Abstract
Brachydactyly type A2 (BDA2, MIM 112600) is characterized by the deviation and shortening of the middle phalange of the index finger and the second toe. Using genome-wide linkage analysis in a Chinese BDA2 family, we mapped the maximum candidate interval of BDA2 to a ∼1.5 Mb region between D20S194 and D20S115 within chromosome 20p12.3 and found that the pairwise logarithm of the odds score was highest for marker D20S156 (Zmax = 6.09 at θ = 0). Based on functional and positional perspectives, the bone morphogenetic protein 2 (BMP2) gene was identified as the causal gene for BDA2 in this region, even though no point mutation was detected in BMP2. Through further investigation, we identified a 4,671 bp (Chr20: 6,809,218-6,813,888) genomic duplication downstream of BMP2. This duplication was located within the linked region, co-segregated with the BDA2 phenotype in this family, and was not found in the unaffected family members and the unrelated control individuals. Compared with the previously reported duplications, the duplication in this family has a different breakpoint flanked by the microhomologous sequence GATCA and a slightly different length. Some other microhomologous nucleotides were also found in the duplicated region. In summary, our findings support the conclusions that BMP2 is the causing gene for BDA2, that the genomic location corresponding to the duplication region is prone to structural changes associated with malformation of the digits, and that this tendency is probably caused by the abundance of microhomologous sequences in the region.