Identification of a missense HOXD13 mutation in a Chinese family with syndactyly type I-c using exome sequencing

Deng,Hao; Tan,Ting; He,Quanyong; Lin,Qiongfen; Yang,Zhijian; Zhu,Anding; Guan,Liping; Xiao,Jingjing; Song,Zhi; Guo,Yi

doi:10.3892/mmr.2017.6576

Identification of a missense HOXD13 mutation in a Chinese family with syndactyly type I-c using exome sequencing

Authors:
- Hao Deng
- Ting Tan
- Quanyong He
- Qiongfen Lin
- Zhijian Yang
- Anding Zhu
- Liping Guan
- Jingjing Xiao
- Zhi Song
- Yi Guo
View Affiliations

Affiliations: Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China, Department of Burn and Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China, BGI‑Shenzhen, Shenzhen, Guangdong 518083, P.R. China, Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
Published online on: May 11, 2017 https://doi.org/10.3892/mmr.2017.6576
Pages: 473-477

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Syndactyly is one of the most common hereditary limb malformations, and is characterized by the fusion of specific fingers and/or toes. Syndactyly type I‑c is associated with bilateral cutaneous or bony webbing of the third and fourth fingers and occasionally of the third to fifth fingers, with normal feet. The aim of the present study was to identify the genetic basis of syndactyly type I‑c in four generations of a Chinese Han family by exome sequencing. Exome sequencing was conducted in the proband of the family, followed by direct sequencing of other family members of the same ancestry, as well as 100 ethnically‑matched, unrelated normal controls. A missense mutation, c.917G>A (p.R306Q), was identified in the homeobox D13 gene (HOXD13). Sanger sequencing verified the presence of this mutation in all of the affected family members. By contrast, this mutation was absent in the unaffected family members and the 100 ethnically‑matched normal controls. The results suggest that the c.917G>A (p.R306Q) mutation in the HOXD13 gene, may be responsible for syndactyly type I‑c in this family. Exome sequencing may therefore be a powerful tool for identifying mutations associated with syndactyly, which is a disorder with high genetic and clinical heterogeneity. The results provide novel insights into the etiology and diagnosis of syndactyly, and may influence genetic counseling and the clinical management of the disease.

