BACKGROUND The causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease. METHODS Retrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease. RESULTS Between 2010 and 2016, 1172 families presented with a child a likely rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive for the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25% to the observed 12% ([95% CI 0·04 to 0·20], p = 0·011). CONCLUSIONS Molecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence.

中文翻译：

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隐性儿科神经遗传疾病的分子诊断有助于减少家庭疾病的复发。

背景技术自从采用下一代测序（NGS）以来，已经发现了数以千计的罕见隐性疾病的病因。在对家庭中年龄较大的孩子进行分子诊断后，父母可以利用这些信息在随后的怀孕中选择胎儿基因分型，这可以为关于选择性终止妊娠的决定提供信息。尚未证明在家庭中使用 NGS 诊断测序可在随后的怀孕中产生益处以减少复发。在这里，我们评估了家庭中年龄较大的儿童的基因诊断是否支持减少隐性神经遗传疾病的复发。方法 回顾性研究涉及患有隐性儿科脑病 (rPBD) 的儿童的家庭，该儿童接受了基于 NGS 的分子诊断。为进行分子诊断的夫妇提供产前分子检测，以帮助寻求预防复发的夫妇。有了这些信息，家庭就做出了选择性终止的决定。对进行到足月的妊娠进行了儿童和母亲健康评估，并与隐性疾病的历史复发风险进行了比较。结果 在 2010 年至 2016 年期间，1172 个家庭的孩子可能患有 rPBD，526 个家庭接受了分子诊断，91 个家庭返回诊所并随后怀孕了 101 次，84 个家庭选择了胎儿基因分型。60 例胎儿双等位基因突变的复发检测结果为阴性，除 1 例自发流产外，所有胎儿均保持足月，随访时未受影响。在双等位基因突变基因分型阳性的 24 人中，16 人被选择性终止，8 人被带到足月，并且表现出与受影响的兄弟姐妹相似的疾病特征。在 101 例妊娠中，存活后代的疾病复发率从预期的 25% 偏离到观察到的 12%（[95% CI 0·04 至 0·20]，p = 0·011）。结论 年龄较大儿童的分子诊断，加上随后怀孕的产前胎儿基因分型和遗传咨询，使家庭能够做出明智的决定，以减少隐性神经遗传疾病的复发。