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Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies

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Abstract

Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. These individuals exhibit both shared and unique clinical manifestations, highlighting the complexity and variability of the disorder. We propose that the involvement of MAP3K20 in endothelial–mesenchymal transition provides a plausible etiology of these features. Together, these findings characterize a disorder that both expands the phenotypic spectrum associated with MAP3K20 and highlights the need for further studies on its role in early human development.

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References

  • Adams DR, Sincan M, Fuentes Fajardo K, Mullikin JC, Pierson TM, Toro C, Boerkoel CF, Tifft CJ, Gahl WA, Markello TC (2012) Analysis of DNA sequence variants detected by high-throughput sequencing. Hum Mutat 33:599–608. https://doi.org/10.1002/humu.22035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249. https://doi.org/10.1038/nmeth0410-248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahmad I, Khan A, Noor Ul Ayan H, Budde B, Altmuller J, Korejo AA, Nurnberg G, Thiele H, Tariq M, Nurnberg P, Erdmann J (2023) A novel MAP3K20 mutation causing centronuclear myopathy-6 with fiber-type disproportion in a Pakistani family. J Hum Genet 68:107–109. https://doi.org/10.1038/s10038-022-01085-2

    Article  CAS  PubMed  Google Scholar 

  • Chang Y, Lu X, Shibu MA, Dai YB, Luo J, Zhang Y, Li Y, Zhao P, Zhang Z, Xu Y, Tu ZC, Zhang QW, Yun CH, Huang CY, Ding K (2017) Structure based design of N-(3-((1H-Pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides as selective leucine-zipper and sterile-alpha motif kinase (ZAK) inhibitors. J Med Chem 60:5927–5932. https://doi.org/10.1021/acs.jmedchem.7b00572

    Article  CAS  PubMed  Google Scholar 

  • Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, Wang Q, Alfoldi J, Watts NA, Vittal C, Gauthier LD, Poterba T, Wilson MW, Tarasova Y, Phu W, Grant R, Yohannes MT, Koenig Z, Farjoun Y, Banks E, Donnelly S, Gabriel S, Gupta N, Ferriera S, Tolonen C, Novod S, Bergelson L, Roazen D, Ruano-Rubio V, Covarrubias M, Llanwarne C, Petrillo N, Wade G, Jeandet T, Munshi R, Tibbetts K, C. Genome Aggregation Database, O’Donnell-Luria A, Solomonson M, Seed C, Martin AR, Talkowski ME, Rehm HL, Daly MJ, Tiao G, Neale BM, MacArthur DG, Karczewski KJ (2024) A genomic mutational constraint map using variation in 76,156 human genomes. Nature 625:92–100. https://doi.org/10.1038/s41586-023-06045-0

    Article  CAS  PubMed  Google Scholar 

  • Collins RL, Brand H, Karczewski KJ, Zhao X, Alfoldi J, Francioli LC, Khera AV, Lowther C, Gauthier LD, Wang H, Watts NA, Solomonson M, O’Donnell-Luria A, Baumann A, Munshi R, Walker M, Whelan CW, Huang Y, Brookings T, Sharpe T, Stone MR, Valkanas E, Fu J, Tiao G, Laricchia KM, Ruano-Rubio V, Stevens C, Gupta N, Cusick C, Margolin L, T. Genome Aggregation Database Production, C. Genome Aggregation Database, Taylor KD, Lin HJ, Rich SS, Post WS, Chen YI, Rotter JI, Nusbaum C, Philippakis A, Lander E, Gabriel S, Neale BM, Kathiresan S, Daly MJ, Banks E, MacArthur DG, Talkowski ME (2020) A structural variation reference for medical and population genetics. Nature 581:444–451. https://doi.org/10.1038/s41586-020-2287-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dill TL, Carroll A, Pinheiro A, Gao J, Naya FJ (2021) The long noncoding RNA Meg3 regulates myoblast plasticity and muscle regeneration through epithelial-mesenchymal transition. Development. https://doi.org/10.1242/dev.194027

