PURPOSE To determine the diagnostic yield of combined exome sequencing (ES) and autopsy in fetuses/neonates with prenatally identified structural anomalies resulting in termination of pregnancy, intrauterine, neonatal, or early infant death. METHODS ES was undertaken in 27 proband/parent trios following full autopsy. Candidate pathogenic variants were classified by a multidisciplinary clinical review panel using American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS A genetic diagnosis was established in ten cases (37%). Pathogenic/likely pathogenic variants were identified in nine different genes including four de novo autosomal dominant, three homozygous autosomal recessive, two compound heterozygous autosomal recessive, and one X-linked. KMT2D variants (associated with Kabuki syndrome postnatally) occurred in two cases. Pathogenic variants were identified in 5/13 (38%) cases with multisystem anomalies, in 2/4 (50%) cases with fetal akinesia deformation sequence, and in 1/4 (25%) cases each with cardiac and brain anomalies and hydrops fetalis. No pathogenic variants were detected in fetuses with genitourinary (1), skeletal (1), or abdominal (1) abnormalities. CONCLUSION This cohort demonstrates the clinical utility of molecular autopsy with ES to identify an underlying genetic cause in structurally abnormal fetuses/neonates. These molecular findings provided parents with an explanation of the developmental abnormality, delineated the recurrence risks, and assisted the management of subsequent pregnancies.

中文翻译：

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通过三重外显子组测序（ES）对产前发现结构异常的胎儿和新生儿进行分子尸检和尸检。

目的 确定联合外显子组测序 (ES) 和尸检对产前发现的结构异常导致妊娠终止、宫内、新生儿或婴儿早期死亡的胎儿/新生儿的诊断率。方法 对 27 名先证者/父母三人组进行全面尸检后进行 ES。多学科临床审查小组根据美国医学遗传学与基因组学学院 (ACMG) 指南对候选致病变异进行分类。结果 10例（37%）基因诊断成立。在 9 个不同的基因中鉴定出致病/可能致病变异，包括 4 个新生常染色体显性基因、3 个纯合常染色体隐性基因、2 个复合杂合常染色体隐性基因和 1 个 X 连锁基因。KMT2D 变异（与出生后歌舞伎综合症相关）出现在两例中。5/13 (38%) 的多系统异常病例、2/4 (50%) 的胎儿运动不能变形序列病例以及 1/4 (25%) 的心脏和大脑异常及水肿病例中均发现了致病变异胎儿。在具有泌尿生殖系统 (1)、骨骼 (1) 或腹部 (1) 异常的胎儿中未检测到致病性变异。结论 该队列证明了使用 ES 进行分子尸检的临床实用性，以确定结构异常胎儿/新生儿的潜在遗传原因。这些分子发现为父母提供了对发育异常的解释，描述了复发风险，并帮助管理随后的妊娠。