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The cardiac phenotype in patients with a CHD7 mutation
Nicole Corsten-Janssen1, Wilhelmina S Kerstjens-Frederikse, Gideon J du Marchie Sarvaas
1Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Insights
Mutations in CHD7 cause CHARGE syndrome, leading to various heart defects in 74% of patients. Atrioventricular septal and conotruncal defects are more common in these individuals.
Area of Science:
- Genetics
- Developmental Biology
- Cardiology
Background:
- Loss-of-function mutations in CHD7 are linked to CHARGE syndrome, a condition characterized by multiple congenital anomalies including heart defects.
- While heart defects are common in CHARGE syndrome (70-92%), detailed classification and large cohort studies are limited.
- This study provides a comprehensive analysis of the cardiac phenotype in a large cohort of patients with CHD7 mutations.
Purpose of the Study:
- To describe the detailed cardiac phenotype in a large cohort of patients with CHD7 mutations.
- To investigate the role of CHD7 in cardiac development.
- To compare the spectrum of heart defects in CHD7 mutation patients with nonsyndromic congenital heart defects.
Main Methods:
- Collected data on congenital heart defects in 299 patients with pathogenic CHD7 mutations.
- Detailed cardiac defect information was available for 202 patients.
- Classified heart defects based on embryonic development and compared with 1007 nonsyndromic heart defects from the EUROCAT registry.
Main Results:
- Congenital heart defects were present in 74% (220/299) of patients with CHD7 mutations.
- Atrioventricular septal defects and conotruncal heart defects were significantly over-represented in patients with CHD7 mutations compared to nonsyndromic controls.
- Truncating CHD7 mutations were associated with a higher incidence of heart defects than missense or splice-site mutations.
Conclusions:
- CHD7 plays a critical role in cardiac development, as evidenced by the wide spectrum of heart defects observed in 74% of patients with CHD7 mutations.
- Conotruncal and atrioventricular septal defects are disproportionately common in individuals with CHD7 mutations.
- Further research into CHD7's function in heart development is warranted.
Background:
Loss-of-function mutations in CHD7 cause Coloboma, Heart Disease, Atresia of Choanae, Retardation of Growth and/or Development, Genital Hypoplasia, and Ear Abnormalities With or Without Deafness (CHARGE) syndrome, a variable combination of multiple congenital malformations including heart defects. Heart defects are reported in 70% to 92% of patients with a CHD7 mutation, but most studies are small and do not provide a detailed classification of the defects. We present the first, detailed, descriptive study on the cardiac phenotype of 299 patients with a CHD7 mutation and discuss the role of CHD7 in cardiac development.
Methods And Results:
We collected information on congenital heart defects in 299 patients with a pathogenic CHD7 mutation, of whom 220 (74%) had a congenital heart defect. Detailed information on the heart defects was available for 202 of these patients. We classified the heart defects based on embryonic cardiac development and compared the distribution to 1007 equally classified nonsyndromic heart defects of patients registered by EUROCAT, a European Registry of Congenital Anomalies. Heart defects are highly variable in patients with CHD7 mutations, but atrioventricular septal defects and conotruncal heart defects are over-represented. Sex did not have an effect on the presence of heart defects, but truncating CHD7 mutations resulted in a heart defect significantly more often than missense or splice-site mutations (χ², P<0.001).
Conclusions:
CHD7 plays an important role in cardiac development, given that we found a wide range of heart defects in 74% of a large cohort of patients with a CHD7 mutation. Conotruncal defects and atrioventricular septal defects are over-represented in patients with CHD7 mutations compared with patients with nonsyndromic heart defects.
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