    Article  PubMed  Google Scholar 

  • Emsley P, Lohkamp B, Scott WG, Cowtan K (2010) Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66:486–501. https://doi.org/10.1107/S0907444910007493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Evans R, O’Neill M, Pritzel A, Antroprova N, Senior A, Green T, Zidek A, Bates R, Blackwell S, Yim J, Ronneberger O, Bodenstein S, Zielinski M, Bridgland A, Potapenko A, Cowie A, Tunyasuvunakool K, Jain R, Clancy E, Kohli P, Jumper J, Hassabis D (2022) Protein complex prediction with AlphaFold-Multimer. bioRxiv 11:e0161879. https://doi.org/10.1101/2021.10.04.463034

    Article  Google Scholar 

  • Funk CR, Huey ES, May MM, Peng Y, Michonova E, Best RG, Schwartz CE, Blenda AV (2020) Rare missense variant p.Ala505Ser in the ZAK protein observed in a patient with split-hand/foot malformation from a non-consanguineous pedigree. J Int Med Res 48:300060519879293. https://doi.org/10.1177/0300060519879293

    Article  CAS  PubMed  Google Scholar 

  • Gonfloni S, Williams JC, Hattula K, Weijland A, Wierenga RK, Superti-Furga G (1997) The role of the linker between the SH2 domain and catalytic domain in the regulation and function of Src. EMBO J 16:7261–7271. https://doi.org/10.1093/emboj/16.24.7261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guero S, Holder-Espinasse M (2019) Insights into the pathogenesis and treatment of split/hand foot malformation (cleft hand/foot). J Hand Surg Eur 44:80–87. https://doi.org/10.1177/1753193418807375

    Article  Google Scholar 

  • Heurtier L, Lamrini H, Chentout L, Deau MC, Bouafia A, Rosain J, Plaza JM, Parisot M, Dumont B, Turpin D, Merlin E, Moshous D, Aladjidi N, Neven B, Picard C, Cavazzana M, Fischer A, Durandy A, Stephan JL, Kracker S (2017) Mutations in the adaptor-binding domain and associated linker region of p110delta cause activated PI3K-delta syndrome 1 (APDS1). Haematologica 102:e278–e281. https://doi.org/10.3324/haematol.2017.167601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu Z, Luo X, Zhang L, Lu F, Dong F, Monsell E, Jiang H (2012) Generation of human inner ear prosensory-like cells via epithelial-to-mesenchymal transition. Regen Med 7:663–673. https://doi.org/10.2217/rme.12.53

    Article  CAS  PubMed  Google Scholar 

  • Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, Musolf A, Li Q, Holzinger E, Karyadi D, Cannon-Albright LA, Teerlink CC, Stanford JL, Isaacs WB, Xu J, Cooney KA, Lange EM, Schleutker J, Carpten JD, Powell IJ, Cussenot O, Cancel-Tassin G, Giles GG, MacInnis RJ, Maier C, Hsieh CL, Wiklund F, Catalona WJ, Foulkes WD, Mandal D, Eeles RA, Kote-Jarai Z, Bustamante CD, Schaid DJ, Hastie T, Ostrander EA, Bailey-Wilson JE, Radivojac P, Thibodeau SN, Whittemore AS, Sieh W (2016) REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 99:877–885. https://doi.org/10.1016/j.ajhg.2016.08.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Zidek A, Potapenko A, Bridgland A, Meyer C, Kohl SAA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Back T, Petersen S, Reiman D, Clancy E, Zielinski M, Steinegger M, Pacholska M, Berghammer T, Bodenstein S, Silver D, Vinyals O, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D (2021) Highly accurate protein structure prediction with AlphaFold. Nature 596:583–589. https://doi.org/10.1038/s41586-021-03819-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kahata K, Dadras MS, Moustakas A (2018) TGF-beta family signaling in epithelial differentiation and epithelial–mesenchymal transition. Cold Spring Harb Perspect Biol 10:a022194. https://doi.org/10.1101/cshperspect.a022194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, Walters RK, Tashman K, Farjoun Y, Banks E, Poterba T, Wang A, Seed C, Whiffin N, Chong JX, Samocha KE, Pierce-Hoffman E, Zappala Z, O’Donnell-Luria AH, Minikel EV, Weisburd B, Lek M, Ware JS, Vittal C, Armean IM, Bergelson L, Cibulskis K, Connolly KM, Covarrubias M, Donnelly S, Ferriera S, Gabriel S, Gentry J, Gupta N, Jeandet T, Kaplan D, Llanwarne C, Munshi R, Novod S, Petrillo N, Roazen D, Ruano-Rubio V, Saltzman A, Schleicher M, Soto J, Tibbetts K, Tolonen C, Wade G, Talkowski ME, Genome Aggregation Database C, Neale BM, Daly MJ, MacArthur DG (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581:434–443. https://doi.org/10.1038/s41586-020-2308-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081. https://doi.org/10.1038/nprot.2009.86

