Identification of novel candidate genes associated with cleft lip and palate using array comparative genomic hybridisation

• Published in: Journal of medical genetics Vol. 45; no. 2; pp. 81 - 86
• Main Authors: Osoegawa, K, Vessere, G M, Utami, K H, Mansilla, M A, Johnson, M K, Riley, B M, L’Heureux, J, Pfundt, R, Staaf, J, van der Vliet, W A, Lidral, A C, Schoenmakers, E F P M, Borg, A, Schutte, B C, Lammer, E J, Murray, J C, de Jong, P J
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.02.2008; BMJ; BMJ Publishing Group LTD
• Subjects: Artificial chromosomes; Base Sequence; Basic Medicine; Biological and medical sciences; Child; Chromosome Deletion; Chromosome Mapping; Chromosomes, Artificial, Bacterial - genetics; Chromosomes, Human, Pair 10 - genetics; Chromosomes, Human, Pair 22 - genetics; Chromosomes, Human, Pair 6 - genetics; Cleft Lip - genetics; Cleft Palate - genetics; Cloning; Deoxyribonucleic acid; DNA; DNA - genetics; Facial bones, jaws, teeth, parodontium: diseases, semeiology; Families & family life; Female; Fundamental and applied biological sciences. Psychology; Gene Dosage; Gene loci; General aspects. Genetic counseling; Genetic testing; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Humans; Intellectual disabilities; Male; Medical and Health Sciences; Medical genetics; Medical Genetics and Genomics (including Gene Therapy); Medical sciences; Medicin och hälsovetenskap; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Molecular and cellular biology; Mutation; Non tumoral diseases; Nucleic Acid Hybridization; Otorhinolaryngology. Stomatology; Phenotype; Studies; Syndrome; Iowa; Philippines; Human; Cleft palate; Cleft lip; Stomatology; Pathogenesis; Genomics; Congenital cleft; Identification; Congenital disease; Genetic determinism; Association; Malformation; Genetics; Oral cavity disease; Comparative study
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2007.052191

Aim and method:We analysed DNA samples isolated from individuals born with cleft lip and cleft palate to identify deletions and duplications of candidate gene loci using array comparative genomic hybridisation (array-CGH).Results:Of 83 syndromic cases analysed we identified one subject with a previously unknown 2.7 Mb deletion at 22q11.21 coinciding with the DiGeorge syndrome region. Eighteen of the syndromic cases had clinical features of Van der Woude syndrome and deletions were identified in five of these, all of which encompassed the interferon regulatory factor 6 (IRF6) gene. In a series of 104 non-syndromic cases we found one subject with a 3.2 Mb deletion at chromosome 6q25.1–25.2 and another with a 2.2 Mb deletion at 10q26.11–26.13. Analyses of parental DNA demonstrated that the two deletion cases at 22q11.21 and 6q25.1–25.2 were de novo, while the deletion of 10q26.11–26.13 was inherited from the mother, who also has a cleft lip. These deletions appear likely to be causally associated with the phenotypes of the subjects. Estrogen receptor 1 (ESR1) and fibroblast growth factor receptor 2 (FGFR2) genes from the 6q25.1–25.2 and 10q26.11–26.13, respectively, were identified as likely causative genes using a gene prioritisation software.Conclusion:We have shown that array-CGH analysis of DNA samples derived from cleft lip and palate subjects is an efficient and productive method for identifying candidate chromosomal loci and genes, complementing traditional genetic mapping strategies.