Within this clinical diversity of developmental disorders, a major unanswered question is whether pathogenic variants in genes other than CHD7 might explain the genetic etiology in individuals not previously diagnosed with CHD7 pathogenic variants. 5, 6, 7, 8 This clinical variability highlights the importance of genetic testing in diagnosis of developmental syndromes. 4 While there is minimal clinical overlap between individual CHD-related disorders, a number of syndromes that mimic CHARGE have been described, including 22q11 deletion syndrome (MIM 188400), Kabuki syndrome (MIM 147920, 300867), renal coloboma syndrome (MIM 610536), and mandibulofacial dysostosis (MIM 610536). The same pathogenic CHD7 variant within a single family can present with disparate features, ranging from multiple organ system involvement to mild developmental delay or isolated clefting and hearing loss. Pathogenic variants in CHD genes are characterized by variable expressivity and reduced penetrance. Pathogenic variants in CHD4 are implicated in Sifram–Hitz–Weiss syndrome (MIM 617159), and CHD8 is an important genetic risk factor for a subtype of autism spectrum disorders (MIM 615032). Despite similarities in protein domain structure between CHD family members, individual CHD genes are associated with clinically distinct syndromes. 3 However, a pathogenic variant in CHD7 cannot be found in up to 30% of individuals with clinical features of CHARGE syndrome, suggesting other genes or pathologies may be involved in a subset of cases.ĬHARGE syndrome is one of several multiorgan developmental disorders attributed to pathogenic variants in genes encoding chromatin remodelers of the CHD family.
2 CHARGE syndrome can be caused by heterozygous pathogenic variants in CHD7, encoding chromodomain helicase DNA binding protein 7, an adenosine triphosphate–dependent chromatin remodeler. 1 It occurs in about 1 in 10,000 births worldwide. Individuals with CHARGE syndrome present with a combination of distinct findings such as coloboma of the eye, choanal atresia, cleft palate, vestibular abnormalities, cranial nerve and other brain anomalies, and characteristic dysmorphology particularly of the ear and face. CHARGE syndrome (MIM 214800) is an autosomal-dominant multiple congenital anomaly condition. De novo pathogenic variants in genes that encode chromatin effectors are important for developmental transcriptional plasticity and make important genetic contributions to developmental disorders. Additionally, they implicate a shared molecular pathology that disrupts epigenetic regulation of multiple-organ development.Įpigenomic regulation is essential for human development. These results demonstrate that the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes. The remaining eight (28.6%) individuals were not found to have pathogenic variants by WES.
A variant of uncertain clinical significance in KDM6A was identified in one (3.5%) individual. Pathogenic variants in CHD7 were present in 15 of 28 individuals (53.6%), whereas 4 (14.3%) individuals had pathogenic variants in other genes ( RERE, KMT2D, EP300, or PUF60). We performed whole-exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome. However, no causal variant can be found in 5–30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome. Pathogenic variants in CHD7, encoding adenosine triphosphate–dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals.
CHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures.
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