Identification of duplication downstream of BMP2 in a Chinese family with brachydactyly type A2 (BDA2).
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.
Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China.
Xudong
X
Liu
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
Linghan
L
Gao
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
Aman
A
Zhao
Department of Genetics and Molecular Biology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China; Xi'an Hong Hui Hospital, the Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China.
Rui
R
Zhang
Department of Psychiatry, School of Medicine, University of California San Diego, San Diego, California, United States of America.
Baohu
B
Ji
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
Lei
L
Wang
Department of Medicine, the University of Chicago, Chicago, Illinois, United States of America.
Yonglan
Y
Zheng
Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China.
Bingfang
B
Zeng
Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Robert K
RK
Valenzuela
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
Lin
L
He
Department of Genetics and Molecular Biology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China; Department of Psychiatry, School of Medicine, University of California San Diego, San Diego, California, United States of America.
Jie
J
Ma
D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D059327:Brachydactyly / Q000235:genetics*; D056905:Chromosome Breakpoints; D005260:Female; D020440:Gene Duplication; D055428:Growth Differentiation Factor 5 / Q000235:genetics; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C525893:GDF5 protein, human; D055428:Growth Differentiation Factor 5; C498214:BMPR1B protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I