Existing prospective, prenatal exome sequencing studies.
The majority of studies describing the use of prenatal exome sequencing
are small, retrospective case series. An informative systematic review
including data from peer reviewed published papers, published
retrospective cohort series and published conference abstracts,
(containing at least five cases) has been published by Chitty’s
group9. There were sixteen ‘citations’ which contained
a range of inclusion criteria of babies with a structural anomaly were
examined (including those associated with miscarriage, perinatal
mortalityand termination of pregnancy). There were a range of isolated
structural abnormalities , fetuses with multiple fetal abnormalities and
those with an increased first trimester nuchal translucency
(NT)(>3.5mm). Many reported fetus only)ES testing whilst
others included ‘trio testing’ (fetus, mother and father), a method
proven to increase diagnostic rate10. These papers
reported a diagnostic rate that ranged from 6.2%11 to
80%12. across sixteen studies13-26.
However last year, two relatively large prospective -recruited
cohort studies (from the United Kingdom and North America), targeting ES
in fetuses with “unselected ultrasound” detected structural anomalies,
were published in the Lancet, in early 201927,28. A
total 844 fetal probands (as eligible consented trios; when QF PCR and
CMA was normal) were studied. In 76 probands (9%), a causative
pathologic genetic variant was identified.
The largest of these was the, Prenatal Assessment
of Genomes and Exomes (PAGE) study
which performed ES on 610 trios in cases of identified a fetal anomaly
and CMA was negative. Overall, ES provided an additional 8.5%
diagnostic yield of pathogenic variants compared with conventional
genetic testing. In addition to pathogenic variants considered to
directly cause the relevant fetal structural anomaly, variants of
uncertain significance (VUS) and of potential clinical relevance were
diagnosed in a further 4% of cases27. The second
prospective prenatal series conducted by Columbia University reported an
additional diagnostic yield of 10.3% (in 234 trios)28. Both these studies gave diagnostic yields that
were part lower than those reported from smaller retrospectively
selected cohorts9.