Significance: Concerted action of thousands of proteins is required for the inner ear to convert acoustic waves into electrical signals for hearing. Many of these proteins are currently unknown. This study uses a genetic approach to identify FAM65B as a gene mutated in a family with sensorineural hearing loss. Characterization of FAM65B shows that it is a component of the plasma membrane of the stereocilia hair bundle, the essential organelle in which electrical signals originate in the inner ear. Thus, FAM65B is a previously unrecognized component of the inner ear that is crucial for hearing.

Significance: The inner ear is a vertebrate organ of delicate and complex architecture that translates sound into electrical signals deciphered by the brain. This study utilizes a genetic approach to associate a mutation ofROR1(receptor tyrosine kinase-like orphan receptor 1) with inner ear anomalies and deafness in humans. Characterization ofRor1mutant mice reveals fasciculation deficiencies of spiral ganglion axons and disruption of sensory hair cell synapses and peripheral innervations. The molecular basis of this phenotype involves alterations of the NF-κB pathway. Thus, we presentROR1as a previously unrecognized gene that is essential for the development of the inner ear and hearing in humans and mice.

2q23.1 microdeletion syndrome is characterized by intellectual disability, motor delay, autistic‐like behaviors, and a distinctive craniofacial phenotype. All patients carry a partial or total deletion of methyl‐CpG‐binding domain protein 5 ( MBD5 ), suggesting that haploinsufficiency of this gene is responsible for the phenotype. To confirm this hypothesis and to examine the role of MBD5 in vivo, we have generated and characterized an Mbd5 gene‐trap mouse model. Our study indicates that the Mbd5 ^{+/ GT} mouse model recapitulates most of the hallmark phenotypes observed in 2q23.1 deletion carriers including abnormal social behavior, cognitive impairment, and motor and craniofacial abnormalities. In addition, neuronal cultures uncovered a deficiency in neurite outgrowth. These findings support a causal role of MBD5 in 2q23.1 microdeletion syndrome and suggest a role for MBD5 in neuronal processes. The Mbd5 ^{+/ GT} mouse model will advance our understanding of the abnormal brain development underlying the emergence of 2q23.1 deletion‐associated behavioral and cognitive symptoms.