    Article  CAS  PubMed  Google Scholar 

  • Li L, Su N, Zhou T, Zheng D, Wang Z, Chen H, Yuan S, Li W (2018) Mixed lineage kinase ZAK promotes epithelial–mesenchymal transition in cancer progression. Cell Death Dis 9:143. https://doi.org/10.1038/s41419-017-0161-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu TC, Huang CJ, Chu YC, Wei CC, Chou CC, Chou MY, Chou CK, Yang JJ (2000) Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. Biochem Biophys Res Commun 274:811–816. https://doi.org/10.1006/bbrc.2000.3236

    Article  CAS  PubMed  Google Scholar 

  • Pais LS, Snow H, Weisburd B, Zhang S, Baxter SM, DiTroia S, O’Heir E, England E, Chao KR, Lemire G, Osei-Owusu I, VanNoy GE, Wilson M, Nguyen K, Arachchi H, Phu W, Solomonson M, Mano S, O’Leary M, Lovgren A, Babb L, Austin-Tse CA, Rehm HL, MacArthur DG, O’Donnell-Luria A (2022) Seqr: a web-based analysis and collaboration tool for rare disease genomics. Hum Mutat 43:698–707. https://doi.org/10.1002/humu.24366

    Article  PubMed  PubMed Central  Google Scholar 

  • Philippakis AA, Azzariti DR, Beltran S, Brookes AJ, Brownstein CA, Brudno M, Brunner HG, Buske OJ, Carey K, Doll C, Dumitriu S, Dyke SO, den Dunnen JT, Firth HV, Gibbs RA, Girdea M, Gonzalez M, Haendel MA, Hamosh A, Holm IA, Huang L, Hurles ME, Hutton B, Krier JB, Misyura A, Mungall CJ, Paschall J, Paten B, Robinson PN, Schiettecatte F, Sobreira NL, Swaminathan GJ, Taschner PE, Terry SF, Washington NL, Zuchner S, Boycott KM, Rehm HL (2015) The matchmaker exchange: a platform for rare disease gene discovery. Hum Mutat 36:915–921. https://doi.org/10.1002/humu.22858

    Article  PubMed  PubMed Central  Google Scholar 

  • Priolo M (2009) Ectodermal dysplasias: an overview and update of clinical and molecular-functional mechanisms. Am J Med Genet A 149A:2003–2013. https://doi.org/10.1002/ajmg.a.32804

    Article  CAS  PubMed  Google Scholar 

  • Priolo M, Lagana C (2001) Ectodermal dysplasias: a new clinical-genetic classification. J Med Genet 38:579–585. https://doi.org/10.1136/jmg.38.9.579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rentzsch P, Schubach M, Shendure J, Kircher M (2021) CADD-Splice-improving genome-wide variant effect prediction using deep learning-derived splice scores. Genome Med 13:31. https://doi.org/10.1186/s13073-021-00835-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siismets EM, Hatch NE (2020) Cranial neural crest cells and their role in the pathogenesis of craniofacial anomalies and coronal craniosynostosis. J Dev Biol 8(3):18. https://doi.org/10.3390/jdb8030018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sobreira N, Schiettecatte F, Valle D, Hamosh A (2015) GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat 36:928–930. https://doi.org/10.1002/humu.22844

