Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation

Abstract

CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 (58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 (73%) predicted premature truncation of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations (54 of 59 in the mutation-positive group vs. 30 of 42 in the mutation-negative group; P=.014), coloboma of the eye (55 of 62 in the mutation-positive group vs. 30 of 43 in the mutation-negative group; P=.022), and facial asymmetry, often caused by seventh cranial nerve abnormalities (36 of 56 in the mutation-positive group vs. 13 of 39 in the mutation-negative group; P=.004). Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facio-acoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch. Microarray gene-expression analysis showed a signature pattern of gene-expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutation from the controls. We conclude that cardiovascular malformations, coloboma, and facial asymmetry are common findings in CHARGE syndrome caused by CHD7 mutation.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

“…CHARGE syndrome is characterized by a non‐random clustering of a complex array of congenital malformations (Jongmans et al, 2006; Lalani et al, 2006; Pagon, Zonana, & Yong, 1981). The discovery of loss‐of‐function mutations in the CHD7 gene in patients with CHARGE syndrome (Janssen et al, 2012; Vissers et al, 2004), has led to significant progress in elucidating the developmental and molecular genetic mechanisms underlying specific phenotypes associated with CHARGE syndrome (Layman, Hurd, & Martin, 2010).…”

CHARGE syndrome: a review of the immunological aspects

“…A variant in CHD7 can be found in over 90% of all children who fulfil the clinical diagnostic criteria. 6,[9][10][11] The CHD7 gene encodes a member of the chromodomain helicase DNA-binding protein family that regulates the transcription of genes during embryonic development. Haploinsufficiency of CHD7 affects multiple organ systems, including the heart, the inner ear and the eye.…”

CHARGE syndrome in a fetus with a large paraesophageal hernia presenting prenatally as esophageal atresia

“…In most cases, de novo truncating mutations in the gene encoding the chromodomain helicase DNA binding protein 7 (CHD7), located on chromosome 8q12, cause the syndrome 2 . Mutations in the CHD7 gene have been demonstrated in 42-64% of cases 3 . The clinical diagnosis is made either if four major features are present, i.e.…”