To explore the use of exome sequencing in the diagnostic evaluation of patients with severe microcephaly
ID
Source
Brief title
Condition
- Neurological disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Number of pathogenic mutations in known genes and newly identified genes
causing severe microcephaly
Secondary outcome
Estimated increase in diagnostic yield and speed compared to currently used
diagnostic evaluations and sequential genetic testing in patients with severe
microcephaly.
Background summary
Head size is determined by brain development. In severe microcephaly, the head
circumference is more than 3 standard deviations below the mean. Usually,
severe microcephaly is associated with mental retardation. Severe microcephaly
can be caused by a very heterogeneous group of disorders and syndromes. After
excluding chromosomal defects, environmental factors (e.g. fetal alcohol
syndrome) and recognizable syndromes, the risk of recurrence is still
substantial (approximately 20%). This suggests a high contribution of autosomal
recessive disorders. To date, multiple genes and gene loci have been
identified. However, the analysis of all these individual genes is not widely
available and laborious. Moreover, mutations in the currently known genes
involved in microcephaly only explain a minority of the cases. So there is a
need for a rapid and broad approach to quicken the diagnostic process, increase
the diagnostic yield and to identify the other, yet unknown, genes involved.
Study objective
To explore the use of exome sequencing in the diagnostic evaluation of patients
with severe microcephaly
Study design
Mutation analysis by exome sequencing
Study burden and risks
The burden and risks associated with participation are minimal. A blood sample
is taken only when no DNA is available. There is no direct benefit for the
patients. The identification of causative mutations may however reduce the
number of other diagnostic evaluations. The identification of causative
mutations may also be beneficial for the family. It could improve genetic
counselling, aid in decision making in relation to reproduction, enable carrier
testing in family members and offer possibilities for prenatal diagnosis.
The study focuses on patients with severe microcephaly because of the expected
high contribution of autosomal recessive disorders. This helps in the
identification of causative genes based on selection by the presence of at
least two mutations (homozygous or compound heterozygous) in the same gene or
by shared haplotypes (identical-by-descent).
Postbus 30.001
9700 RB Groningen
NL
Postbus 30.001
9700 RB Groningen
NL
Listed location countries
Age
Inclusion criteria
A head circumference below -3 SD at birth or below -4 SD at other ages
Exclusion criteria
Causative chromosomal abnormality identified by array CGH
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 | NL38198.042.11 |