We aim to proof that introduction of (rapid) NGS-based sequencing (WES/WGS) as a first tier genetic test in the diagnostic process for critically ill newborns admitted at the NICU and patients with severe neurodevelopmental disorders leads to faster…
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome measure: number of definitive genetic diagnosis
Secondary outcome
Secondary outcome measures: time-to-diagnosis, cost-of-diagnosis,
cost-effectiveness, perspective analysis of joint decision-making process and
the impact on therapeutic interventions.
Background summary
There are approximately 5,000-8000 rare diseases, affecting 6-8% of the
population. Rare diseases are often lifethreatening and can lead to chronic and
serious disabilities. As these diseases are rare, detailed knowledge on the
disorders is often lacking, making the diagnostic odessey for patients a
lengthy one. For 3,879 of these rare diseases, the underlying genetic cause is
known. Hence, genetic testing is the ultimate way to diagnose patients with
rare disease.
Approximately 75% of rare diseases manifests during childhood and 30% of
children dies before the age of 5. Many of rare diseases even manifest during
the neonatale fase, and account for a substantial part of neonatal deaths.
Clinical symptoms of these rare diseases during this early stage of life are
often aspecific, and heterogeneous, thereby not allowing for accurate
diagnosis, confirmed by geneticu testing. Treatment of this patient cohort is
therefore mostly focussed on clinical symptoms without exact and detailed
knowledge of the underying cause and prognosis.
For at least 6-8% of neonates admitted to the NICU, a genetic diagnosis would
be a welcome addition to determine the appropriate treatment plan. This can
either be surgical intervention for a patient with good prognosis, but could
also be withdrawal of interventions in case of terminal illness preventing
needless suffering. The incidence of severe intellecutal disability is 0,5% in
the Western World. Many of these patients experience a diagnostic odessey
taking years to identify the genetic cause of disease. This quest consists of
multiple sequential gene-based tests, and exome sequencing as 'last resource'
test.
Genetic diagnostic testing is mostly based on a gene-by-gene basis, leading to
a turn-around time that exceeds the window of opportunity to influence medical
decision making in the acute fase of a NICU setting. Technological
developments, such as next generation sequencing, now allow to determine the
genetic blueprint of an individual in a single experiment. Application of these
tests has led to increasing diagnostic yields, especially for clinical and
genetically heterogeneous disorders. Hence, this technology would have immense
value for neonates admitted to the NICU if turn-around-times could be further
reduced to ~5-7 days. Recently, the genetic test, referred to as 'exome
sequencing' even further improved, making such turn-around times achievable.
Hence, the goal of our project is to determine the added value of implementing
rapid genetic exome sequencing for neonates admitted to the NICU.
In addition, we wish to proof that the use of NGS-based testing (WES and WGS)
are most efficient when used as a 'first tier test' rather than a last
resource. We hypothesize that the use of WES/WGS as first tier test will
increase the diagnostic yield, using less diagnostic testing, while decreasing
costs and being less burdensome to patients.
Study objective
We aim to proof that introduction of (rapid) NGS-based sequencing (WES/WGS) as
a first tier genetic test in the diagnostic process for critically ill newborns
admitted at the NICU and patients with severe neurodevelopmental disorders
leads to faster and more accurate diagnosis, more targeted treatments and
interventions and a reduction of health care costs, and being less burdensome
to patients.
Study design
Prospective parallel design where patients receive the 'intervention' along
side the standard diagnostic work-up.
Intervention
The control arm receives genetic care involving sequential gene-by-gene Sanger
sequencing guided by clinical phenotype, and the invention arm receives rapid
next generation sequencing (NGS), by whole exome (WES).
Study burden and risks
The study involves the comparison of two genetic diagnostic procedures, e.g.
the routine gene-by-gene testing using Sanger sequencing and whole exome
sequencing and the procedure where WES/WGS is used as first tier (rapid) test.
The patient will not have to undergo additional invasive tests when
participating in our study, as venapuncture for genetic testing is withdrawn as
standard work-up for patients admitted at the NICU who are suspected of a
genetic disorder. We also wish to measure the role of the genetic report in
*shared decision making* and the impact of the diagnosis on the medical
decision making process. Hereto, parents will be asked to fill out 4-6
questionnaires, taking ~10-20 minutes each.
The risks of participating are minimal as WES is currently used as a routine
diagnostic test in (older) patients (and their respective parents), and
detailed protocols on the entire procedure, to which we will adhere, are
available within the participating centres.
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Geert Grooteplein 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
We focus on critically ill neonates and patients with severe neurodevelopmental disorders of which it is expected that the condition has a genetic defect. ;In the Netherlands, ~4,100 critically ill newborns are annually admitted to the NICU. At least 6% of these patient (285 newborns) will suffer from such rare genetic condition, but due to ascertainment bias given the patient population we are facing, this percentage is likely to be an extreme underestimation.;The newborns with disease of suspected genetic origin may present with various symptoms e.g. encephalopathies, ataxia, growth retardation, seizures and/or MCA. Providing a differential diagnosis in these newborns is difficult as the symptoms are frequently aspecific and newborns are too young to show all recognizable features of disease.;For neurodevelopmental disorders, >3,500 patients are seen in tertiary clinical genetic centres.;Patients are eligable for inclusion if both the consulting clinical geneticist (and neonatologist for NICU [atients) believes that the cause of the symptoms observed in the patient could be of genetic origin, and when the patient has not had any other genetic testing done before.
Exclusion criteria
Patient who are not eligable for inclusion are those who have (lifetreatening) disorder of clear non-genetic origin such as (birth)trauma, or those who have had genetic testing done before.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL57511.091.16 |