Mutations in the TBX1 gene located in the commonly deleted region cause a similar phenotype, and thus TBX1 haploinsufficiency appears to significantly contribute to the features of 22q11.2 deletion syndrome. The majority of patients with velocardiofacial syndrome and DiGeorge syndrome have a 3.0- (90%) or 1.5-Mb (8%) hemizygous deletion of chromosome 22q11.2 that can be identified using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) or genome-wide array analysis. This syndrome is inherited in an autosomal dominant manner from a parent in 10% of new cases but mostly occurs de novo. Since velocardiofacial syndrome and DiGeorge syndrome describe variable clinical expressions of the same entity, the term 22q11.2 deletion syndrome is now more commonly used (features summarised in fig. DiGeorge syndrome (OMIM 188400) is another associated phenotype that includes features of congenital heart defects of the outflow tract, hypocalcaemia and immunodeficiency. Ĭhromosome 22q11.2 microdeletions have an estimated birth incidence between 10 and 26 per 100,000 live births and cause a highly variable clinical phenotype including velocardiofacial syndrome (OMIM 192430) which is the combination of velopharyngeal incompetence and other palate abnormalities, congenital heart defects, and dysmorphic facial features. Heterozygous CHD7 mutations are found in more than 90% of the patients, who fulfil the clinical criteria of CHARGE syndrome, but can also be detected in patients with an atypical phenotype. CHD7 codes for a chromodomain helicase DNA-binding protein that has a cell type-specific and embryonic stage-dependent function in regulating the expression of other developmental genes. CHARGE syndrome is inherited in an autosomal dominant fashion, but most cases are sporadic due to de novo mutations in the CHD7 gene. The major clinical features include choanal atresia, coloboma of the eye, hypoplastic semicircular canals, external ear anomalies, and cranial nerve dysfunction (as summarised in fig. A patient is currently diagnosed with CHARGE syndrome if the clinical diagnostic criteria of Blake et al.
We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation.ĬHARGE syndrome has an estimated birth incidence of 5.8-6.7 per 100,000 live births. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap.
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