A novel EBP c.224T>A mutation supports the existence of a male-specific disorder independent of CDPX2.

Mutations in the Emopamil-binding protein (EBP) gene cause X-linked dominant chondrodysplasia punctata 2 (CDPX2), a disorder in which at least 95% of liveborn individuals are female and male intrauterine lethality is assumed. Several affected males with mutations in EBP have been reported. These males exhibit a phenotype similar to CDPX2 due to either somatic mosaicism or a 47, XXY karyotype in association with a null EBP allele. Alternatively, affected males may exhibit a distinct phenotype if they are hemizygous for a hypomorphic allele of EBP. Recently, we described a novel X-linked phenotype associated with digital abnormalities, intellectual disability and short stature, and mapped it to Xp11.4-p11.21. X-exome sequencing was performed to identify the mutated gene responsible for this phenotype. A novel missense variant, c.224T>A (p.I75N), was identified in EBP. SIFT and PolyPhen-2 predicted this change to be deleterious. The pathogenicity of this variant was subsequently supported by increased plasma levels of 8(9)-cholestenol in the proband and his mother. The molecular and biochemical evidence convincingly supports the pathogenicity and association of the p.I75N mutation with this newly described phenotype. This study expands the current phenotypic spectrum of males with hypomorphic EBP mutations and supports to the hypothesis that there exists an X-linked recessive entity independent of CDPX2.