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Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.

ABSTRACT: OBJECTIVE:Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. METHOD:Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. RESULTS:Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. CONCLUSION:We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.

SUBMITTER: Stals KL

PROVIDER: S-EPMC5836855 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.

Stals Karen L KL Wakeling Matthew M Baptista Júlia J Caswell Richard R Parrish Andrew A Rankin Julia J Tysoe Carolyn C Jones Garan G Gunning Adam C AC Lango Allen Hana H Bradley Lisa L Brady Angela F AF Carley Helena H Carmichael Jenny J Castle Bruce B Cilliers Deirdre D Cox Helen H Deshpande Charu C Dixit Abhijit A Eason Jacqueline J Elmslie Frances F Fry Andrew E AE Fryer Alan A Holder Muriel M Homfray Tessa T Kivuva Emma E McKay Victoria V Newbury-Ecob Ruth R Parker Michael M Savarirayan Ravi R Searle Claire C Shannon Nora N Shears Deborah D Smithson Sarah S Thomas Ellen E Turnpenny Peter D PD Varghese Vinod V Vasudevan Pradeep P Wakeling Emma E Baple Emma L EL Ellard Sian S

Prenatal diagnosis 20171203 1

<h4>Objective</h4>Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred.<h4>Method</h4>Exome sequencing was carried out in a consecutive series of 50 couples who ha ...[more]

PMID: 29096039

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Project description:BackgroundThe cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear.MethodsWe evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited.ResultsIn 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases.ConclusionsIn this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.).

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Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.

Publications

Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.

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