CHARGE syndrome (Hall-Hittner syndrome) is inherited in an autosomal dominant manner, but in most cases it occurs sporadically with a frequency of about 1:10,000. The acronym CHARGE stands for coloboma, heart defects, atresia choanal, growth retardation, genital hypoplasia and ear abnormalities. According to Verloes (2005), the main criteria are colobomas, choanal atresia and semicircular canal hypoplasia, while secondary criteria are functional disorders of the brain stem, such as paresis in the area of the VII to VIII cranial nerves, deafness, disturbances of the hypothalamus-pituitary axis, which includes growth hormone and gonadotropins, abnormalities of the outer and middle ear, malformations of mediastinal organs, such as the heart and esophagus and intellectual disability. The diagnosis is correct if three main criteria or two main and two secondary criteria are present. There is wide clinical variability. Life expectancy depends on the severity of the abnormalities; up to one third of those affected die within the first six months of life. In most cases there is a psychomotor developmental delay, although occasionally intelligence is within the normal range.
Pathogenic variants in the CHD7 gene are found in 60 to 70 % of patients. (CHD: chromodomain, ATPase/helicase domain and a DNA-binding domain). CHD proteins, which belong to the family of chromatin remodeling factors, influence chromatin structure and gene expression and thus have an important function in embryonic development. The variants extend over the entire coding region (exons 2-38) of the CHD7 gene. In the majority of cases, they are truncating variants that lead to a premature termination of protein synthesis. In 1-2% of the cases there are deletions. There are no genotype-phenotype correlations. In at least one case, a germ cell mosaic has been detected, so that even where there in no evidence of a variant in the parents, a low risk of recurrence cannot be excluded.
Moccia et al. 2018, Genet Med 20:1022 / Butcher et al. 2017, Am J Hum Genet 100:773 / Hale et al. 2016, Am J Med Genet A 170:344 / Hsu et al. 2014, J Paediatr Child Health 50:504 / Schulz et al. 2014, Hum Genet 133:997 / Pauli et al. 2009, Clin Genet 75:473 / Wincent et al. 2009, Eur J Med Genet 52:271 / Sanlaville et al. 2007, Eur J Hum Genet 15:389 / Blake et al. 2006, OJRD 1:34 / Aramaki et al. 2006, J Pediatr 148:410 / Jongmans et al. 2006, J Med Genet 43:306 / Lalani et al. 2006, Am J Hum Genet 78:303 / Verloes et al. 2005, Am J Med Genet 133A:306 / Vissers et al. 2004, Nat Genet 36:955