Genetic analysis of CHARGE syndrome identifies overlapping molecular biology

Abstract

Purpose CHARGE syndrome is an autosomal dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding ATP-dependent Chromodomain Helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome. Methods We performed whole exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome. Results Pathogenic variants in CHD7 were present in 15 of 28 individuals (53.6%), whereas four(14.3%) individuals had pathogenic variants in other genes (RERE, KMT2D, EP300, or PUF60). A variant of uncertain clinical significance in KDM6A was identified in one (3.5%) individual. The remaining eight (28.6%)individuals were not found to have pathogenic variants by WES. Conclusion These results demonstrate that the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes. Additionally, they implicate a shared molecular pathology that disrupts epigenetic regulation of multiple-organ development.

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, ).…”

“…CHD7 and TBX1 (the locus associated with 22q11.2 DS specific cardiac defects [Lindsay et al, ; Merscher et al, ]) are synergistic in cardiac phenotypes of CHARGE (Randall et al, ) and both are partially mediated through effects on p53 (Caprio & Baldini, ; Van Nostrand et al, ). There is also an overlap of Kabuki syndrome, which is caused with pathogenic variations in lysine‐specific chromatin modifiers ( KMT2D , OMIM 602113 and KDM6A , OMIM 300128), which operate through the same chromatin remodeling machinery as CHD7 and can lead to CHD7 ‐negative CHARGE syndrome (Butcher et al, ; Moccia et al, ; Sakata et al, ; Schulz et al, ). Chromatin and abnormal methylation patterning are also implicated in multifactorial causes of conotruncal defects (Radhakrishna et al, ).…”

“…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, ).…”

“…Given the range of pathogenic variants seen in CHARGE syndrome (Moccia et al, 2018;Zentner et al, 2010) (2013) and Corsten-Janssen, Saitta, et al (2013). (Aramaki et al, 2006;Blake, Russell-Eggitt, Morgan, Ratcliffe, & Wyse, 1990;Busa et al, 2016;Corsten-Janssen, Kerstjens-Frederikse, et al, 2013;Corsten-Janssen, Saitta, et al, 2013;Cyran, Martinez, Daniels, Dignan, & Kaplan, 1987;Gennery et al, 2008 (Bergman et al, 2011;Corsten-Janssen, Kerstjens-Frederikse, et al, 2013;Corsten-Janssen, Saitta, et al, 2013;Hale et al, 2016;Legendre et al, 2017;Vissers et al, 2004;Zentner et al, 2010).…”

Clinical characterization of aPUF60variant in a patient with Dubowitz‐like syndrome

“…disease, ocular coloboma, renal and spinal anomalies. Patients have been described with either single-site variants or deletions involving the PUF60 gene (Dauber et al, 2013;El Chehadeh et al, 2016;Graziano et al, 2017;Low et al, 2017;Moccia et al, 2018;Santos-Simarro et al, 2017;Zhao et al, 2018). Of those, seven patients were described in the DECIPHER database (Firth et al, 2009) with 8q24.3 microdeletion syndrome or Verheij syndrome (MIM# 615583).…”