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Congenital heart defects in CHARGE syndrome

News

Feb. 2014: The cause of brain defects in CHARGE syndrome identified.

Projects

Congenital heart defects are reported in 66-92% of patients with CHARGE syndrome. In order to establish the prevalence and spectrum of congenital heart defects in our cohort of patients with a proven CHD7 mutation, we collected clinical information on 299 patients and found that 220 (74%) had a congenital heart defect. Various types of heart defects were present, but a relatively high number of atrioventricular septal defects (AVSDs) and conotruncal defects were found. This project was funded by Fonds NutsOhra.

The clinical overlap between CHARGE and 22q11.2 deletion syndrome

CHARGE syndrome shows clinical overlap with several other genetic syndromes. This is most obvious with the 22q11.2 deletion syndrome. Overlapping features include congenital heart defects, cleft palate, ear abnormalities, hearing loss, growth deficiency, developmental delay, renal abnormalities, hypocalcaemia and immune deficiency.

We studied 22q11.2 deletions in patients presenting with clinical typical CHARGE syndrome and, conversely, we performed CHD7 analysis in patients suspected of 22q11.2 deletion syndrome and looked at 22q11.2 deletion features in a large cohort of patients with a CHD7 mutation. Our results show that the clinical diagnosis of these two highly variable syndromes is challenging. We therefore advise performing CHD7 analysis in patients suspected of 22q11.2 deletion syndrome but who do not have a 22q11.2 deletion. Similarly, we recommend performing a genome-wide array analysis with special focus on the 22q11.2 region in patients suspected of CHARGE syndrome but without a mutation in the CHD7 gene. Corsten-Janssen et al., Mol Syndromol. 2013;4(5):235-45

Guidelines for CHD7 diagnostics

Finding a CHD7 mutation has important implications for clinical surveillance and genetic counselling. It is therefore important to know which patients should be screened for a CHD7 mutation. We have drawn up a guideline for CHD7 analysis ( Bergman et al. 2011 ), and are studying patient groups who have a clinical overlap with CHARGE syndrome (as described above and below).

Missense mutations in CHD7: interpretation and clinical phenotype

Most pathogenic mutations found in CHD7 result in a truncated protein, while a minority are missense mutations. Besides pathogenic mutations, benign missense variants are also frequently found. Correct interpretation of missense variants is essential for genetic counselling, but can be difficult, especially since most CHD7 variants are unique and a functional assay is not yet available. To overcome this problem we have compiled a new classification system that can assist in predicting the effect of CHD7 missense variants in a diagnostic setting. We classified 145 CHD7 missense variants as either benign, pathogenic or unclassified variant (unknown pathogenicity). We also compared a group of patients with pathogenic missense mutations to a group of patients with truncating mutations, and found that the missense mutations are more often associated with a milder phenotype.

Mutation update on the CHD7 gene involved in CHARGE syndrome

Since 2004 we know that CHD7 mutations are the major cause of CHARGE syndrome and a lot has been learned. We reviewed all 528 pathogenic variants. Most variants are unique for a patient or family, but 94 were recurrent, predominantly arginine to stop codons. We summarized the latest data on CHD7 expression studies, animal models, and functional studies, and discussed the latest clinical insights into CHARGE syndrome. Janssen et al., Hum Mutat. 2012;33(8):1149-60

The clinical and pathogenetic overlap between CHARGE and Kallmann syndromes

CHARGE syndrome and Kallmann syndrome share many features, among which are delayed puberty (due to hypogonadotropic hypogonadism, HH) and inability to smell (anosmia). We hypothesised that patients with Kallmann syndrome could have undiagnosed CHARGE syndrome. We therefore performed CHD7 analysis in 36 patients with Kallmann syndrome and identified CHD7 mutations in three of them (8%). These patients were carefully re-examined and were all found to have additional features of CHARGE syndrome. Based on our results, we recommend performing CHD7 analysis in any patients with Kallmann syndrome who have at least two additional CHARGE features or semicircular canal anomalies. Bergman et al., JCEM, 2012; Jongmans et al., Clin Genet, 2009

We also investigated smell and pubertal development in a mouse model for CHARGE syndrome. We showed that a proportion of mice with a Chd7 mutation have a decreased smell and smaller reproductive organs. Surprisingly, the genetically identical (inbred) mice showed a large phenotypic variability. Bergman et al., EJHG, 2009
This project was funded by the Netherlands Organization of Health Research and Development (ZonMw 920-03-460) and GUIDE.

Smell and pubertal development in CHARGE syndrome

We studied smell and pubertal development in 35 patients with CHARGE syndrome aged 10 years or older. We showed that anosmia (inability to smell) and hypogonadotropic hypogonadism (delayed/absent puberty) were 100% correlated in our cohort; therefore smell testing seems an attractive method to predict absence of puberty in CHARGE patients. This is a way to prevent delay in inducing puberty with hormone replacement treatment (HRT), resulting in an age-appropriate puberty. A timely start of HRT has a positive effect on the patient’s socio-emotional well-being, and can reduce the risk of related osteoporosis and cardiovascular disease (Bergman et al., J Pediatr, 2010).
This study was funded by the Netherlands Organization of Health Research and Development (ZonMw 920-03-460) and GUIDE.

Death in CHARGE syndrome after the neonatal period

We studied post-neonatal death in patients with CHARGE syndrome and collected medical data on seven children who had died unexpectedly. We analyzed which factors had contributed to their death. From our findings and a literature review, we suggest that swallowing problems, gastro-oesophageal reflux disease, respiratory aspiration and post-operative airway events are important contributors to post-neonatal death in CHARGE syndrome. We therefore advise that every CHARGE patient with feeding difficulties should be assessed by a multidisciplinary team and that surgical procedures should be combined whenever possible (Bergman et al., Clin Genet 2010).
In order to further unravel factors that might contribute to mortality in CHARGE syndrome, we are now conducting a study on adrenal and immunological functions (see Ongoing projects).

See Publications section for all the references given above.