Here, we review the range of congenital heart defects and the molecular effects of CHD7 on cardiovascular development that lead to an over-representation of atrioventricular septal, conotruncal, and aortic arch defects in CHARGE syndrome.
We hypothesize that a germline mutation in CHD7 or other similar regulatory gene causative of CHARGE syndrome and craniofacial developmental abnormalities may have contributed to the unusual location of the teratoma in this case.
We found that chd7 heterozygous mutants exhibited anxious-like behavior and aggressive-like behavior in the open-field test and in the mirror-induced attack test, respectively, which resembled the reported behavioral abnormalities in CHARGE syndrome in humans.
CHARGE syndrome (CS) is a multiple congenital anomalies condition with the majority of cases caused by dominant loss-of-function mutations of the CHD7 gene.
Simultaneously, a de novo splicing acceptor alteration in c.7165-4 A>G, in chromodomain helicase DNA binding protein-7 (CHD7), located in chromosome 8q12 was detected, and the patient was diagnosed with 21-OHD and CS.
Point mutations in the CHD7 gene are causal in CHARGE syndrome (a developmental disorder causing coloboma, heart defects, atresia choanae, retardation of growth, and genital and ear anomalies) and interrupt the epigenetic functions of CHD7 in regulating neural stem cell maintenance and development.
We aimed to investigate the phenotype spectrum of neonatal patients suspected to have CHARGE syndrome with pathogenic or likely pathogenic variants in the CHD7 gene.
For this cross-sectional study, we selected 32 children with CS and a CHD7 mutation at the Dutch CHARGE Family Day in 2016 or 2017 and the International CHARGE conference in Orlando, Florida, in 2017.
The 4 known diseases were Opitz G/BBB syndrome caused by MID1 gene mutation, Loeys‑Dietz syndrome caused by TGFBR1 gene mutation, Ritscher‑Schinzel/3C syndrome caused by KIAA0196 gene mutation and CHARGE syndrome caused by CHD7 gene mutation.
The CHD7 gene is a member of the chromodomain helicase DNA-binding family and, when mutated, has been shown to be the cause of the CHARGE syndrome, a severe developmental human disorder.
Mutations in the CHD7 gene cause CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital hypoplasia and Ear abnormalities), but have also been found in patients with isolated CHH.
In addition to these neurodevelopmental features, a wide range of other developmental defects are associated with mutants of these genes, especially with regards to CHD7 haploinsufficiency, which is the primary cause of CHARGE syndrome.
In addition to our seven previously reported cases, we identified an additional six with 22q11.2DS and another coexisting condition identified via: molecular/cytogenetic studies, newborn screening, coagulation factor studies, or enzyme testing; these include CHARGE syndrome (CHD7 mutation), cystic fibrosis, a maternally inherited 17q12 deletion, G6PD deficiency, von Willebrand disease, and 1q21.1 deletion, resulting in an incidence of dual diagnoses at our center of 0.9%.
Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.
Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome.
In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE-neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome.