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Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly

Abstract

Polydactyly is the most common limb malformation that occurs in 1.6–10.6 per one thousand live births, with incidence varying with ancestry. The underlying gene has been identified for many of the ~100 syndromes that include polydactyly. While for the more common form, nonsydromic polydactyly, eleven candidate genes have been reported. We investigated the underlying genetic cause of autosomal recessive nonsyndromic postaxial polydactyly in four consanguineous Pakistani families. Some family members with postaxial polydactyly also present with syndactyly, camptodactyly, or clinodactyly. Analysis of the exome sequence data revealed two novel homozygous frameshift deletions in EFCAB7: [c.830delG;p.(Gly277Valfs*5)]; in three families and [c.1350_1351delGA;p.(Asn451Phefs*2)] in one family. Sanger sequencing confirmed that these variants segregated with postaxial polydactyly, i.e., family members with postaxial polydactyly were found to be homozygous while unaffected members were heterozygous or wild type. EFCAB7 displays expressions in the skeletal muscle and on the cellular level in cilia. IQCE-EFCAB7 and EVC-EVC2 are part of the heterotetramer EvC complex, which is a positive regulator of the Hedgehog (Hh) pathway, that plays a key role in limb formation. Depletion of either EFCAB7 or IQCE inhibits induction of Gli1, a direct Hh target gene. Variants in IQCE and GLI1 have been shown to cause nonsyndromic postaxial polydactyly, while variants in EVC and EVC2 underlie Ellis van Creveld and Weyers syndromes, which include postaxial polydactyly as a phenotype. This is the first report of the involvement of EFCAB7 in human disease etiology.

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Fig. 1: Pedigrees of postaxial polydactyly families MB1, BD547, BD635, and BD727.
Fig. 2: Photographs of hands and feet of affected pedigree members.

Data availability

The identified variants have been submitted to the ClinVar database [Accession numbers: SCV003804323 and SCV003804374].

References

  1. Ahmad Z, Liaqat R, Palander O, Bilal M, Zeb S, Ahmad F, et al. Genetic overview of postaxial polydactyly: Updated classification. Clin Genet. 2023;103:3–15.

    Article  CAS  PubMed  Google Scholar 

  2. Umair M, Ahmad F, Bilal M, Ahmad W, Alfadhel M. Clinical genetics of polydactyly: An updated review. Front Genet. 2018;9:447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pompe van Meerdervoort HF. Congenital musculoskeletal malformation in South Africa Blakcs-a study of incidence. S Afr Med J. 1976;50:1853–5.

    CAS  PubMed  Google Scholar 

  4. Woolf CM, Myrianthopoulos NC. Polydactyly in American negroes and whites. American. J Hum Genet. 1973;25:397.

    CAS  Google Scholar 

  5. Kondoh S, Sugawara H, Harada N, Matsumoto N, Ohashi H, Sato M, et al. A novel gene is disrupted at a 14q13 breakpoint of t(2;14) in a patient with mirror-image polydactyly of hands and feet. J Hum Genet. 2002;47:136–9.

    Article  CAS  PubMed  Google Scholar 

  6. Klopocki E, Kähler C, Foulds N, Shah H, Joseph B, Vogel H, et al. Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly. Eur J Hum Genet. 2012;20:705–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kalsoom UE, Klopocki E, Wasif N, Tariq M, Khan S, Hecht J, et al. Whole exome sequencing identified a novel zinc-finger gene ZNF141 associated with autosomal recessive postaxial polydactyly type A. J Med Genet. 2013;50:47–53.

    Article  PubMed  Google Scholar 

  8. Bakar A, Ullah A, Bibi N, Khan H, Rahman AU, Ahmad W, et al. A novel homozygous variant in the GLI1 underlies postaxial polydactyly in a large consanguineous family with intra familial variable phenotypes. Eur J Med Genet. 2022;65:104599.

    Article  CAS  PubMed  Google Scholar 

  9. Umair M, Shah K, Alhaddad B, Haack TB, Graf E, Strom TM, et al. Exome sequencing revealed a splice site variant in the IQCE gene underlying post-axial polydactyly type A restricted to lower limb. Eur J Hum Genet. 2017;25:960–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ullah I, Kakar N, Schrauwen I, Hussain S, Chakchouk I, Liaqat K, et al. Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly. Hum Genet. 2019;138:593–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Umair M, Wasif N, Albalawi AM, Ramzan K, Alfadhel M, Ahmad W, et al. Exome sequencing revealed a novel loss‐of‐function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly. Mol Genet Genom Med. 2019;7:e00627.

    Article  Google Scholar 

  12. Schrauwen I, Giese AP, Aziz A, Lafont DT, Chakchouk I, Santos-Cortez RLP, et al. FAM92A underlies nonsyndromic postaxial polydactyly in humans and an abnormal limb and digit skeletal phenotype in mice. J Bone Min Res. 2019;34:375–86.

    Article  CAS  Google Scholar 

  13. Umair M, Palander O, Bilal M, Almuzzaini B, Alam Q, Ahmad F, et al. Biallelic variant in DACH1, encoding Dachshund Homolog 1, defines a novel candidate locus for recessive postaxial polydactyly type A. Genomics 2021;113:2495–502.

