PURPOSE. Pathologic myopia described as myopia accompanied by severe deformation of the eye besides excessive elongation of eye, is usually a genetic heterogeneous disorder characterized by extreme, familial, early-onset vision loss. However, the exact pathogenesis of pathologic myopia remains unclear. In this study, we screened a Han Chinese family with pathologic myopia to identify the causative mutation and explore the possible pathogenic mechanism based on evaluation of the biological functions of the mutation. METHODS.We identified the mutations in a family with pathologic myopia by single nucleotide polymorphism array combined with short tandem repeat microsatellite marker analysis and exome sequencing. Mutations were validated among family members by direct Sanger sequencing. The subcellular localization of the protein variant was investigated by immunofluorescence, and the stability of the mutant protein was determined by immunoblotting. Intracellular levels of adenosine triphosphate and reactive oxygen species and complex I activity were measured by traditional biochemical methods to determine the functional role of the disease-associated mutation.RESULTS. The novel missense mutation: c.798C>G (p.Asp266Glu) in NDUFAF7, cosegregated with the disease and the resulting amino acid substitution affected a highly conserved residue in its protein. The mutation D266E in NDUFAF7 impaired complex I activity, which resulted in decreased ATP levels in cultured cells. CONCLUSIONS.We propose that the heterozygous mutation (c.798C>G) in NDUFAF7 may contribute to the pathogenesis of pathologic myopia, possibly by interfering with the phototransduction cascade. Mitochondrial dysfunction during eye development may lead to pathologic myopia.Keywords: pathologic myopia, NDUFAF7, causative mutation H igh myopia is an extreme form of myopia, usually defined by an ocular axial length >26 mm or a refractive error < À6.00 diopters (D). High myopia is a leading cause of blindness worldwide, with a relatively high prevalence of 1% to 5% in Asian countries, and as high as 4.1% in China. [1][2][3][4] High myopia can be complicated by pathology in 8% of high myopia in that there might be other genetic variants that play a role in this process compared to high myopia without pathology.5-8 Pathologic myopia (PM) generally causes irreversible visual impairment, which involves not only elongation of the eye, but also characteristic pathologic changes in the retina, choroid, and sclera, such as posterior sclera staphyloma, macular degeneration, lacquer cracks, and chorioretinal atrophy.9 Pathologic myopia is highly heritable, and genetic linkage studies have identified over 20 loci for PM, with autosomal dominant, autosomal recessive, or X-linked recessive modes of inheritance. [10][11][12][13] More than 70 genes related to refractive variation have been screened out by association studies. 14 Furthermore, recent studies have indicated that environment is another factor influencing the growth of the eye.15 Environmental factors, such as ...

X-linked intellectual disability (XLID) has been associated with various genes. Diagnosis of XLID, especially for non-syndromic ones (NS-XLID), is often hampered by the heterogeneity of this disease. Here we report the case of a Chinese family in which three males suffer from intellectual disability (ID). The three patients shared the same phenotype: no typical clinical manifestation other than IQ score ≤ 70. For a genetic diagnosis for this family we carried out whole exome sequencing on the proband, and validated 16 variants of interest in the genomic DNA of all the family members. A missense mutation (c.710G > T), which mapped to exon 6 of the Rab GDP-Dissociation Inhibitor 1 (GDI1) gene, was found segregating with the ID phenotype, and this mutation changes the 237th position in the guanosine diphosphate dissociation inhibitor (GDI) protein from glycine to valine (p. Gly237Val). Through molecular dynamics simulations we found that this substitution results in a conformational change of GDI, possibly affecting the Rab-binding capacity of this protein. In conclusion, our study identified a novel GDI1 mutation that is possibly NS-XLID causative, and showed that whole exome sequencing provides advantages for detecting novel ID-associated variants and can greatly facilitate the genetic diagnosis of the disease.