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The CHARGE association (OMIM 214800) refers to a nonrandom pattern of
congenital anomalies, most notably coloboma, heart
defects, choanal atresia, retarded growth
and development and/or CNS abnormalities, genital
anomalies and ear anomalies or deafness. It has a
birth incidence of about 1:12,000. Most cases occur sporadically,
although there is some evidence of a genetic component, ie, rare
reports of familial cases and cytogenetic abnormalities. Attempts to
identify the genetic component have been unsuccessful to date
including sequencing suspected candidate genes PAX2 and PITX2 and
conventional comparative genomic hybridization (CGH).
CGH involves hybridizing genomic DNA from a test patient and from a
reference (normal) individual to fragments of DNA arrayed so that
they correspond to ordered segments of chromosomes. CGH reveals DNA
sequence that is present in greater or lesser amounts than normal and
maps its chromosomal location, thereby allowing detection of
submicroscopic deletions, insertions and gene amplifications. The
use of smaller and smaller DNA fragments and chip technology to array
the fragments and analyze hybridization has made high-throughput,
high-resolution, genome-wide screening for submicroscopic copy number
changes possible.1,2 Vissers and co-workers have utilized
this approach to identify mutations responsible for the CHARGE
association.
The investigators co-hybridized genomic DNA from 2 patients with CHARGE
and reference DNA onto a genome-wide BAC (bacterial artificial
chromosome) array with 1 Mb resolution. The CGH profile of one of
the patients revealed a deletion of ~5 Mb that mapped to chromosome
8q12. DNA from this patient was then hybridized to a more precise
array of 918 overlapping BAC clones corresponding to a linear
representation of chromosome 8. The results showed deletion of 31
overlapping BAC clones spanning 4.8 Mb of chromosome 8q12.
The
authors next confirmed 2 microdeletions in a patient with CHARGE
association previously reported with a balanced chromosome 8
translocation. Comparing DNA from the 2 patients with
microdeletions, they narrowed the region of deletion overlap to 2.3
Mb and screened 17 patients with CHARGE association for similar
deletions. None were detected. However, when they sequenced the
coding regions and intron-exon boundaries of the 9 genes thought to
reside in or adjacent to the critical 2.3 Mb region, they detected 10
heterozygous mutations in one of the resident genes – CHD7.
Seven of the mutations were stop codon mutation predicted to cause
loss of function leading the authors to conclude that CHARGE
association results from haploinsufficiency of CHD7.
CHD7
encodes a member of the chromodomain helicase
DNA-binding proteins. They are believed to have
important roles in modulating chromatin structure and regulating gene
expression during early development.
Vissers
LE, van Ravenswaaij CM, Admiraal R, et al. Mutations in a new
member of the chromodomain gene family cause CHARGE syndrome. Nat
Genet 2004;36:955-7.
First
Editor’s Comment: This paper is informative not only
because it identifies the genetic basis of the CHARGE association,
but it validates the use of high-throughput, high-resolution CGH to
screen for submicroscopic changes in gene copy number in infants with
sporadic malformation syndromes. As the technology becomes widely
available it will likely become a valuable diagnostic tool for the
clinical geneticist/dysmorphologist.
William A. Horton, MD
Second
Editor’s Comment: Within the structure of the chromodomain
helicase DNA-binding protein superfamily are 2 amino acid sequences
or domains shared by its members - a "chromo (chromatin
organization modifier) domain" and an SNF2-related
helicase/ATPase domain (OMIM 602118). These proteins alter gene
expression by modifying chromatin structure, thereby altering access
of transcription factors to their gene targets. With the
identification of a specific gene defect in patients with the cited
association of structural anomalies (CHARGE), the disorder may now be
referred to as the CHARGE syndrome. For their studies, the
investigators employed an optimized, high resolution "array
comparative genomic hybridization" assay that may be applicable
to the study of other patients with sporadic multi-malformation
syndromes.
Allen W. Root, MD
References - (linked to  )
- Albertson DG, Pinkel D. Hum Mol Genet 2003;12:R145-2.
- Vissers LE, de Vries BB, Osoegawa K,et al. Am J Hum Genet 2003;73:1261-70.
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Current GGH - Vol. 24 No. 1
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