Rare genetic variations in MEPE are associated with otosclerosis and craniofacial bone disorder with facial paresis and mixed hearing loss

Craniofacial bone disorders comprise a group of diseases caused by abnormal growth and/or development of the head and facial bones, and can be associated with hearing loss due to abnormalities of the outer, middle or inner ear. In this study, we identified a heterozygous frameshift variant c.1273delC (p.Gln425Lysfs*38) in the MEPE gene in a family with non-progressive Hereditary Congenital Facial Paresis (HCFP) and mixed conductive-sensorineural hearing loss associated with diploic thickening and sclerosis of the skull. MEPE encodes a matrix extracellular phosphoglycoprotein and plays an inhibitory role in bone mineralization. Next, we hypothesized that this gene might also be important in otosclerosis bone remodeling disorder and screened for mutations in MEPE in 91 individuals with familial otosclerosis. We identified an additional heterozygous frameshift variant, c.199_202delGAAA (p.Lys70Ilefs*26), that segregated with the phenotype in two apparently unrelated families with otosclerosis, albeit with some reduced penetrance which is typically observed in otosclerosis families. Furthermore, we screened 1398 unrelated cases with otosclerosis and 1447 ethnically-matched controls. We observed the rare c.209_212del frameshift variant in eight affected individuals with otosclerosis only. None of the controls carried this variant (Fisher’s Exact p = 0.003). Two other rare variants (c.184G>T: p.Glu62* and c.229G>A: p.Ala77Thr) were identified in cases and not in controls (cumulative Fisher’s Exact p = 0.0008). Our results pinpoint MEPE as a key player in temporal bone and middle ear mineralization, which is involved in the pathogenesis of otosclerosis and other craniofacial bone disorders associated with mixed hearing loss.