Cochlear nerve deficiency in SOX11-related Coffin-Siris syndrome

The phenotypic spectrum of SOX11-related Coffin-Siris syndrome (CSS) is expanding with reports of new associations. SOX11 is implicated in neurogenesis and inner ear development. Cochlear nerve deficiency, absence or hypoplasia, is commonly associated with cochlear canal stenosis or with CHARGE syndrome, a monogenic condition that affects inner ear development. SOX11 is a transcription factor essential for neuronal identity, highly correlated with the expression of CHD7, which regulates SOX11. We present two unrelated probands, each with novel de novo SOX11 likely pathogenic variants and phenotypic manifestations of CSS including global developmental delay, growth deficiency, and hypoplastic nails. They have unilateral sensorineural hearing loss due to cochlear nerve deficiency confirmed on MRI. SOX11 is implicated in sensory neuron survival and maturation. It is highly expressed in the developing inner ear. Homozygous ablation of SOX11 in a mouse model resulted in a reduction in sensory neuron survival and decreased axonal growth. A heterozygous knockout mice model had hearing impairment with grossly normal inner ear structures like the two probands reported. We propose cochlear nerve deficiency as a new phenotypic feature of SOX11-related CSS. Magnetic resonance imaging is useful in delineating the cochlear nerve deficiency and other CSS-related brain malformations.