Targeted next-generation sequencing analysis in couples at increased risk for autosomal recessive disorders.
Targeted next-generation sequencing analysis in couples at increased risk for autosomal recessive disorders.
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在夫妻中，有针对性的下一代测序分析会增加常染色体隐性疾病的风险。
DOI：
10.1186/s13023-018-0763-0
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发表时间：
2018-01-26
影响因子：
3.7
通讯作者：
Schweiger S
中科院分区：
文献类型：
--
作者：
Komlosi K;Diederich S;Fend-Guella DL;Bartsch O;Winter J;Zechner U;Beck M;Meyer P;Schweiger S
许多导致前或新生儿期或幼儿期死亡的遗传性儿童疾病遵循常染色体隐性遗传模式，对遗传咨询和产前诊断提出了具体挑战。父母是携带者，但临床上不受影响，疾病罕见，但在同一家庭中复发风险为25%。通常情况下，受影响的儿童（或胎儿）在基因诊断可以建立之前死亡，尸检分析和表型描述不足，并且受影响的胎儿或儿童的DNA无法用于以后的分析。然而，显示双等位基因致病突变的基因诊断需要在父母中进行有针对性的携带者检测，并在进一步怀孕中进行产前和植入前基因诊断。我们进行了有针对性的下一代测序（NGS）的载体筛选常染色体隐性致死性疾病的8个近亲和5个非近亲夫妇与一个或多个受影响的儿童。我们使用一组已知导致罕见常染色体隐性遗传疾病且预后不良的430个基因，搜索父母DNA中的杂合变体（非同义编码或剪接变体），然后过滤双方重叠基因中存在的变体。如果材料可用，则在受影响的胎儿或儿童中检测推定的致病性变体的共分离。13对夫妇中有5对被诊断为儿童过早死亡。在无法确定病因诊断的8对夫妇中，有4对同意接受进一步分析，其中2对夫妇在新的候选基因中发现了潜在的病因变异。对于那些可以确定致病变异的家庭，这些变异现在可以用于产前和植入前遗传诊断。我们的数据表明，NGS为基础的基因面板测序选定的基因参与致命的常染色体隐性遗传病是一种有效的工具，在父母的载体筛选和隐性基因缺陷的识别，并提供了产前和植入前遗传诊断的可能性，在家庭中经历了死亡的幼儿和/或多次流产的进一步怀孕。本文的在线版本（10.1186/s13023-018-0763-0）包含补充材料，可供授权用户使用。
Many of the genetic childhood disorders leading to death in the pre- or neonatal period or during early childhood follow autosomal recessive modes of inheritance and bear specific challenges for genetic counseling and prenatal diagnostics. Parents are carriers but clinically unaffected, and diseases are rare but have recurrence risks of 25% in the same family. Often, affected children (or fetuses) die before a genetic diagnosis can be established, post-mortem analysis and phenotypic descriptions are insufficient and DNA from affected fetuses or children is not available for later analysis. A genetic diagnosis showing biallelic causative mutations is, however, the requirement for targeted carrier testing in parents and prenatal and preimplantation genetic diagnosis in further pregnancies. We undertook targeted next-generation sequencing (NGS) for carrier screening of autosomal recessive lethal disorders in 8 consanguineous and 5 non-consanguineous couples with one or more affected children. We searched for heterozygous variants (non-synonymous coding or splice variants) in parents’ DNA, using a set of 430 genes known to be causative for rare autosomal recessive diseases with poor prognosis, and then filtering for variants present in genes overlapping in both partners. Putative pathogenic variants were tested for cosegregation in affected fetuses or children where material was available. The diagnosis for the premature death in children was established in 5 of the 13 couples. Out of the 8 couples in which no causative diagnosis could be established 4 consented to undergo further analysis, in two of those a potentially causative variant in a novel candidate gene was identified. For the families in whom causative variants could be identified, these may now be used for prenatal and preimplantation genetic diagnostics. Our data show that NGS based gene panel sequencing of selected genes involved in lethal autosomal recessive disorders is an effective tool for carrier screening in parents and for the identification of recessive gene defects and offers the possibility of prenatal and preimplantation genetic diagnosis in further pregnancies in families that have experienced deaths in early childhood and /or multiple abortions. The online version of this article (10.1186/s13023-018-0763-0) contains supplementary material, which is available to authorized users.
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影响因子：
16
作者：
Bao, Qing;Lu, Wenyun;Shi, Yigong
通讯作者：
Shi, Yigong
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作者：
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作者：
van der Hout, Sanne;Holtkamp, Kim C. A.;Dondorp, Wybo J.
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Dondorp, Wybo J.
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