Identification Of The Causative Mutation Of A Family With Congenital Brachydactyly Type A2

Brachydactyly type A2(BDA2)is a rare autosomal dominant disorder.The main manifestation of BDA2 is the radial deviation of the distal phalanx/phalange of second finger/toe,which brings about functional and aesthetic problems.By now,the pathogenic mutation of a large number of BDA2 families remains unknown.We found a large BDA2 family and recruited 10 patients and 7 unaffected members from the outpatient department.The clinical and radiographic presentations were identified.The peripheral blood samples were collected from all the available family members.We performed wholeexome sequencing to search for causative mutation.According to the previous studies,we chose BMPR1 B,GDF5 and BMP2 as candidate genes and performed Sanger sequencing on them.We also screened for duplications in the downstream region of BMP2 gene.A novel 4671 bp duplication downstream the BMP2 gene was identified in all the patients undergoing molecular analysis but not in the unaffected individuals and 100 healthy controls,with a pair of 28 bp microhomology flanking it.There was no mutation in all the exons of BMPR1 B,GDF5,and BMP2 in all the tested family members.We identify a novel duplication downstream the BMP2 gene,which has different breakpoints and flanking microsatellite markers compared to the previous ones,though highly overlapped with them.Our finding expands the mutation spectrum of BDA2 and narrows the range of the potential cisregulatory sequence downstream BMP2 gene.Congenital insensitivity to pain with anhidrosis(CIPA)is a rare autosomal recessive disorder resulting from NTRK1 mutation,which is the only causative gene of it.The NTRK1 mutations lead to loss of function of the TrkA protein,causing defects in the NGF-dependent neurons,and therefore induce various clinical phenotypes such as insensitivity to pain,anhidrosis,immune defects and mental retardation.Three patients from unrelated families with CIPA were subjected to detailed clinical examinations involving medical history,physical signs,radiology and laboratory examinations.Blood samples were collected from all the patients and their parents,as well as 200 healthy volunteers.Sanger sequencing for all the exons and splicing sites of NTRK1 was performed on all samples.The conservation and pathogenicity of the identified mutations were analyzed,as well as the phenotype-genotype relationship and the genetic epidemiology of Chinese CIPA patients.A total of four different NTRK1 mutations [c.851-33T>A,c.44G>A(p.Trp15*),c.287+2dupT,c.1549G>C(p.Gly517Arg)] were identified in these families,and c.1549G>C(p.Gly517Arg)was a novel mutation that had not been reported previously.The ‘mild’ manifestations observed in patients with c.851-33T>A indicated this mutation as a ‘mild’ mutation.After reviewing studies reporting mutations in Chinese CIPA patients,we speculate the mutation c.851-33T>A is one of the founder mutations in the Chinese population.Our research expanded the spectrum of the NTRK1 mutations associated with CIPA patients,provided additional clues relating to the phenotype-genotype relationship in CIPA,and summarized the features of the genetic epidemiology of CIPA in the Chinese ethnic group.