More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated

Abstract

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. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. 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. 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. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. 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.

CHARGE syndrome: a review of the immunological aspects

“…39 The most remarkable phenotypic overlap is with 22q11.2 deletion syndrome (#MIM 192430, TBX1), including the DiGeorge phenotype, where immunodeficiency is an important symptom. Congenital heart defects, cognitive and motor delay, hearing loss, external ear anomaly, cleft lip and palate, growth deficiency, and renal anomaly are seen in both syndromes.…”

“…Congenital heart defects, cognitive and motor delay, hearing loss, external ear anomaly, cleft lip and palate, growth deficiency, and renal anomaly are seen in both syndromes. 14,39 The total absence of the thymus, and therefore complete T-cell lymphopenia (DiGeorge phenotype), is rare and is seen in less than 1.5% of patients with 22q11.2 deletion syndrome. 40 Patients with the typical 1.5 or 3.0 Mb deletion of 22q11.2 rarely show the full presentation of the syndrome and only a minority develop opportunistic infections.…”

“…Alagille syndrome (#MIM 118450), caused by variants in JAG1, shares abnormalities in the semicircular canals, heart defects, renal anomalies and intellectual disabilities with CHARGE syndrome. 39 Recurrent ear and respiratory tract infections are seen in about a quarter of patients with Alagille syndrome. 48 The underlying immunological dysfunction was described in one paper as a diminished T-helper 1 response.…”

“…49 Patients with Pfeiffer syndrome (#MIM 101600, FGFR1) have overlapping features with CHARGE syndrome regarding cleft-lip and/or palate and hearing loss. 39 The immunological function in 12 patients with craniofacial malformation syndromes, including Pfeiffer syndrome, was studied by Scheuerle et al 50 Unfortunately, they did not specify the immunological dysfunction per syndrome. However, seven patients were tested for T-cell numbers and T-cell lymphopenia was reported in one patient, decreased T-helper cells in three patients and decreased T-killer cells in three patients.…”

Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula

“…9,10 In addition to their well-established role in the development of congenital anatomical malformations in general, 11 CNVs contribute to disease aetiology in several genetic syndromes. These include those having OA/TOF as part of their phenotypic spectrum such as Feingold syndrome, 12 22q11 deletion syndrome, 13 CHARGE syndrome 14 and mandibulofacial dysostosis. 15 Furthermore, de novo disease-causing CNVs have been described in patients with non-syndromic OA/TOF and the VACTERL association.…”