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Miles–Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in  ZC4H2 , was identified in a XLID re-sequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three  ZC4H2  mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features.  In silico  modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in  zc4h2  were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specific markers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt  ZC4H2  rescued the mutant phenotype. Mutant zebrafish injected with human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support  ZC4H2  as a novel XLID gene with a required function in interneuron development. Loss of function of  ZC4H2  thus likely results in altered connectivity of many brain and spinal circuits.

ZC4H2 , an XLID gene, is required for the generation of a specific subset of CNS interneurons