Program Nr: 845 for the 2006 ASHG Annual Meeting

Chromosome Microarray Analysis (CMA) Detects a Large X Chromosome Deletion Including FMR1 and IDS in a Female Patient with Mental Retardation. F.J. Probst1, E.R. Roeder2, V.B. Enciso2, M.L. Cooper1, P. Eng1, J. Li1, Y. Gu1, A.C. Chinault1, Z. Ou1, C.A. Shaw1, S.W. Cheung1, D.L. Nelson1. 1) Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX; 2) Division of Genetics and Metabolic Disorders, Department of Pediatrics, The University of Texas Health Science Center at San Antotonio, San Antonio, TX.
   Chromosome Microarray Analysis (CMA) by array-based comparative genomic hybridization (CGH) is a new clinical test that can screen for hundreds of different submicroscopic chromosomal deletions and duplications. We report here a 6-year-old girl who presented for evaluation of mildly dysmorphic facies and marked developmental delay. She did not walk until 24 months of age and did not speak her first words until 5 years. Physical examination revealed overgrowth, a prominent forehead with nevus flammeus, mildly upslanting palpebral fissures, and a flat nasal bridge. Previous studies included a normal brain MRI; a normal 46, XX karyotype; and Fragile X studies yielding a single allele of 30 CGG repeats. CMA showed a loss in copy number of four clones from the genomic region cytogenetically defined as Xq27.3-Xq28. This loss was also seen by FISH analysis. Further studies have confirmed a complete loss of one copy each of the FMR1 and FMR2 genes (which are mutated in Fragile X Syndrome and FRAXE Syndrome, respectively) and at least a partial deletion of one copy of the IDS gene (which is mutated in Hunter Syndrome). Skewed X-inactivation has been previously reported in females with deletions in this region and can lead to a combined Fragile X/Hunter Syndrome phenotype in affected girls. A possible diagnosis of Hunter Syndrome is therefore being pursued, as enzyme replacement therapy is possible for this disease. Currently, efforts are underway to define precisely the childs deletion breakpoints, to determine this childs X-inactivation status (normal vs. skewed), and to assess her IDS activity. This clinical case demonstrates the utility of CMA for both making the diagnosis of a submicroscopic chromosomal deletion and for suggesting further testing that could possibly lead to therapeutic options for patients with developmental delay.