CHARGE syndrome

CHD7 disorder presents at birth as multiple congenital anomalies. Cardinal clinical features comprise ocular coloboma, choanal atresia, characteristic external ear malformations with cochlear and semicircular canal hypoplasia, sensorineural hearing loss, vestibular dysfunction, anosmia, and cranial-nerve palsies including facial palsy. Cardiovascular involvement typically reflects conotruncal and outflow-tract defects, while tracheoesophageal anomalies, dysphagia, and gastro-oesophageal reflux dominate the gastrointestinal spectrum. Endocrine features include hypogonadotropic hypogonadism, growth deficiency, and hypothyroidism; central nervous system findings encompass developmental delay, cerebellar and clival hypoplasia, and seizures. Skeletal anomalies, renal involvement, and T-cell deficiency with recurrent infections are also recognised. Phenotypic severity is highly variable, both between and within families carrying the same pathogenic variant, ranging from severe multisystem disease with life-threatening complex cardiac and airway anomalies to milder atypical presentations; intellectual outcome is within the normal range in 50% of affected individuals.

The estimated prevalence is 1/15,000-1/8,500, based on newborn cohorts.

CHARGE syndrome is caused by germline pathogenic variants in CHD7 on 8q12.2, the sole established causative gene. CHD7 encodes an ATP-dependent chromatin remodeller of the chromodomain family that uses ATP to alter nucleosome positioning and acts as an epigenetic regulator of chromatin accessibility. Decreased or lost CHD7 function is the molecular mechanism underlying the multisystem phenotype.

CHARGE syndrome is an autosomal dominant disorder that is typically caused by a de novo pathogenic variant. However, in rare instances, an affected individual inherits the pathogenic variant from a heterozygous parent. Recurrence risk to siblings depends on whether a parent carries the pathogenic variant. Prenatal molecular testing is possible once the familial pathogenic variant has been identified.

The clinical diagnosis is supported by the . Meeting these criteria establishes the clinical diagnosis. Additional criterion sets, the Blake et al. CHARGE association criteria and the Hale et al. broadened criteria for atypical CHD7-related phenotypes, refine clinical recognition. Temporal bone CT typically demonstrates the Mondini defect of the cochlea with absent or hypoplastic semicircular canals; brain MRI shows clivus and cerebellar vermis hypoplasia.

Main differential diagnoses include:

• 22q11.2 deletion syndrome: heart, palatal, immune, and hearing overlap, but semicircular canal anomalies and coloboma are rare; 22q11.2 deletion
• : heart, palatal, and hearing overlap; characteristic facies distinguishes; KMT2D, KDM6A
• Mandibulofacial dysostosis with microcephaly: choanal atresia and ear anomalies overlap; malar hypoplasia distinguishes; EFTUD2

• Establishing the molecular genetic diagnosis confirms the clinical suspicion and provides the basis for accurate genetic counselling.
• The molecular diagnosis enables specific and individualised surveillance and clinical management; this is a prerequisite for targeted medical care, the implementation of which lies with the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variant permits predictive testing of at-risk relatives and informs reproductive options.

• van Ravenswaaij-Arts CM, Hefner M, Blake K, Martin DM. CHD7 Disorder. 2006 Oct 2 [Updated 2025 Aug 14]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301296. Available from:
• Janssen N, Bergman JE, Swertz MA, Tranebjaerg L, Lodahl M, Schoots J, et al. Mutation update on the CHD7 gene involved in CHARGE syndrome. Human mutation. 2012;33(8):1149-60. doi: 10.1002/humu.22086. PMID: .
• Verloes A. Updated diagnostic criteria for CHARGE syndrome: a proposal. American journal of medical genetics. Part A. 2005;133A(3):306-8. doi: 10.1002/ajmg.a.30559. PMID: .
• Thomas AT, Waite J, Williams CA, Kirk J, Oliver C, Richards C. Phenotypic characteristics and variability in CHARGE syndrome: a PRISMA compliant systematic review and meta-analysis. Journal of neurodevelopmental disorders. 2022;14(1):49. doi: 10.1186/s11689-022-09459-5. PMID: . PMCID: PMC9429597.