在血缘和内婚流行率很高的地方，NGS可以作为产前诊断的一线测试。
方法：这是一项回顾性研究，对在2020年至2022年之间在印度南部三级护理围产期中心进行了疑似单基因疾病的夫妇进行了外显子组测序（仅对先证者进行单测试或仅对父母进行双测试或对先证者和父母进行三测试）。遵循美国医学遗传学学会(ACMG)指南对通过外显子组测序鉴定的变体的致病性进行分类。
结果：通过获得的致病性/可能的致病性变体定义的总体诊断产率为（23/43）53.4％。各个子集具有以下诊断产量。,单5/6（83%）；承运人16/32（50%）；三重奏2/5（40%）。近亲夫妇的诊断率明显更高。然而,流产史,器官系统受累对诊断率没有显着影响。根据外显子组结果为7例患者提供产前诊断。一个胎儿被证实具有复合杂合致病变体。
结论：我们队列中外显子组测序的诊断率为53%。在进行单外显子组测序的那些情况下，致病性变体的检测最大。在血缘和内婚流行率很高的地方，NGS可以作为产前诊断的一线测试。
