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

Abstract

ObjectiveRare 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.MethodExome 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.ResultsParental 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.ConclusionWe 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.

The 2018 Malcolm Ferguson‐Smith Young Investigator Award

“…It is with great pleasure that the Editors and Publisher of Prenatal Diagnosis announce that Karen Stals (Figure ) is the winner of the 2018 Award for her paper entitled Diagnosis of lethal or prenatal‐onset autosomal recessive disorders by parental exome sequencing , published in the January 2018 issue of the journal …”

In case you missed it: The Prenatal Diagnosis editors bring you the most significant advances of 2017

“…Many of us have counseled couples who have had pregnancies complicated by serious, and often fatal, fetal, or neonatal abnormalities in which there is no remaining biosample available to analyze. Now that whole exome sequencing is available to identify parental carriers of recessive conditions, this can enable a diagnosis in the proband and prenatal diagnosis in future pregnancies . Whilst it is clear that sequencing can have significant benefits, it also brings additional practical and ethical issues.…”

“…Now that whole exome sequencing is available to identify parental carriers of recessive conditions, this can enable a diagnosis in the proband and prenatal diagnosis in future pregnancies. 24 Whilst it is clear that sequencing can have significant benefits, it also brings additional practical and ethical issues. These are discussed in a series of articles initially published on-line in Prenatal Diagnosis in 2017 23,25,26 that will be the focus of our 2018 special topic issue.…”

Genetics of neuromuscular fetal akinesia in the genomics era

“…However, this requires large quantities of high-quality DNA from the affected offspring. Access to sufficient quantity/quality of material is often limited, particularly in cases of fetal demise 12. An alternative approach is parental exome sequencing, which searches for rare, heterozygous variants occurring in the same gene in both parents.…”

“…An alternative approach is parental exome sequencing, which searches for rare, heterozygous variants occurring in the same gene in both parents. Despite being unable to identify de novo variants, this method had an overall success rate of 52% in a cohort of 50 couples 12. Although various sequencing approaches offer hope of rapid and non-invasive diagnosis, cost, feasibility and ethical issues require consideration before routine implementation of these in a diagnostic setting 15…”