Abstract
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.
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Acknowledgements
Funding sources: This research was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research (RP-PG-0707-10107) and the NIHR Comprehensive Local Research Network. LSC is partially funded by the NIHR comprehensive Biomedical Research Centre at Great Ormond Street Hospital. The research funded is independent, and the views expressed in the article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding was also provided by the International Fund Congenital Adrenal Hyperplasia and the European Society for Paediatric Endocrinology.
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Drury, S. et al. (2016). Implementing Non-Invasive Prenatal Diagnosis (NIPD) in a National Health Service Laboratory; From Dominant to Recessive Disorders. In: Gahan, P., Fleischhacker, M., Schmidt, B. (eds) Circulating Nucleic Acids in Serum and Plasma – CNAPS IX. Advances in Experimental Medicine and Biology, vol 924. Springer, Cham. https://doi.org/10.1007/978-3-319-42044-8_14
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DOI: https://doi.org/10.1007/978-3-319-42044-8_14
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