Discovery of novel cytogenetic abnormalities in patients with develomental delay, dysmorphology, and mental retardation
Completion of the Human Genome Project and availability of high-density DNA clones have facilitated the development of rapid and highly sensitive assays to detect quantitative changes in genetic material. We have used microarray-based comparative genomic hybridization to study a cohort of 20 patients with developmental delay, dysmorphology, and mental retardation. Conventional cytogenetic analysis had yielded normal results for these patients. Virtually all patients carried large-scale deletion and duplication polymorphisms, some of which were new. Five of the 20 patients demonstrated unique deletion mutations of various sizes between 3 and 6 megabases. All of these mutations had occurred de novo. Three of the five mutations had not been previously reported and represented novel genetic syndromes. Of the five mutations, the first was a 15q11q12 deletion associated with Prader-Willi syndrome (PWS), although the patient did not exhibit a classic PWS phenotype. The second mutation was an interstitial deletion in 1p36, but the patient’s phenotype did not resemble that of other patients with 1p36 deletions. The third mutation was an 8q22 deletion that resulted in a phenotype characterized by short palpebral fissures, hypertelorism, sparse eyebrows, everted upper lip, dysplastic ear helices, shiny and tight facial skin, and abnormal hair patterning. The fourth mutation was an Xq26q27 deletion overlapping the F9 gene. The patient suffered from a bleeding disorder because of factor IX deficiency, as expected, but also exhibited macrocephaly and developmental delay. The fifth mutation was a deletion in 4q31, resulting in cleft lip and palate, heart defects, vertebral anomalies, and cryptorchidism. These last three cases add to an increasing number of microdeletion syndromes. As genes in the respective deletion intervals are further studied, these novel syndromes will provide valuable insight into mechanisms that regulate prenatal and neonatal development.