    Article  PubMed  PubMed Central  Google Scholar 

  • Spielmann M, Kakar N, Tayebi N, Leettola C, Nurnberg G, Sowada N, Lupianez DG, Harabula I, Flottmann R, Horn D, Chan WL, Wittler L, Yilmaz R, Altmuller J, Thiele H, van Bokhoven H, Schwartz CE, Nurnberg P, Bowie JU, Ahmad J, Kubisch C, Mundlos S, Borck G (2016) Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice. Genome Res 26:183–191. https://doi.org/10.1101/gr.199430.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM, Eng CM, Esteves C, Gahl WA, Hamid R, Jacob HJ, Kikani B, Koeller DM, Kohane IS, Lee BH, Loscalzo J, Luo X, McCray AT, Metz TO, Mulvihill JJ, Nelson SF, Palmer CGS, Phillips JA 3rd, Pick L, Postlethwait JH, Reuter C, Shashi V, Sweetser DA, Tifft CJ, Walley NM, Wangler MF, Westerfield M, Wheeler MT, Wise AL, Worthey EA, Yamamoto S, Ashley EA, Undiagnosed Diseases N (2018) Effect of genetic diagnosis on patients with previously undiagnosed disease. N Engl J Med 379:2131–2139. https://doi.org/10.1056/NEJMoa1714458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Teer JK, Bonnycastle LL, Chines PS, Hansen NF, Aoyama N, Swift AJ, Abaan HO, Albert TJ, Program NCS, Margulies EH, Green ED, Collins FS, Mullikin JC, Biesecker LG (2010) Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencing. Genome Res 20:1420–1431. https://doi.org/10.1101/gr.106716.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Umair M, Hayat A (2020) Nonsyndromic split-hand/foot malformation: recent classification. Mol Syndromol 10:243–254. https://doi.org/10.1159/000502784

    Article  CAS  PubMed  Google Scholar 

  • Vasli N, Harris E, Karamchandani J, Bareke E, Majewski J, Romero NB, Stojkovic T, Barresi R, Tasfaout H, Charlton R, Malfatti E, Bohm J, Marini-Bettolo C, Choquet K, Dicaire MJ, Shao YH, Topf A, O’Ferrall E, Eymard B, Straub V, Blanco G, Lochmuller H, Brais B, Laporte J, Tetreault M (2017) Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion. Brain 140:37–48. https://doi.org/10.1093/brain/aww257

    Article  PubMed  Google Scholar 

  • Vind AC, Snieckute G, Blasius M, Tiedje C, Krogh N, Bekker-Jensen DB, Andersen KL, Nordgaard C, Tollenaere MAX, Lund AH, Olsen JV, Nielsen H, Bekker-Jensen S (2020) ZAKalpha recognizes stalled ribosomes through partially redundant sensor domains. Mol Cell 78(700–713):e707. https://doi.org/10.1016/j.molcel.2020.03.021

    Article  CAS  Google Scholar 

  • Wright JT, Fete M, Schneider H, Zinser M, Koster MI, Clarke AJ, Hadj-Rabia S, Tadini G, Pagnan N, Visinoni AF, Bergendal B, Abbott B, Fete T, Stanford C, Butcher C, D’Souza RN, Sybert VP, Morasso MI (2019) Ectodermal dysplasias: classification and organization by phenotype, genotype and molecular pathway. Am J Med Genet A 179:442–447. https://doi.org/10.1002/ajmg.a.61045

    Article  PubMed  Google Scholar 

  • Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, Stray-Pedersen A, Liu P, Wen S, Alcaraz W, Cui H, Walkiewicz M, Reid J, Bainbridge M, Patel A, Boerwinkle E, Beaudet AL, Lupski JR, Plon SE, Gibbs RA, Eng CM (2014) Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 312:1870–1879. https://doi.org/10.1001/jama.2014.14601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank the patients and families for participating in this research study.

Funding

Research reported in this manuscript was supported by the National Institutes of Health (NIH) Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Numbers U01HG007709 and U01HG007943. This work was also supported by the Clinical Translational Section of the Baylor College of Medicine Center for Precision Medicine Models (NIH U54OD030165), the SJD Translational Diagnostics & Therapy Program, the CIBERER grant ACCI2021-016, and Horizon Europe grant HORIZON-HLTH-2023-TOOL-05 101136262. This work was also supported in part by the National Institutes of Health grant R01-GM142143 (S.L.) and the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from the Eunice Kennedy Shriver NICHD. Use of the Macromolecular X-ray Crystallography Core at Baylor College of Medicine was supported in part by National Institutes of Health grant S10-OD030246 (S.L.). L.C.B. is supported by a Burroughs Wellcome Fund Career Award for Medical Scientists. Sequencing and analysis of the P5 trio were provided by the Broad Institute Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute grants UM1HG008900, U01HG0011755, and R01HG009141 and in part by Chan Zuckerberg Initiative grants DAF2019-199278 and DAF2022-316726 (https://doi.org/10.37921/236582yuakxy) from the Chan Zuckerberg Initiative DAF, an advised fund of Silicon Valley Community Foundation (funder DOI https://doi.org/10.13039/100014989). The Hospital Sant Joan de Déu is a member of the European Reference Network ITHACA. The contents of this publication are solely the responsibility of the authors and do not necessarily reflect the official views or policies of the NIH. The mention of trade names, commercial products, or organizations does not imply endorsement by the US Government.

