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.
Highlights
The term brachydactyly (BD) is derived from the ancient Greek
We excluded bone morphogenetic receptor 1 b (BMPR1B) and growth/differentiation factor 5 (GDF5), which were found to cause Brachydactyly Type A2 (BDA2) in the previous studies [17,18,19,20,21], and mapped BDA2 to the locus within chromosome 20p12.3 because a strong linkage was observed between the BDA2 locus and the microsatellite markers in this chromosome region
The results of genome-wide scan showed that bone morphogenetic protein 2 (BMP2) is the only known gene in the candidate interval, i.e., this gene is located at 6.697–6.709 Mb within the candidate interval (6.65–7.61 Mb on chromosome 20p12.3)
Summary
The term brachydactyly (BD) is derived from the ancient Greek (brachy-: short; dactylos: digit). This term indicates the shortening of digits due to abnormal development of the phalanges and/or the metacarpals and may be accompanied by other hand malformations, such as syndactyly, polydactyly, reduction defects, or symphalangism [1]. BD can occur either as an isolated malformation or as part of a complex malformation syndrome. The isolated BDs are classified clinically into BDA-E and three other subgroups [3]. BD types have certain overlapping features, including hypoplasia/ aplasia of phalanges and abnormal interdigital joint formation, suggesting that the formations of phalanges and joints are linked on a developmental and molecular basis
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