Intellectual Disability Clinical Trial
Official title:
Molecular Characterization of Apparently Balanced Chromosomal Rearrangements by Next-generation Sequencing in 55 Patients With Intellectual Disability and/or Multiple Congenital Anomalies
Apparently balanced chromosomal rearrangement (ABCR) associated with an abnormal phenotype
is a rare but problematic event. It occurs in 6% of de novo reciprocal translocations and 9%
of de novo inversions. Abnormal phenotype, including intellectual disability and / or
multiple congenital anomalies (ID/MCA) may be explained either by associated cryptic genomic
imbalances detectable by array-CGH or by gene disruption at the breakpoint. However,
breakpoint cloning using conventional methods (i.e., fluorescent in situ hybridization
(FISH), Southern blot) is often laborious and time consuming and cannot be performed
routinely. Without complete investigation of these rearrangements, genetic counseling is a
real challenge. Recently, the investigators and others showed that Next-Generation
Sequencing (NGS) is a powerful and rapid technique to characterize ABCR breakpoints at the
molecular level.
The ANI project (ABCR NGS ID) aims at characterizing at the molecular level ABCR in 55
patients presenting with intellectual disability and/or multiple congenital anomalies
(ID/MCA) using NGS. The investigators make the hypothesis that ABCR account for the patient
phenotype, either by gene disruption or position effect, since genomic imbalance would have
been previously excluded by array-Comparative Genomic Hybridization (CGH).
The ANI project is a 3-year-long study that will be conducted by a consortium of 21
partners, including 19 french hospital cytogenetics laboratories, a research team (TIGER),
and a cellular biotechnology center. Patients will be recruited by each Cytogenetics
laboratory. ABCR breakpoints will be molecularly characterized by NGS and a first
bio-informatics analysis. The results will be verified by amplification of junction
fragments by polymerase Chain Reaction (PCR) followed by Sanger sequencing, allowing the
localization of breakpoints at the base-pair level. In some complex cases, FISH experiment
will be necessary to clarify the results. A second bio-informatics analysis will then
determine breakpoints' characteristics (sequence, repeated elements, gene and regulatory
elements). Finally, for each breakpoint, gene expression studies will be performed including
the gene disrupted by the breakpoint and two neighboring genes. All these data, together
with those already available in the literature and databases will be integrated to determine
if the gene could account for the patient's phenotype, allowing an appropriate genetic
counseling.
This project will identify new candidate genes involved in ID and developmental anomalies.
It will also contribute to the development and evaluation of NGS as a diagnostic tool for
ABCR and ID/MCA. It will also allow unraveling mechanisms and functional consequences of
ABCR, in particular in term of position effect.
In conclusion, the ANI project will contribute to the improvement of diagnostic management
and genetic counseling of patients with ID/MCA and ABCR. It will also contribute to the
understanding of ABCR physiopathology and to the unraveling of pathway involved in
development and brain function, thus improving genetic counseling for ID/MCA patients in
general.
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