De novo and complex imbalanced chromosomal rearrangements revealed by array CGH in a patient with an abnormal phenotype and apparently "balanced" paracentric inversion of 14(q21q23)

Paracentric inversions are one of the common chromosomal rearrangements typically associated with a normal phenotype. However, if dosage-sensitive genes are disrupted by the breakpoints, an abnormal phenotype could result. Detection of paracentric inversions often relies on careful high resolution banding, which has limited sensitivity. We report here cytogenetic studies performed on a 4-year-old female patient with global developmental delay, hypotonia, and dysmorphic features. The initial cytogenetic evaluation by G-banding revealed a de novo inversion of chromosome 14. Subsequent array CGH analysis using both a targeted BAC array and a high-resolution oligonucleotide array revealed microdeletions at the breakpoints of 14q21.1 (0.8 Mb) and 14q23.1 (0.9 Mb). Unexpectedly, a microdeletion in the region of 16q23.1 (1.3 Mb) was also identified, which overlaps with the common fragile site FRA16D. Parental chromosome and FISH analyses were normal, supporting the conclusion that these microdeletions were de novo in the patient and likely contributed to her abnormal phenotype. The case report presented illustrates the value of using high-resolution microarray analysis for phenotypically abnormal individuals with apparently balanced chromosomal rearrangements, including inversions.     

Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males.

PURPOSE: Mutations in the MECP2 gene are associated with Rett syndrome, an X-linked mental retardation disorder in females. Mutations also cause variable neurodevelopmental phenotypes in rare affected males. Recent clinical testing for MECP2 gene rearrangements revealed that entire MECP2 gene duplication occurs in some males manifesting a progressive neurodevelopmental syndrome. METHODS: Clinical testing through quantitative DNA methods and chromosomal microarray analysis in our laboratories identified seven male patients with increased MECP2 gene copy number. RESULTS: Duplication of the entire MECP2 gene was found in six patients, and MECP2 triplication was found in one patient with the most severe phenotype. The Xq28 duplications observed in these males are unique and vary in size from approximately 200 kb to 2.2 Mb. Three of the mothers who were tested were asymptomatic duplication carriers with skewed X-inactivation. In silico analysis of the Xq28 flanking region showed numerous low-copy repeats with potential roles in recombination. CONCLUSIONS: These collective data suggest that increased MECP2 gene copy number is mainly responsible for the neurodevelopmental phenotypes in these males. These findings underscore the allelic and phenotypic heterogeneity associated with the MECP2 gene and highlight the value of molecular analysis for patient diagnosis, family members at risk, and genetic counseling.