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Author notes

  1. Daniel Brooks and Elizabeth Burke are equally contributing first authors. Jill A. Rosenfeld and Lindsay C. Burrage are equally contributing senior authors.

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    Daniel Brooks, Tanya N. Eble, Shweta U. Dhar, Lisa Emrick, Pengfei Liu, Seema Lalani, Jill A. Rosenfeld & Lindsay C. Burrage

  2. NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USA

    Elizabeth Burke, Michelle Nehrebecky, Ellen Macnamara & David Adams

  3. Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA

    Sukyeong Lee

  4. Advanced Technology Core for Macromolecular X-Ray Crystallography, Baylor College of Medicine, Houston, TX, USA

    Sukyeong Lee

  5. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Melanie O’Leary, Ikeoluwa Osei-Owusu & Heidi L. Rehm

  6. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Heidi L. Rehm

  7. Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA

    Lisa Emrick

  8. Texas Children’s Hospital, Houston, TX, USA

    Lisa Emrick, Seema Lalani & Lindsay C. Burrage

  9. Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA

    David Bick

  10. Department of Genetic Medicine, Pediatric Institute of Rare Diseases (IPER), CIBER on Rare Diseases (CIBERER), Hospital Sant Joan de DéuEsplugues de Llobregat, 08950, Barcelona, Spain

    Dídac Casas-Alba, Judith Armstrong, Antonio F. Martínez-Monseny & Francesc Palau

  11. Department of Dermatology, Hospital Sant Joan de Deu, Esplugues de Llobregat, 08950, Barcelona, Spain

    Carolina Prat

  12. Division of Pediatrics, University of Barcelona School of Medicine and Health Sciences, Barcelona, Spain

    Francesc Palau

  13. Baylor Genetics, Houston, TX, USA

    Pengfei Liu

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  1. Daniel Brooks
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Undiagnosed Diseases Network

Contributions

All authors participated in study conception, data acquisition, and data interpretation. Dan Brooks, Elizabeth Burke, Jill Rosenfeld and Lindsay Burrage led the data analysis and initial draft preparation. Sukyeong Lee led the structural modeling of the variants. All authors had the opportunity to participate in editing the final manuscript and approved the final manuscript.

Corresponding authors

Correspondence to Jill A. Rosenfeld or Lindsay C. Burrage.

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Conflict of interest

Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of Baylor Genetics, which performs genetic testing and derives revenue. Pengfei Liu is an employee of BCM and derives support through a professional services agreement with Baylor Genetics. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics. Francesc Palau is a consultant in neurogenetics of Engrail Therapeutics. Heidi Rehm receives funding for rare disease research from Illumina and Microsoft.

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Supplementary Information

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Suppl Fig 1

Cranial CT revealed a progressive growth of the mastoid process and over the nasal root, along with fibrous dysplasia involving skull base and facial bones in P2. Supplementary file1 (TIF 1340 KB)

Suppl Fig 2

The Cys273Arg variant causes a steric clash with surrounding residues. A. The Cys273 side chain (marked with arrow) and surrounding residues are shown as a stick and space-filling models. B. The side chain of the arginine mutant is shown as a stick model and dotted surface, and the surrounding residues are represented as a stick and space-filling models. Residues clashing with the arginine side chain are labelled. Supplementary file2 (TIF 1733 KB)

Supplementary file3 (DOCX 29 KB)

Supplementary file4 (DOCX 21 KB)

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Brooks, D., Burke, E., Lee, S. et al. Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies. Hum. Genet. 143, 279–291 (2024). https://doi.org/10.1007/s00439-024-02657-2

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