![]() ![]() Sequence analysis of CHD7 is performed to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Individuals with suggestive findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical findings are more likely to be diagnosed using genomic testing (see Option 2). Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas genomic testing does not. Molecular genetic testing approaches can include a combination of gene-targeted testing ( CHD7 single-gene testing, multigene panel) and comprehensive genomic testing ( chromosomal microarray, exome sequencing, exome array, genome sequencing) depending on the phenotype. ![]() (2) Identification of a heterozygous CHD7 variant of uncertain significance does not establish or rule out the diagnosis. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and " likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. The diagnosis of CHD7 disorder is established in a proband with suggestive clinical and imaging findings and a heterozygous pathogenic (or likely pathogenic) variant in CHD7 identified by molecular genetic testing (see Table 1). Once the CHD7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. 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. 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. In rare instances, an individual with CHD7 disorder inherits a pathogenic variant from a heterozygous parent. Despite these complications, the life expectancy for many individuals can be normal.ĬHD7 disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant. 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. 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. 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. 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). 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.
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