Objective: Because in most patients with mental retardation (MR), who constitute 2 to 3% of the population, the etiology remains unknown, we wanted to identify novel chromosomal candidate regions and genes associated with the MR phenotype.
Methods: We screened for microimbalances in 60 clinically well-characterized patients with unexplained MR mostly combined with congenital anomalies. Genome-wide array-based comparative genomic hybridization was performed on DNA microarrays with an average resolution of <0.5 Mb. We verified every nonpolymorphic array clone outside the diagnostic thresholds by fluorescence in situ hybridization and performed breakpoint analyses on confirmed imbalances.
Results: Six presumably causal microimbalances were detected, five of which have not been reported. Microdeletions were found in five patients with MR and distinctive facial features, who also had neurologic findings (three cases), brain anomalies (two cases), and growth retardation (two cases), in chromosomal bands 6q11.1-q13 (10.8 Mb), Xq21.31-q21.33 (4.0 Mb), 1q24.1-q24.2 (3.8 Mb), 19p13.12 (2.1 Mb), and 4p12-p13 (1.1 Mb). One microduplication was detected in 22q11.2 (2.8 Mb) including the DiGeorge syndrome critical region in a patient with mild MR, microcephaly at birth, and dysmorphisms. Three imbalances were shown to be de novo and two inherited. The Xq21 microdeletion in a boy with borderline intellectual functioning was inherited from a normal mother; the 22q11.2 microduplication was inherited from a normal father and was present in two affected siblings.
Conclusion: We could identify novel microimbalances as the probable cause of mental retardation in 10% of patients with unclear etiology. The gene content of the microimbalances was found to correlate with phenotype severity. Precise breakpoint analyses allowed the identification of deleted genes presumably causing mental retardation.