Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis

• Published in: American journal of medical genetics. Part A 2008-05, Vol.146A (9), p.1117-1127
• Main Authors: Kulkarni, Shashikant, Nagarajan, Prabakaran, Wall, Jonathan, Donovan, Diana J., Donell, Robert L., Ligon, Azra H., Venkatachalam, Sundaresan, Quade, Bradley J.
• Format: Article
• Language: English
• Subjects: Adolescent; Animals; Base Sequence; Biological and medical sciences; Cell Line; CHD2; chromodomain; chromosomal translocation; Chromosome aberrations; Chromosomes, Human, Pair 15 - genetics; Chromosomes, Human, X - genetics; congenital vertebral malformation; Developmental Disabilities - genetics; Developmental Disabilities - metabolism; Disease Models, Animal; Diseases of the osteoarticular system; Diseases of the spine; DNA Helicases - deficiency; DNA Helicases - genetics; DNA Primers - genetics; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Female; Gene Expression Regulation, Developmental; helicase; Hirsutism - genetics; Hirsutism - metabolism; Humans; Learning Disorders - genetics; Learning Disorders - metabolism; Male; Medical genetics; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Phenotype; scoliosis; Scoliosis - genetics; Scoliosis - metabolism; Translocation, Genetic
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.32178

Herein we characterize an apparently balanced de novo translocation, t(X;15)(p22.2;q26.1)dn, in a female patient with scoliosis, hirsutism, learning problems, and developmental delay (DGAP025). Other clinical findings include a high‐arched palate, 2–3 syndactyly of the toes, and mildly elevated serum testosterone. No known or predicted genes are disrupted by the Xp22.2 breakpoint. The 15q26.1 breakpoint disrupts chromodomain helicase DNA binding protein 2 (CHD2). Another member of the chromatin‐remodeling gene family, CHD7, has been associated with a defined constellation of congenital anomalies known as coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear anomalies syndrome (CHARGE) and idiopathic scoliosis. Monosomy of 15q26 also has been associated with a spectrum of congenital abnormalities and growth retardation that overlaps with those of DGAP025. To provide a biological correlate, we characterized a mutant mouse model with Chd2 disruption that is associated with embryonic and perinatal lethality. Expression analysis indicated that Chd2 is expressed in the heart, forebrain, extremities, facial and dorsal regions during specific times of embryonic development. Chd2+/m mice showed pronounced lordokyphosis, reduced body fat, postnatal runting, and growth retardation. These data suggest that haploinsufficiency for CHD2 could result in a complex of abnormal human phenotypes that includes scoliosis and possibly features similar to CHARGE syndrome. © 2008 Wiley‐Liss, Inc.