CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene

Abstract

Background: CHARGE syndrome is a non-random clustering of congenital anomalies including coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia. Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula. Specific behavioural problems, including autistic-like behaviour, have been described. The CHD7 gene on chromosome 8q12.1 was recently discovered as a major gene involved in the aetiology of this syndrome. Methods: The coding regions of CHD7 were screened for mutations in 107 index patients with clinical features suggestive of CHARGE syndrome. Clinical data of the mutation positive patients were sampled to study the phenotypic spectrum of mutations in the CHD7 gene. Results: Mutations were identified in 69 patients. Here we describe the clinical features of 47 of these patients, including two sib pairs. Most mutations were unique and were scattered throughout the gene. All patients but one fulfilled the current diagnostic criteria for CHARGE syndrome. No genotype-phenotype correlations were apparent in this cohort, which is best demonstrated by the differences in clinical presentation in sib pairs with identical mutations. Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism. Conclusions: CHD7 mutations account for the majority of the cases with CHARGE syndrome, with a broad clinical variability and without an obvious genotype-phenotype correlation. In one case evidence for germline mosaicism was provided.

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.…”

“…In addition to the above symptoms, other common clinical features of CHARGE syndrome are: absent or hypoplastic semicircular canals, cranial nerve dysfunction (including facial nerve palsy), cleft lip and/or palate, anosmia, feeding difficulties and skeletal abnormalities. 8,9,13 Furthermore, deficits in the immune system have been described in CHARGE patients, which might lead to morbidity and even mortality. 14 Here, we provide an overview of the current literature on immunological dysfunction in CHARGE syndrome.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…The term CHARGE is an acronym for the syndrome's six core features: C, coloboma of the iris/retina; H, heart defects; A, atresia of the choanae; R, retardation of growth/development; G, genital abnormalities; and E, ear abnormalities. Occurring once in every 8500-10,000 live births [42,43], CHARGE syndrome also involves a range of secondary features, including deafness, laryngomalacia, vestibulocochlear defects, facial [80][81][82][83][84][85][86][87] CHARGE = C, coloboma of the iris/retina; H, heart defects; A, atresia of the choanae; R, retardation of growth/development; G, genital abnormalities; and E, ear abnormalities; PI3K = phosphoinositide 3-kinase; AKT = protein kinase B; MAPK = mitogen-activated protein kinase; mTOR = mammalian target of rapamycin nerve palsy, and oral clefts [44][45][46][47]. Many individuals with CHARGE syndrome are reported to exhibit autistic-like behaviors, with an estimated 27.5% meeting classification for autism [45].…”