Monogenic diseases that result in early pregnancy loss or neonatal death are genetically and phenotypically highly variable. This often poses significant challenges in arriving at a molecular diagnosis for reproductive planning. Molecular autopsy by proxy (MABP) refers to the genetic testing of relatives of deceased individuals to deduce the cause of death. Here, we specifically tested couples who lost one or more children/pregnancies with no available DNA. We developed our testing strategy using whole exome sequencing data from 83 consanguineous Saudi couples. We detected the shared carrier state of 50 pathogenic variants/likely pathogenic variants in 43 families and of 28 variants of uncertain significance in 24 families. Negative results were seen in 16 couples after variant reclassification. In 10 families, the risk of more than one genetic disease was documented. Secondary findings were seen in 10 families: either genetic variants with potential clinical consequences for the tested individual or a female carrier for X-linked conditions. This couple-based approach has enabled molecularly informed genetic counseling for 52% (43/83 families). Given the predominance of autosomal recessive causes of pregnancy and child death in consanguineous populations, MABP can be a helpful approach to consanguineous couples who seek counseling but lack molecular data on their deceased offspring.

中文翻译：

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孕前咨询中的代理分子尸检

导致早期流产或新生儿死亡的单基因疾病在遗传和表型上具有高度可变性。这通常会给生殖计划的分子诊断带来重大挑战。代理分子尸检（MABP）是指对死者亲属进行基因检测以推断死因。在这里，我们专门测试了失去一个或多个孩子/怀孕但没有可用 DNA 的夫妇。我们使用来自 83 对近亲沙特夫妇的全外显子组测序数据制定了我们的测试策略。我们检测了 43 个家族中 50 个致病变异/可能致病变异和 24 个家族中 28 个不确定性变异的共享携带状态。变异重新分类后，在 16 对夫妇中看到了阴性结果。在10个家庭中，记录了不止一种遗传疾病的风险。在 10 个家庭中发现了次要发现：要么是对受试个体具有潜在临床后果的遗传变异，要么是 X 连锁疾病的女性携带者。这种基于夫妻的方法为 52%（43/83 个家庭）提供了分子信息遗传咨询。鉴于在近亲人群中妊娠和儿童死亡的常染色体隐性原因占主导地位，MABP 对于寻求咨询但缺乏其已故后代的分子数据的近亲夫妇来说可能是一种有用的方法。这种基于夫妻的方法为 52%（43/83 个家庭）提供了分子信息遗传咨询。鉴于在近亲人群中妊娠和儿童死亡的常染色体隐性原因占主导地位，MABP 对于寻求咨询但缺乏其已故后代的分子数据的近亲夫妇来说可能是一种有用的方法。这种基于夫妻的方法为 52%（43/83 个家庭）提供了分子信息遗传咨询。鉴于在近亲人群中妊娠和儿童死亡的常染色体隐性原因占主导地位，MABP 对于寻求咨询但缺乏其已故后代的分子数据的近亲夫妇来说可能是一种有用的方法。