Diagnosis of MR/DD by CGH
BACKROUND:
Karyotype analysis has been the primary method for genome-wide identification of chromosomal amplifications and deletions for decades but quantitative genomic changes smaller than 3-5 million base pairs escape detection by this method. Comparative genomic hybridization (CGH) is a microarray based method that provides much more sensitive detection of such copy number variants ( CNV ) throughout the genome, identifying changes of 100kb and smaller. Advances in CGH technology have led to the discovery that small de novo CNVs are associated with developmental disorders and susceptibility to human disease (1). For example, there is now good evidence that 10% or more of autism cases are due to a number of duplication and deletion CNVs (2). Concurrently, numerous polymorphic CNVs have been identified (3) and the current challenge in using CNVs for diagnosis is that these benign CNVs have not been fully catalogued. For this reason, it is important that samples from both parents are analysed as well as the patient to assist in the clinical evaluation of the results.
Our CGH microarray is a modification of the Agilent Technologies 44,000 oligonucleotide probe array which retains genome-wide coverage of quantitative variants while providing comprehensive assessment of known microdeletion syndromes and detailed coverage of all subtelomeric regions (4).
(1) Ann Rev Genomics Hum Genet (2002) 3 : 199-242
(2) Nature Genet (2007) 39 : 319-328
(3) Am J Hum Genet (2007) 80 : 91-104
(4) Am J Med Genet (2007) 143 : 824-829
INDICATIONS FOR TESTING:
Persons with mental retardation and/ or developmental delay of unknown etiology.
Patients with additional syndromic features have a particularly high yeild of genomic deletions and duplications.
However, the CGH technology has shown positive results when no obvious syndromic feaures are found.
SAMPLE REQUIREMENTS:
5 ml. blood in lavender (EDTA) vacutainer, or
2 cheek cell brushes
Note that frequently, a definitive diagnosis may require reflex testing of parental samples in order to rule out benign copy number variants, found in both the patient and a parent.
Therefore consider submission of parental samples with the patient sample if this is practical.
INTERPRETATION:
There are three possible types of positive results.
1. A known microdeletion syndrome is identified.
2. A copy number variant (deletion or duplication) is found de novo in the patient. It is likely that this is the cause of the phenotype but if it is not on the international data base of CNV's, it cannot be definitively determined at this time if this is the cause.
As the data base of normal CNV's is updated, we will check to determine if our results appear on the database as either normal or abnormal and report these results to the referring physican.
3. A unique variant is found but parental sample(s) are not available. Under these circumstances we do not know if the CNV is de novo to the patient or inherited from a parent. In the latter case, if the parent is normal, the CNV is not the cause of the diagnosis.