Clinical characteristics: CHD7 disorder encompasses the entire phenotypic spectrum of heterozygous CHD7 pathogenic variants that includes CHARGE syndrome as well as subsets of features that comprise the CHARGE syndrome phenotype. The mnemonic CHARGE syndrome, introduced in the premolecular era, stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness). Following the identification of the genetic cause of CHD7 disorder, the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies. Life expectancy highly depends on the severity of manifestations; mortality can be high in the first few years when severe birth defects (particularly complex heart defects) are present and often complicated by airway and feeding issues. In childhood, adolescence, and adulthood, decreased life expectancy is likely related to a combination of residual heart defects, infections, aspiration or choking, respiratory issues including obstructive and central apnea, and possibly seizures. Despite these complications, the life expectancy for many individuals can be normal.
Diagnosis/testing: The diagnosis of CHD7 disorder is established in a proband with suggestive clinical and imaging findings and a heterozygous pathogenic variant in or deletion of CHD7 identified by molecular genetic testing.
Management: Treatment of manifestations: Management of the manifestations of CHD7 disorder can be complex and require a multidisciplinary approach involving clinicians, therapists, and educators.
Surveillance: Requires routine follow up of manifestations identified in infancy/childhood, as well as ongoing monitoring of growth, development, educational progress, behavior, and possible endocrine issues.
Agents/circumstances to avoid: Because of the increased risk of post-anesthesia airway complications, procedures requiring anesthesia should be minimized and combined whenever possible.
Genetic counseling: CHD7 disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant. In rare instances, an individual with CHD7 disorder inherits a pathogenic variant from a heterozygous parent. The risk to the sibs of the proband depends on the genetic status of the proband's parents: (1) If a parent of the proband has a CHD7 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%; (2) If the CHD7 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs of a proband is approximately 1%-2% because of the possibility of parental germline mosaicism. Although many individuals with CHD7 disorder are not able to reproduce, each child of an individual with CHD7 disorder has a 50% chance of inheriting the pathogenic variant. Once the CHD7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
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