Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Novel HOXD13 variants in syndactyly type 1b and type 1c, and a new spectrum of TP63-related disorders

Journal of Human Genetics volume 67, pages 43–49 (2022)Cite this article

Subjects

Abstract

Syndactyly is the most common limb defect depicting the bony and/or cutaneous fusion of digits. Syndactyly can be of various types depending on the digits involved in the fusion. To date, eight syndactyly-associated genes have been reported, of which HOXD13 and GJA1 have been explored in a few syndactyly but most of them have unknown underlying genetics. In the present study HOXD13, GJA1 and TP63 genes have been screened by resequencing in 24 unrelated sporadic cases with various syndactyly. The screening revealed two pathogenic HOXD13 variants, NM_000523:c.500 A > G [p.(Y167C)], and NM_000523:c.961 A > C [p.(T321P)] in syndactyly type 1b and type 1c, respectively. This is the first report to identify HOXD13 pathogenic variant in syndactyly type 1b and third report in syndactyly type 1c pathogenesis. Furthermore, this study also reports a TP63 pathogenic variant, NM_003722:c.953 G > A [p.(R318H)] in Ectrodactyly and Cleft lip and palate (ECLP). In conclusion, the current study expands the clinical spectrum of HOXD13 and TP63-related disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The data that support the findings of this study are openly available in the ClinVar variant depository at www.ncbi.nlm.nih.gov/clinvar/, reference numbers SUB8902537, SCV000257698 and SCV000659689.

References

  1. Hay S. Incidence of selected congenital malformations in iowa. Am J Epidemiol [Internet]. 1971;94:572–84. [cited 2020 May 23] Available from:

    Article  Google Scholar 

  2. Malik S. Syndactyly: phenotypes, genetics and current classification. Eur J Hum Genet [Internet]. 2012;20:817–24. [cited 2020 May 22] Available from:

    Article  CAS  Google Scholar 

  3. Castilla EE, Paz JE, Orioli-Parreiras IM, Opitz JM, Hermann J. Syndactyly: frequency of specific types. Am J Med Genet [Internet]. 1980;5:357–64. https://doi.org/10.1002/ajmg.1320050406. [cited 2020 May 23]Available from

    Article  CAS  Google Scholar 

  4. Deng H, Tan T, He Q, Lin Q, Yang Z, Zhu A, et al. Identification of a missense HOXD13 mutation in a Chinese family with syndactyly type I-c using exome sequencing. Mol Med Rep. 2017;16:473–7.

    Article  CAS  Google Scholar 

  5. Jamsheer A, Zemojtel T, Kolanczyk M, Stricker S, Hecht J, Krawitz P. et al. Whole exome sequencing identifies FGF16 nonsense mutations as the cause of X-linked recessive metacarpal 4/5 fusion. 2013;50:579–84 [cited 2020 May 23]. Available from: http://jmg.bmj.com/.

  6. Ngoc NT, Duong NT, Quynh DH, Ton ND, Duc HH, Huong LTM, et al. Identification of novel missense mutations associated with non-syndromic syndactyly in two vietnamese trios by whole exome sequencing. Clin Chim Acta.2020;506:16–21.

    Article  Google Scholar 

  7. Dai L, Liu D, Song M, Xu X, Xiong G, Yang K, et al. Mutations in the homeodomain of HOXD13 cause syndactyly type 1-c in two Chinese families. PLoS One. 2014;9:e96192.

  8. Sutton VR, van Bokhoven H. TP63-Related Disorders [Internet]. GeneReviews®. 1993 [cited 2020 May 23]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK43797/.

  9. Barrow LL, van Bokhoven H, Daack-Hirsch S, Andersen T, van Beersum SEC, Gorlin R, et al. Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts. J Med Genet [Internet]. 2002 Aug 1 [cited 2020 May 23]; 39:559–66. Available from: http://www.jmedgenet.com.

  10. Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, et al. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet. 2003;72:408–18.

    Article  CAS  Google Scholar 

  11. Parsons JK, Saria EA, Nakayama M, Vessella RL, Sawyers CL, Isaacs WB, et al. Comprehensive mutational analysis and mRNA isoform quantification of TP63 in normal and neoplastic human prostate cells. Prostate [Internet]. 2009;69:559–69. [cited 2020 Jul 4] Available from: /pmc/articles/PMC2875878/?report=abstract

    Article  CAS  Google Scholar 

  12. Zhao X, Sun M, Zhao J, Leyva JA, Zhu H, Yang W, et al. Mutations in HOXD13 underlie syndactyly type V and a novel brachydactyly-syndactyly syndrome. Am J Hum Genet. 2007;80:361–71.

    Article  CAS  Google Scholar 

  13. Ibrahim DM, Tayebi N, Knaus A, Stiege AC, Sahebzamani A, Hecht J, et al. A homozygous HOXD13 missense mutation causes a severe form of synpolydactyly with metacarpal to carpal transformation. Am J Med Genet Part A. 2016;170:615–21.

    Article  CAS  Google Scholar 

  14. Brison N, Debeer P, Tylzanowski P. Joining the fingers: a HOXD13 story. Dev Dyn [Internet]. 2014;243:37–48. https://doi.org/10.1002/dvdy.24037. [cited 2020 Jul 4]Available from

    Article  CAS  PubMed  Google Scholar 

  15. Low KJ, Nwbury-Ecob RA. Homozygous nonsense mutation in HOXD13 underlies synpolydactyly with a cleft. Clin Dysmorphol [Internet].2012;21:141–3. [cited 2020 Jul 4] Available from: .

