Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome

Abstract

International audienceCHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (2006). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent

Fetal MRI findings in a retrospective cohort of 26 cases of prenatally diagnosed CHARGE syndrome individuals

“…Among postnatal criteria for CS, our study confirms that arhinencephaly (ARh) and semicircular canal agenesis (SCA) can be observed prenatally in the vast majority of cases, as they were present in 100% and 92.3% of cases, respectively, corroborating recent literature . MRI demonstrates a high rate of detection of both criteria (100%), whereas ultrasound tends to be less sensitive (ARh, 38.4%; SCA, 33.3%).…”

“…Isolated or multiple congenital anomalies were only detected in 58% of the pregnancies. The most recent study of Legendre et al reported an estimated incidence of detected prenatal anomalies in 46.6% in their 116 postnatal cases. The most frequent isolated features were described by ultrasonography and included heart defects, cleft lip and palate, polyhydramnios, and growth restriction.…”

Congenital heart defects in CHARGE: The molecular role of CHD7 and effects on cardiac phenotype and clinical outcomes

“…Given the range of pathogenic variants seen in CHARGE syndrome (Moccia et al, ; Zentner et al, ), it is important to understand the impact of causative CHD7 variants on the CHARGE syndrome cardiac phenotype. Within the spectrum of CHD in CHARGE syndrome, there appears to be no significant difference in presence of CHD in patients with or without a CHD7 pathogenic variant (Bergman et al, ; Corsten‐Janssen, Kerstjens‐Frederikse, et al, ; Corsten‐Janssen, Saitta, et al, ; Hale et al, ; Legendre et al, ; Vissers et al, ; Zentner et al, ). However, some larger series suggest an increase in congenital heart disease in CHD7 ‐positive patients (66–92%) compared to 71% of CHD7 ‐negative patients (Jongmans et al, ; Jyonouchi, McDonald‐McGinn, Bale, Zackai, & Sullivan, ; Lalani et al, ).…”

“…The primary limitation of these data to detect more detailed genotype–phenotype relationships is the sample size in individual studies. The growing repository of large cohort studies that collect the cardiac phenotype and presence of CHD7 variant or CHD7 variant type (truncating or nontruncating; Corsten‐Janssen, Kerstjens‐Frederikse, et al, ; Corsten‐Janssen, Saitta, et al, ; Jongmans et al, ; Lalani et al, ; Legendre et al, ; Vissers et al, ; Wincent et al, ) should allow for pooling of these large datasets for more detailed meta‐analysis. However, the overlap of pathogenic variant data and congenital heart defect phenotype is not routinely presented in most studies, which prevents data aggregation and meta‐analysis and argues for publication of supplemental datasets including this information.…”

“…The primary features of CHARGE—ocular coloboma (C), heart malformations (H), atresia of the choanae (A), retardation of growth (R), genital hypoplasia (G), and ear abnormalities (E)—form an acronym that serves as the name of the condition. CHARGE was subsequently defined as a syndrome with the identification of autosomal dominant pathogenic variants in the CHD7 gene in 2004 (Vissers et al, ), which occurs in 58–90% of patients with CHARGE syndrome (Jongmans et al, ; Lalani et al, ; Legendre et al, ; Zentner, Layman, Martin, & Scacheri, ). An additional spectrum of single gene pathogenic variants have been identified in individuals with the clinical features of CHARGE (Moccia et al, ).…”