Περίληψη:
Background. Fetal malformations and other structural abnormalities are
relatively frequent findings in the course of routine prenatal
ultrasonographic examination. Due to their considerable genetic and
clinical heterogeneity, the underlying genetic cause is often elusive
and the resulting inability to provide a precise diagnosis precludes
proper reproductive arid fetal risk assessment. We report the
development arid first applications of an expanded exome
sequencing-based test, coupled to a bioinformatics driven prioritization
algorithm, targeting gene disorders presenting with abnormal prenatal
ultrasound findings.
Methods. We applied the testing strategy to14 euploid fetuses, from 11
on-going preg nancies and three products of abortion, all with various
abnormalities or malformations detected through prenatal ultrasound
examination. Whole exome sequencing (WES) was followed by variant
prioritization, utilizing a custom analysis pipeline (Fetalis
algorithm), targeting 758 genes associated with genetic disorders which
may present with abnormal fetal ultrasound findings.
Results. A definitive or highly-likely diagnosis was made in 6 of 14
cases (43%), of which 3 were abortuses (Ellis-van Creveld syndrome,
Ehlers-Danlos syndrome and Nemaline myopathy 2) and 3 involved on-going
pregnancies (Citrullinemia, Noonan syndrome, PROKR2-related Kallmann
syndrome). In the remaining eight on-going pregnancy cases (57%), a
ZICI variant of unknown clinical significance was detected in one case,
while in seven cases testing did not reveal any pathogenic variant(s).
Pregnancies were followed-up to birth, resulting in one neonate
harboring the PROKR2 mutation, presenting with isolated minor structural
cardiac abnormalities, and in seven apparently healthy neonates.
Discussion. The expanded targeted exome sequencing-based approach
described herein (Fetall s), provides strong evidence suggesting a
definite and beneficial increase in our diagnostic capabilities in
prenatal diagnosis of otherwise chromosomally balanced fetuses with
troubling ultrasound abnormalities.Furthermore, the proposed targeted
exome sequencing strategy, designed primarily as a diagnostic rather
than a research discovery tool, overcomes many of the problems and
limitations associated with clinical wide-scale WES testing in a
prenatal setting.
Συγγραφείς:
Pangalos, Constantinos
Hagnefelt, Birgitta
Lilakos, Konstantinos
and Konialis, Christopher