    Article  Google Scholar 

  16. Ravel A, Chouery E, Stora S, Jalkh N, Villard L, Temtamy S, et al. How many entities exist for the spectrum of disorders associated with brachydactyly, syndactyly, short stature, microcephaly, and intellectual disability? Am J Med Genet Part A [Internet]. 2011;155:880–4. https://doi.org/10.1002/ajmg.a.33879. Available from

    Article  Google Scholar 

  17. Morgunova E, Yin Y, Das PK, Jolma A, Zhu F, Popov A, et al. Two distinct DNA sequences recognized by transcription factors represent enthalpy and entropy optima. Elife. 2018;7:e32963. https://doi.org/10.7554/eLife.32963.

  18. Al-Qattan M. M. A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis. Vol. 2019, Biomed Res Int. 2019;15:9652649.

  19. Opitz JM, Frias JL, Cohen MM. The ECP syndrome, another autosomal dominant cause of monodactylous ectrodactyly. Eur J Pediatr [Internet]. 1980;133:217–20. https://doi.org/10.1007/BF00496079. [cited 2020 May 26]Available from

    Article  CAS  Google Scholar 

  20. Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell [Internet]. 1999;99:143–53 [cited 2020 Jul 3] Available from https://linkinghub.elsevier.com/retrieve/pii/S0092867400816463

    Article  CAS  Google Scholar 

  21. Ianakiev P, Kilpatrick MW, Toudjarska I, Basel D, Beighton P, Tsipouras P. Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. Am J Hum Genet [Internet]. 2000;67:59–66. [cited 2020 Jul 3] Available from https://pubmed.ncbi.nlm.nih.gov/10839977/

    Article  CAS  Google Scholar 

  22. Bougeard G, Hadj-Rabia S, Faivre L, Sarafan-Vasseur N, Frébourg T. The Rapp-Hodgkin syndrome results from mutations of the TP63 gene. Eur J Hum Genet [Internet]. 2003;11:700–4. [cited 2020 Jul 3] Available from http://www.nature.com/ejhg

    Article  CAS  Google Scholar 

  23. van Bokhoven H, Brunner HG. Splitting p63. Am J Hum Genet [Internet]. 2002;71(Jul):1–13. [cited 2020 Jul 4]Available from: /pmc/articles/PMC384966/?report=abstract

    PubMed Central  Google Scholar 

  24. Van Bokhoven H, Hamel BCJ, Bamshad M, Sangiorgi E, Gurrieri F, Duijf PHG, et al. p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet [Internet]. 2001;69:481–92. [cited 2020 Jul 4]Available from:

    Article  Google Scholar 

  25. South AP, Ashton GHS, Willoughby C, Ellis IH, Bleck O, Hamada T, et al. EEC (Ectrodactyly, Ectodermal dysplasia, Clefting) syndrome: Heterozygous mutation in the p63 gene (R279H) and DNA-based prenatal diagnosis. Br J Dermatol [Internet]. 2002;146:216–20. [cited 2020 Jul 4]Available from:

    Article  CAS  Google Scholar 

  26. Al Ghamdi MA, Al-Qattan MM, Hadadi A, Alabdulrahman A, Almuzzaini B, Alatwi N, et al. A classification system for split-hand/ foot malformation (SHFM): A proposal based on 3 pedigrees with WNT10B mutations. Eur J Med Genet [Internet]. 2020 Mar [cited 2021 Mar 31]; 63:103738. Available from: https://doi.org/10.1016/j.ejmg.2019.103738.

  27. Lewandoski M, Sun X, Martin GR. Fgf8 signalling from the AER is essential for normal limb development. Nat Genet. 2000;26:460–3.

    Article  CAS  Google Scholar 

  28. Lu P, Minowada G, Martin GR. Increasing Fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function. Dev [Internet]. 2006;133:33–42 [cited 2021 Apr 12]Available from https://dev.biologists.org/content/133/1/33

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the patients, family members and control volunteers for willingly participating in this study. We are grateful to Science and Engineering Research Board (SERB)-DST-Government of India, for research grant (SB/YS/LS-46/2013) to Dr A. Ali; and to CSIR-Government of India, for providing junior and senior research fellowships to Dr R. Patel. We are also grateful to Dr A. Mani, and Dr B.S. Yadav, MNNIT, Allahabad for help during in silico work and to ISLS-I.Sc.-BHU for providing their laboratory facilities.

Author information

Author notes

  1. Rashmi Patel

    Present address: National Cancer Institute, Frederick, NIH, USA

Authors and Affiliations

  1. Centre for Genetic Disorders, Institute of Science, Banaras Hindu University, Varanasi, India

    Rashmi Patel & Akhtar Ali

  2. G S Memorial Plastic Surgery Hospital & Trauma Center, Varanasi, India

    Subodh Kumar Singh

  3. Department of Plastic Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

    Visweswar Bhattacharya

Authors
  1. Rashmi Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Subodh Kumar Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Visweswar Bhattacharya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akhtar Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RP: Conducted the study, interpreting and reporting of GLI3 variants and manuscript preparation; SKS and VB: Clinical evaluation and sample collection; AA: Conceived and led the project, study design, data analysis, manuscript preparation, and supervised the study.

Corresponding author

Correspondence to Akhtar Ali.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patel, R., Singh, S.K., Bhattacharya, V. et al. Novel HOXD13 variants in syndactyly type 1b and type 1c, and a new spectrum of TP63-related disorders. J Hum Genet 67, 43–49 (2022). https://doi.org/10.1038/s10038-021-00963-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-021-00963-5

This article is cited by

Search

Advanced search

Quick links