View Figures

View References

1	Malik S: Syndactyly: Phenotypes, genetics and current classification. Eur J Hum Genet. 20:817–824. 2012. View Article : Google Scholar : PubMed/NCBI
2	Malik S, Schott J, Ali SW, Oeffner F, Amin-ud-Din M, Ahmad W, Grzeschik KH and Koch MC: Evidence for clinical and genetic heterogeneity of syndactyly type I: The phenotype of second and third toe syndactyly maps to chromosome 3p21.31. Eur J Hum Genet. 13:1268–1274. 2005. View Article : Google Scholar : PubMed/NCBI
3	Jordan D, Hindocha S, Dhital M, Saleh M and Khan W: The epidemiology, genetics and future management of syndactyly. Open Orthop J. 6:14–27. 2012. View Article : Google Scholar : PubMed/NCBI
4	Sobreira NL, Cernach MC, Brunoni D and Perez AB: Complex toe syndactyly with characteristic facial phenotype: A new syndrome? Am J Med Genet A. 146A:1725–1728. 2008. View Article : Google Scholar : PubMed/NCBI
5	Fujii S, Yabe K, Kimura Y, Ito Y, Rokukawa M, Furukawa M, Ito K, Matsuura M and Kiguchi M: Syndactyly lethal: New mutation with multiple malformations occurring in Sprague Dawley rats. Congenit Anom (Kyoto). 49:262–268. 2009. View Article : Google Scholar : PubMed/NCBI
6	Jamsheer A, Zemojtel T, Kolanczyk M, Stricker S, Hecht J, Krawitz P, Doelken SC, Glazar R, Socha M and Mundlos S: Whole exome sequencing identifies FGF16 nonsense mutations as the cause of X-linked recessive metacarpal 4/5 fusion. J Med Genet. 50:579–584. 2013. View Article : Google Scholar : PubMed/NCBI
7	Zhou X, Zheng C, He B, Zhu Z, Li P, He X, Zhu S, Yang C, Lao Z, Zhu Q and Liu X: A novel mutation outside homeodomain of HOXD13 causes synpolydactyly in a Chinese family. Bone. 57:237–241. 2013. View Article : Google Scholar : PubMed/NCBI
8	Zhao X, Sun M, Zhao J, Leyva JA, Zhu H, Yang W, Zeng X, Ao Y, Liu Q, Liu G, et al: Mutations in HOXD13 underlie syndactyly type V and a novel brachydactyly-syndactyly syndrome. Am J Hum Genet. 80:361–371. 2007. View Article : Google Scholar : PubMed/NCBI
9	Deng H and Tan T: Advances in the molecular genetics of non-syndromic syndactyly. Curr Genomics. 16:183–193. 2015. View Article : Google Scholar : PubMed/NCBI
10	Guo Y, Yuan L, Yi J, Xiao J, Xu H, Lv H, Xiong W, Zheng W, Guan L, Zhang J, et al: Identification of a GJA3 mutation in a Chinese family with congenital nuclear cataract using exome sequencing. Indian J Biochem Biophys. 50:253–258. 2013.PubMed/NCBI
11	Wang JL, Cao L, Li XH, Hu ZM, Li JD, Zhang JG, Liang Y San-A, Li N, Chen SQ, et al: Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain. 134:3490–3498. 2011. View Article : Google Scholar :
12	Shi Y, Li Y, Zhang D, Zhang H, Li Y, Lu F, Liu X, He F, Gong B, Cai L, et al: Exome sequencing identifies ZNF644 mutations in high myopia. PLoS Genet. 7:e10020842011. View Article : Google Scholar : PubMed/NCBI
13	Li R, Li Y, Kristiansen K and Wang J: SOAP: Short oligonucleotide alignment program. Bioinformatics. 24:713–714. 2008. View Article : Google Scholar : PubMed/NCBI
14	Hu J and Ng PC: SIFT Indel: Predictions for the functional effects of amino acid insertions/deletions in proteins. PLoS One. 8:e779402013. View Article : Google Scholar : PubMed/NCBI
15	Adzhubei I, Jordan DM and Sunyaev SR: Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet Chapter. 7:Unit 7.20. 2013. View Article : Google Scholar
16	Lei J, Deng X, Zhang J, Su L, Xu H, Liang H, Huang X, Song Z and Deng H: Mutation screening of the HDC gene in Chinese Han patients with Tourette syndrome. Am J Med Genet B Neuropsychiatr Genet. 159B:72–76. 2012. View Article : Google Scholar : PubMed/NCBI
17	Yuan L, Song Z, Xu H, Gu S, Zhu A, Gong L, Zhao Y and Deng H: EIF4G1 Ala502Val and Arg1205His variants in Chinese patients with Parkinson disease. Neurosci Lett. 543:69–71. 2013. View Article : Google Scholar : PubMed/NCBI
18	Guo Y, Yuan J, Liang H, Xiao J, Xu H, Yuan L, Gao K, Wu B, Tang Y, Li X and Deng H: Identification of a novel COL4A5 mutation in a Chinese family with X-linked Alport syndrome using exome sequencing. Mol Biol Rep. 41:3631–3635. 2014. View Article : Google Scholar : PubMed/NCBI
19	Brison N, Tylzanowski P and Debeer P: Limb skeletal malformations-what the HOX is going on? Eur J Med Genet. 55:1–7. 2012. View Article : Google Scholar : PubMed/NCBI
20	Dai L, Liu D, Song M, Xu X, Xiong G, Yang K, Zhang K, Meng H, Guo H and Bai Y: Mutations in the homeodomain of HOXD13 cause syndactyly type 1-c in two Chinese families. PLoS One. 9:e961922014. View Article : Google Scholar : PubMed/NCBI
21	Cooper DN and Youssoufian H: The CpG dinucleotide and human genetic disease. Hum Genet. 78:151–155. 1988. View Article : Google Scholar : PubMed/NCBI
22	Kurban M, Wajid M, Petukhova L, Shimomura Y and Christiano AM: A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance. J Hum Genet. 56:701–706. 2011. View Article : Google Scholar : PubMed/NCBI
23	Akarsu AN, Stoilov I, Yilmaz E, Sayli BS and Sarfarazi M: Genomic structure of HOXD13 gene: A nine polyalanine duplication causes synpolydactyly in two unrelated families. Hum Mol Genet. 5:945–952. 1996. View Article : Google Scholar : PubMed/NCBI
24	Jamsheer A, Sowinska A, Kaczmarek L and Latos-Bielenska A: Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: A case report. BMC Med Genet. 13:42012. View Article : Google Scholar : PubMed/NCBI
25	Bruneau S, Johnson KR, Yamamoto M, Kuroiwa A and Duboule D: The mouse Hoxd13(spdh) mutation, a polyalanine expansion similar to human type II synpolydactyly (SPD), disrupts the function but not the expression of other Hoxd genes. Dev Biol. 237:345–353. 2001. View Article : Google Scholar : PubMed/NCBI
26	Zakany J and Duboule D: Synpolydactyly in mice with a targeted deficiency in the HoxD complex. Nature. 384:69–71. 1996. View Article : Google Scholar : PubMed/NCBI
27	Dollé P, Dierich A, LeMeur M, Schimmang T, Schuhbaur B, Chambon P and Duboule D: Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs. Cell. 75:431–441. 1993. View Article : Google Scholar : PubMed/NCBI