Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures

Abstract

The inner ear contains the sensory organs for hearing and balance. Both hearing and balance are commonly affected in individuals with CHARGE syndrome (CS), an autosomal dominant condition caused by heterozygous pathogenic variants in the CHD7 gene. Semicircular canal dysplasia or aplasia is the single most prevalent feature in individuals with CHARGE leading to deficient gross motor skills and ambulation. Identification of CHD7 as the major gene affected in CHARGE has enabled acceleration of research in this field. Great progress has been made in understanding the role of CHD7 in the development and function of the inner ear, as well as in related organs such as the middle ear and auditory and vestibular neural pathways. The goals of current research on CHD7 and CS are to (a) improve our understanding of the pathology caused by CHD7 pathogenic variants and (b) to provide better tools for prognosis and treatment. Current studies utilize cells and whole animals, from flies to mammals. The mouse is an excellent model for exploring mechanisms of Chd7 function in the ear, given the evolutionary conservation of ear structure, function, Chd7 expression, and similarity of mutant phenotypes between mice and humans. Newly recognized developmental functions for mouse Chd7 are shedding light on how abnormalities in CHD7 might lead to CS symptoms in humans. Here we review known human inner ear phenotypes associated with CHD7 pathogenic variants and CS, summarize progress toward diagnosis and treatment of inner ear-related pathologies, and explore new avenues for treatment based on basic science discoveries.

Approaches for the study of epigenetic modifications in the inner ear and related tissues

“…One such example CHD7, a chromodomain helicase that is recruited to enhancer regions of DNA and positively correlates with transcription factor recruitment and gene activation, is recruited to the DNA by H3K4me (Schnetz et al, 2010). As mutations in CHD7 are a known cause of CHARGE syndrome, which can result in hearing loss and vestibular dysfunction, there are a number of articles that have examined the role of CHD7 in the development and function of auditory and vestibular tissues (Choo et al, 2017;Green et al, 2014;Micucci et al, 2014;Yao et al, 2018). Review of these and other articles pertaining to histone related proteins are beyond the scope of this already extensive review.…”

Imaging of inner ear malformations: a primer for radiologists

“…Dysplasia of the SSCs is more frequent than aplasia. The absence of all semicircular ducts with normal cochlea occurs commonly in CHARGE syndrome [33][34][35][36], while patients with Waardenburg syndrome and Alagille syndrome show isolated aplasia of the posterior semicircular duct [33]. CT scans are important for corroborating the diagnosis of SCC aplasia and differentiating it from fibrous or calcified obliteration of the canals.…”

Neural crest contributions to the ear: Implications for congenital hearing disorders

“…The past decade of research has revealed critical roles for epigenetic factors, including chromatin remodelers and DNA methyltransferases, in neural crest development. Indeed, multiple neurocristopathies affecting ear development and hearing are caused by loss of function of epigenetic factors, including CHARGE syndrome (CHD7, (Choo et al, 2017;Vissers et al, 2004)), Kabuki syndrome (KMT2D, (Bogershausen and Wollnik, 2013)), Williams syndrome (WSTF, (Barnett et al, 2012)), and Brachydactyly Mental Retardation syndrome (HDAC4, (Williams et al, 2010)). However, the specific roles of epigenetic factors in NC derivatives in the ear are largely unknown.…”

“…Middle ear cavitation and ossicles (Church et al, 2007;Farlie et al, 2016;Goh et al, 2018) Mandibulofacial dysostosis with alopecia (MFDA)…”