American Journal of Medical Genetics 131A:29–35 (2004) Detection of an Interstitial Deletion of 2q21-22 by High Resolution Comparative Genomic Hybridization in a Child With Multiple Congenital Anomalies and an Apparent Balanced Translocation A.L. Shanske, 1 * L. Edelmann, 2 N.B. Kardon, 2 P. Gosset, 3 and B. Levy 2 1 Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York 2 Departments of Human Genetics and Pediatrics, Mount Sinai School of Medicine, New York, New York 3 Departement de Genetique, et Unite INSERM U-393, Hopital Necker-Enfants Malades, Paris, France Various molecular cytogenetic techniques are currently available to accurately characterize chromosome rearrangements in patients with multiple congenital anomalies. Among these is comparative genomic hybridization (CGH) whose main advantage is the ability to perform a whole genome scan without prior knowledge of the un- derlying chromosome abnormality. It has been used mostly in the area of cancer cytogenetics, but its role in clinical genetics is now expanding to even include preimplantation genetic diagnosis. We have used this method to reveal an interstitial deletion in a patient with multiple anomalies, who had for years been thought to have a de novo balanced translocation involving chromosomes 1 and 2. A review of published reports suggests that there is significant phenotypic and genetic heterogeneity in the small group of patients including our own with interstitial deletions of 2q21-q22. ß 2004 Wiley-Liss, Inc. KEY WORDS: comparative genomic hybridization (CGH); florescence in situ hybridi- zation (FISH); chromosome 2; trans- location; interstitial deletion INTRODUCTION Molecular cytogenetic methods are currently available to accurately characterize chromosome rearrangements in patients with multiple congenital anomalies. These include florescence in situ hybridization (FISH) with various locus specific and painting probes, multicolor FISH (M-FISH and SKY), reverse FISH (R-FISH), and comparative genomic hy- bridization (CGH). CGH is a reverse FISH technique that allows for the identification of chromosomal gains or losses by scanning the entire genome in a single step. It is accomplished by in situ hybridization of differentially labeled total genomic specimen DNA and normal reference DNA to normal human metaphase chromosome spreads. Hybridization of the speci- men and reference DNA can be distinguished by their different florescent colors. Test and reference DNA’s are isolated and labeled with different florochromes, the test DNA with florescein (green) and the reference with Texas Red (red). The use of CGH is expanding rapidly in clinical cytogenetics. It has been used to resolve constitutional chromosomal ab- normalities [Levy et al., 1998], for prenatal diagnosis [Levy et al., 2000], for cryptic telomere translocation screening [Ghaffari et al., 1998], and more recently for preimplantation genetic diagnosis [Wilton et al., 2001; Wells and Levy, 2003]. We have utilized CGH to unambiguously identify an inter- stitial deletion of the long arm of chromosome 2 in a child with an apparently de novo balanced translocation. MATERIALS AND METHODS Clinical Report Our patient was the 2,800 g product of a full-term pregnancy complicated by maternal migraine headaches. He was delivered by spontaneous vaginal delivery to a 32-year-old gravida 4, para 3,013 mother who noted poor fetal movements. He was transferred to our hospital for neurosurgical evaluation because of a skull deformity and lethargy. A CAT scan of the head revealed a subarachnoid hemorrhage that did not require surgery. An echocardiogram indicated a newborn murmur was secondary to a patent ductus arteriosus (PDA), which resolved spontaneously. He required several more admissions because of chronic intestinal obstruction resulting in a derota- tion of a malrotation and lysis of Ladd bands at 11 months. A seromuscular colonic biopsy at the time of surgery revealed normal ganglion cells. He developed a tonic-clonic seizure disorder at 2 years by which time a second CAT scan indicated resolution of the subarachnoid hemorrhage and ventriculome- galy. When last examined at 67 months of age, his growth and development were severely delayed (Fig. 1a,b). His weight was 15.6 kg (below 5 centile), his height 101 cm (below 5 centile), and his head circumference was 51.25 cm (25 centile). The physical examination at that time revealed craniofacial disproportion, relative macrocephaly and a large fontanelle, and prominent scalp venous pattern. The pinna were posteriorly rotated with thickened helices. There were posterior helical longitudinal dimples and preauricular fistulae (Fig. 2). He had hypotelorism, hypoplastic ala nasae, and corneal asymmetry. The outer canthal distance was 8.5 cm and the inner 2.5 cm. His abdomen was distended, he was chronically flatulent and had right cryptorchidism. The neurologic examination revealed a hypo- tonic, nonverbal youngster who could sit, stand, cruise, transfer, and hold his bottle. A number of self-stimulatory behaviors were noted. He was able to tolerate only a soft diet and had never been tried on a lactose-free diet. *Correspondence to: A.L. Shanske, M.D., Center for Congenital Disorders, Children’s Hospital at Montefiore, 111 East 210th Street, Bronx, New York 10467. E-mail: Ashanske@Montefiore.org Received 28 October 2003; Accepted 12 May 2004 DOI 10.1002/ajmg.a.30311 ß 2004 Wiley-Liss, Inc.