先天性小耳畸形染色体变异及相关基因的研究

Objective To find the chromosomal malfomations among microtia patients and the neighbouring genes of chromosomal aberrations or genes in the extra or deleted chromosome fragments would be screened to investigate the possible causative genes. Methods According to the inclusion criteria, case group was selected from microtia patients referred to Plastic Surgery Hospital, Chinese Academy of Medical Science, between January 2012 and January 2014, and the control group was the normal people of similar age received plastic surgery in the same hospital in the same time who did not have any congenital genetic disease. Blood samples of two groups were collected, and genomic DNA was extracted, then copy number variation (CNV) analysis was performed in the two groups with gene chip technology and associated software for large fragment chromosomal malformations. The variations of chromosome copy number were recorded to further analyze the type and length of chromosome structure variation. The genes at the loci of break points were further screened referring to B allele frequency to interpret associated genes related to the occurrence of microtia. Fisher exact test were used for statistical analysis, and the difference was statistically significant (P< 0. 05). Results 942 patients with congenital microtia were included in the case group, 695 males and 247 females, aged (11. 4±3. 2) years; 1 802 normal controls, 1 290 males and 512 females, aged (11. 6±4. 9) years. Large chromosomal fragments variations were detected in 5 patients in chromosome in case group (P = 0. 003). The difference between the two groups was statistically significant(P= 0. 003). Three cases were found to carry an extra X chromosome. Among the 3 cases, one patient suffered from XXY karyotype and the other 2 patients X trisomy. Two cases were proved to be associated with chromosome structural variations. The malformations of the first case presented partial duplication of the long arm of chromosome 13 and 14. On searching for causative genes, OTX2, BMP4 and GSC were detected to be in the chromosome structural variations. The second case presented to be partial duplication of the long arm of chromosome 5. FGF pathway associated genes FGF18, FGFR4, FGF1 and BMP pathway associated genes FST, MSX2, SMAD5 were incorporated in the extra duplicated chromosome for possible gene dosage effect. Conclusions The results indicated the possible association of chromosome abnormity and microtia and provide new insights in microtia-associated chromosome instability. Ten related genes were involved in the occurrence of microtia through various ways.