Genetic disorders with both hearing loss and cardiovascular abnormalities

There has been a growing appreciation for conditions that affect hearing and which are accompanied by significant cardiovascular disorders. In this chapter we consider several broad classes of conditions including deafness due to abnormal structural development of the inner ear, those with physiological abnormalities in the inner ear sensory apparatus, and conditions with progressive loss of function of sensory cells or middle ear functions. Because of shared developmental controls, inner ear malformations are often associated with congenital heart defects and can be part of complex syndromes that affect other organs and neurodevelopmental outcome. Physiological disorders of the hair cells can lead to hearing loss and can be associated with cardiac arrhythmias, especially long QT syndrome. In addition, cellular energy defects such as mitochondrial disorders can affect maintenance of hair cells and are often associated with cardiomyopathy. Lysosomal storage diseases and other disorders affecting connective tissue can lead to chronic middle ear disease, with conductive hearing loss and also cause cardiac valve disease and/or cardiomyopathy. The genetic basis for these conditions is heterogeneous and includes chromosomal/genomic disorders, de novo dominant mutations, and familial dominant, autosomal-recessive, and mitochondrial (matrilineal) inheritance. Taken together, there are more than 100 individual genes implicated in genetic hearing impairment that are also associated with congenital and/or progressive cardiac abnormalities. These genes encode transcription factors, chromatin remodeling factors, components of signal transduction pathways, ion channels, mitochondrial proteins and assembly factors, extracellular matrix proteins, and enzymes involved in lysosomal functions.