WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome

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White, Janson J. ^[1] ; Mazzeu, Juliana F. ^{[2, 3]} ; Coban-Akdemir, Zeynep ^[1] ; Bayram, Yavuz ^[1] ; Bahrambeigi, Vahid ^[4] ; Hoischen, Alexander ^{[5, 6, 7]} ; van Bon, Bregje W. M. ^[5] ; Gezdirici, Alper ^[8] ; Gulec, Elif Yilmaz ^[8] ; Ramond, Francis ^[9] ; Touraine, Renaud ^[9] ; Thevenon, Julien ^{[10, 11, 12]} ; Shinawi, Marwan ^[13] ; Beaver, Erin ^[14] ; Heeley, Jennifer ^[14] ; Hoover-Fong, Julie ^[15] ; Durmaz, Ceren D. ^[16] ; Karabulut, Halil Gurhan ^[16] ; Marzioglu-Ozdemir, Ebru ^[17] ; Cayir, Atilla ^[18] ; Duz, Mehmet B. ^[19] ; Seven, Mehmet ^[19] ; Price, Susan ^[20] ; Ferreira, Barbara Merfort ^[2] ; Vianna-Morgante, Angela M. ^[21] ; Ellard, Sian ^{[22, 23]} ; Parrish, Andrew ^[22] ; Stals, Karen ^[22] ; Flores-Daboub, Josue ^[24] ; Jhangiani, Shalini N. ^[25] ; Gibbs, Richard A. ^[25] ; Brunner, Han G. ^{[26, 27]} ; Sutton, V. Reid ^[28] ; Lupski, James R. ^{[25, 28, 1]} ; Carvalho, Claudia M. B. ^[1] ; Mendelian, Baylor-Hopkins Ctr

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^[1] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 - USA

^[2] Univ Brasilia, BR-70910 Brasilia, DF - Brazil

^[3] Robinow Syndrome Fdn, Anoka, MN 55303 - USA

^[4] Univ Texas MD Anderson Canc Ctr, Sch Hlth Profess, Grad Program Diagnost Genet, Houston, TX 77030 - USA

^[5] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Human Genet, NL-6500 HB Nijmegen - Netherlands

^[6] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6500 HB Nijmegen - Netherlands

^[7] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis RCI, NL-6500 HB Nijmegen - Netherlands

^[8] Kanuni Sultan Suleyman Training & Res Hosp, Dept Med Genet, TR-34303 Istanbul - Turkey

^[9] CHU Hop Nord, Serv Genet, F-42000 St Etienne - France

^[10] Univ Bourgogne Franche Comte, Genet Dev Anomalies, Inserm UMR 1231 GAD Team, F-21000 Dijon - France

^[11] CHU Dijon, Univ Bourgogne, FHU TRANSLAD, F-21000 Dijon - France

^[12] CHU Grenoble Alpes, Hop Couple Enfant, Ctr Genet, F-38700 La Tronche - France

^[13] Washington Univ, Sch Med, Dept Pediat, Div Genet & Genom Med, St Louis, MO 63110 - USA

^[14] Mercy Childrens Hosp St Louis, Mercy Clin Kids Genet, St Louis, MO 63141 - USA

^[15] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Greenberg Ctr Skeletal Dysplasias, Baltimore, MD 21287 - USA

^[16] Ankara Univ, Sch Med, Dept Med Genet, TR-06100 Ankara - Turkey

^[17] Erzurum Reg & Training Hosp, Dept Med Genet, TR-25070 Erzurum - Turkey

^[18] Erzurum Training & Res Hosp, Dept Pediat Endocrinol, TR-25070 Erzurum - Turkey

^[19] Istanbul Univ, Cerrahpasa Med Sch, Dept Med Genet, TR-34452 Istanbul - Turkey

^[20] Nuffield Orthopaed Ctr, Oxford Ctr Genom Med, Oxford OX3 7LD - England

^[21] Inst Biosci, Dept Genet & Evolutionary Biol, BR-05508090 Sao Paulo - Brazil

^[22] Royal Devon & Exeter NHS Fdn Trust, Dept Mol Genet, Exeter EX2 5DW, Devon - England

^[23] Univ Exeter, Med Sch, Inst Biomed & Clin Sci, Exeter EX1 2LU, Devon - England

^[24] Univ Utah, Sch Med, Dept Pediat Genet, Salt Lake City, UT 84108 - USA

^[25] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 - USA

^[26] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behaviour, Dept Human Genet, NL-6500 HB Nijmegen - Netherlands

^[27] Maastricht Univ, Med Ctr, GROW Sch Oncol & Dev Biol, Dept Clin Genet, NL-6202 AZ Maastricht - Netherlands

^[28] Texas Childrens Hosp, Houston, TX 77030 - USA

• Tipo de documento: Artigo Científico
• Fonte: American Journal of Human Genetics; v. 102, n. 1, p. 27-43, JAN 4 2018.
• Citações Web of Science: 19

Resumo

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, similar to 70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered-1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways. (AU)

• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs