title: Implementing Non-Invasive Prenatal Diagnosis (NIPD) in a National Health Service Laboratory; From Dominant to Recessive Disorders.
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.
authors.affiliation: North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital, London, UK. suzanne.drury@gosh.nhs.uk.|Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK. suzanne.drury@gosh.nhs.uk.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Drury
authors.affiliation: North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mason
authors.affiliation: North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital, London, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: McKay
authors.affiliation: Paul O'Gorman Building, UCL Cancer Institute, 72 Huntley Street, London, UK.
authors.forename: Kitty
authors.initials: K
authors.lastname: Lo
authors.affiliation: North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital, London, UK.|Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Boustred
authors.affiliation: North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital, London, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Jenkins
authors.affiliation: North East Thames Regional Genetics Laboratory, Great Ormond Street Hospital, London, UK.|Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Lyn S
authors.initials: LS
authors.lastname: Chitty
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D004247:DNA / Q000097:blood / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D030342:Genetic Diseases, Inborn / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D013677:Medical Laboratory Science / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013222:State Medicine; D013255:Steroid 21-Hydroxylase / Q000235:genetics; D006113:United Kingdom
chemical_list: D004247:DNA; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase
keywords: Cell free DNA; Fetal; Monogenic disorders; Non-invasive prenatal diagnosis (NIPD)