    Article  CAS  PubMed  Google Scholar 

  14. Pusapati GV, Hughes CE, Dorn KV, Zhang D, Sugianto P, Aravind L, et al. EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia. Dev Cell. 2014;28:483–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009;2009:1754–60.

    Article  Google Scholar 

  16. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome AnalysisToolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yang H, Wang K. Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat Protoc. 2015;10:1556–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kircher M, Witten DM, Jain P, O’roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014 Mar;46:310–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020;581:434–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kowalski MH, Qian H, Hou Z, Rosen JD, Tapia AL, Shan Y, et al. Use of >100,000 NHLBI Trans-Omics for PrecisionMedicine (TOPMed) Consortium whole genome sequences improves imputation quality anddetection of rare variant associations in admixed African and Hispanic/Latino populations. PLOS Genet. 2019;15:e1008500.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Scott EM, Halees A, Itan Y, Spencer EG, He Y, Azab MA, et al. Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery. Nat Genet. 2016;48:1071–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lyles CR, Lunn MR, Obedin-Maliver J, Bibbins-Domingo K. The new era of precision population health: insights for the All of Us Research Program and beyond. J Transl Med. 2018;16:1–4.

    Article  Google Scholar 

  23. Khan H, Ahmed S, Nawaz S, Ahmad W, Rafiq MA. Greig cephalopolysyndactyly syndrome: phenotypic variability associated with variants in two different domains of GLI3. Klin Padiatr. 2021;233:53–8.

    Article  PubMed  Google Scholar 

  24. Zhang Z, Xin D, Wang P, Zhou L, Hu L, Kong X, et al. Noisy splicing, more than expression regulation, explains why some exons are subject to nonsense-mediated mRNA decay. BMC Biol. 2009;7:1–3.

    Article  Google Scholar 

  25. Dorn KV, Hughes CE, Rohatgi R. A Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Dev Cell. 2012;23:823–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gigante ED, Caspary T. Signaling in the primary cilium through the lens of the Hedgehog pathway. Wiley Interdiscip Rev: Dev Biol. 2020;9:e377.

    Article  PubMed  Google Scholar 

  27. Speir ML, Bhaduri A, Markov NS, Moreno P, Nowakowski TJ, Papatheodorou I, et al. UCSC Cell Browser: visualize your single-cell data. Bioinformatics 2021;37:4578–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Muñoz-Fuentes V, Cacheiro P, Meehan TF, Aguilar-Pimentel JA, Brown SD, Flenniken AM, et al. The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation. Conserv Genet. 2018;19:995–1005.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Breslow DK, Hoogendoorn S, Kopp AR, Morgens DW, Vu BK, Kennedy MC, et al. A CRISPR-based screen for Hedgehog signaling provides insights into ciliary function and ciliopathies. Nat Genet. 2018;50:460–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Umair M, Seidel H, Ahmed I, Ullah A, Haack TB, Alhaddad B, et al. Ellis–van Creveld syndrome and profound deafness resulted by sequence variants in the EVC/EVC2 and TMC1 genes. J Genet. 2017;96:1005–14.

    Article  CAS  PubMed  Google Scholar 

  31. Hussain S, Nawaz S, Khan H, Acharya A, Schrauwen I, Ahmad W, et al. A splice site variant in TCTN3 underlies an atypical form of orofaciodigital syndrome IV. Ann Hum Genet. 2022;86:291–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shamseldin HE, Shaheen R, Ewida N, Bubshait DK, Alkuraya H, Almardawi E, et al. The morbid genome of ciliopathies: an update. Genet Med. 2020;22:1051–60.

    Article  PubMed  Google Scholar 

  33. Nguyen TQ, Doan NM, Trinh HT, Mizuguchi M. Novel mutation in EFCAB7 alters expression and interaction of Ellis–van Creveld ciliary proteins. Congenit Anom. 2019;59:49–50.

    Article  Google Scholar 

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Acknowledgements

We are highly obliged to members of the families for their cooperation and participation in this study. Muhammad Bilal, Hammal Khan and Muhammad Javed Khan were supported by Indigenous PhD and IRSIP fellowships from Higher Education Commission (HEC), Islamabad, Pakistan.

Funding

This research was funded by Higher Education Commission of Pakistan, Pediatric Genomics Discovery Program, and the Department of Neurology, Columbia University Medical Center.

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Contributions

MB, HK, and MJK performed the laboratory experiments, analyzed the genomic data, and drafted the manuscript. IS, KL, AA, TB, N, HA, SA, KU, MSH, and AU collected samples and analyzed clinical and genomic data. WA and SML designed the project, analyzed the data, edited the manuscript, and provided funds for the study.

Corresponding author

Correspondence to Suzanne M. Leal.

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Bilal, M., Khan, H., Khan, M.J. et al. Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly. Eur J Hum Genet 31, 1270–1274 (2023). https://doi.org/10.1038/s41431-023-01450-5

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