Implementing Non-Invasive Prenatal Diagnosis (NIPD) in a National Health Service Laboratory; From Dominant to Recessive Disorders
Implementing Non-Invasive Prenatal Diagnosis (NIPD) in a National Health Service Laboratory; From Dominant to Recessive Disorders
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DOI：
10.1007/978-3-319-42044-8_14
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发表时间：
2016-01-01
期刊：
影响因子：
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通讯作者：
Chitty, Lyn S.
中科院分区：
文献类型：
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作者：
Drury, Suzanne;Mason, Sarah;Chitty, Lyn S.
我们的英国国家卫生服务区域遗传学实验室为常染色体显性遗传和新发疾病（软骨发育不全、致死性发育不良、Apert综合征）提供NIPD，为囊性纤维化提供父系突变排除和一系列定制测试。NIPD避免了与侵入性检测相关的风险，使高遗传风险家庭更容易获得产前诊断。然而，在为常染色体隐性遗传疾病提供明确诊断方面仍然存在挑战，这由于无细胞DNA样品中母体突变等位基因的优势而变得复杂，因此需要各种不同的方法。先天性肾上腺皮质增生症（CAH）的NIPD的验证和诊断实施进一步复杂的假基因的存在，需要不同的方法。我们使用了一种针对CAH基因（CYP21A2）周围约6700个杂合SNP的检测方法来构建高风险的亲本单倍型，并在5例病例中测试了这种方法，表明使用NIPD可以正确识别亲本等位基因的遗传。我们正在评估胎儿分数的各种措施，以帮助确定父母突变的遗传。目前，我们正在探索一个NIPD多疾病面板常染色体隐性遗传病的效用，使测试更广泛地适用于各种严重的遗传条件的家庭。
Our UK National Health Service regional genetics laboratory offers NIPD for autosomal dominant and de novo conditions (achondroplasia, thanataphoric dysplasia, Apert syndrome), paternal mutation exclusion for cystic fibrosis and a range of bespoke tests. NIPD avoids the risks associated with invasive testing, making prenatal diagnosis more accessible to families at high genetic risk. However, the challenge remains in offering definitive diagnosis for autosomal recessive diseases, which is complicated by the predominance of the maternal mutant allele in the cell-free DNA sample and thus requires a variety of different approaches. Validation and diagnostic implementation for NIPD of congenital adrenal hyperplasia (CAH) is further complicated by presence of a pseudogene that requires a different approach. We have used an assay targeting approximately 6700 heterozygous SNPs around the CAH gene (CYP21A2) to construct the high-risk parental haplotypes and tested this approach in five cases, showing that inheritance of the parental alleles can be correctly identified using NIPD. We are evaluating various measures of the fetal fraction to help determine inheritance of parental mutations. We are currently exploring the utility of an NIPD multi-disorder panel for autosomal recessive disease, to make testing more widely applicable to families with a variety of serious genetic conditions.