%0 Journal Article %J Am J Hum Genet %D 2018 %T WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. %A White, Janson J %A Mazzeu, Juliana F %A Coban-Akdemir, Zeynep %A Bayram, Yavuz %A Bahrambeigi, Vahid %A Hoischen, Alexander %A van Bon, Bregje W M %A Gezdirici, Alper %A Gulec, Elif Yilmaz %A Ramond, Francis %A Touraine, Renaud %A Thevenon, Julien %A Shinawi, Marwan %A Beaver, Erin %A Heeley, Jennifer %A Hoover-Fong, Julie %A Durmaz, Ceren D %A Karabulut, Halil Gurhan %A Marzioglu-Ozdemir, Ebru %A Cayir, Atilla %A Duz, Mehmet B %A Seven, Mehmet %A Price, Susan %A Ferreira, Barbara Merfort %A Vianna-Morgante, Angela M %A Ellard, Sian %A Parrish, Andrew %A Stals, Karen %A Flores-Daboub, Josue %A Jhangiani, Shalini N %A Gibbs, Richard A %A Brunner, Han G %A Sutton, V Reid %A Lupski, James R %A Carvalho, Claudia M B %K Adolescent %K Adult %K Base Sequence %K Child %K Child, Preschool %K Chromosome Segregation %K Craniofacial Abnormalities %K Diagnosis, Differential %K Dwarfism %K Female %K Genes, Dominant %K Genetic Association Studies %K Genetic Heterogeneity %K Humans %K Limb Deformities, Congenital %K Male %K Middle Aged %K Mutation, Missense %K Phenotype %K Urogenital Abnormalities %K Wnt Signaling Pathway %X

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, ∼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.

%B Am J Hum Genet %V 102 %P 27-43 %8 2018 Jan 04 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29276006?dopt=Abstract %R 10.1016/j.ajhg.2017.10.002 %0 Journal Article %J Am J Hum Genet %D 2017 %T De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder. %A Lessel, Davor %A Schob, Claudia %A Küry, Sébastien %A Reijnders, Margot R F %A Harel, Tamar %A Eldomery, Mohammad K %A Coban-Akdemir, Zeynep %A Denecke, Jonas %A Edvardson, Shimon %A Colin, Estelle %A Stegmann, Alexander P A %A Gerkes, Erica H %A Tessarech, Marine %A Bonneau, Dominique %A Barth, Magalie %A Besnard, Thomas %A Cogné, Benjamin %A Revah-Politi, Anya %A Strom, Tim M %A Rosenfeld, Jill A %A Yang, Yaping %A Posey, Jennifer E %A Immken, Ladonna %A Oundjian, Nelly %A Helbig, Katherine L %A Meeks, Naomi %A Zegar, Kelsey %A Morton, Jenny %A Schieving, Jolanda H %A Claasen, Ana %A Huentelman, Matthew %A Narayanan, Vinodh %A Ramsey, Keri %A Brunner, Han G %A Elpeleg, Orly %A Mercier, Sandra %A Bézieau, Stéphane %A Kubisch, Christian %A Kleefstra, Tjitske %A Kindler, Stefan %A Lupski, James R %A Kreienkamp, Hans-Jürgen %K Adenosine Triphosphatases %K Adolescent %K Amino Acids %K Cell Line %K Cell Line, Tumor %K Central Nervous System %K Child %K Child, Preschool %K Developmental Disabilities %K Female %K HEK293 Cells %K Humans %K Intellectual Disability %K Male %K Mutation, Missense %K RNA %K RNA Helicases %X

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

%B Am J Hum Genet %V 101 %P 716-724 %8 2017 Nov 02 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/29100085?dopt=Abstract %R 10.1016/j.ajhg.2017.09.014 %0 Journal Article %J Genet Med %D 2016 %T Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis. %A Ockeloen, Charlotte W %A Khandelwal, Kriti D %A Dreesen, Karoline %A Ludwig, Kerstin U %A Sullivan, Robert %A van Rooij, Iris A L M %A Thonissen, Michelle %A Swinnen, Steven %A Phan, Milien %A Conte, Federica %A Ishorst, Nina %A Gilissen, Christian %A RoaFuentes, Laury %A van de Vorst, Maartje %A Henkes, Arjen %A Steehouwer, Marloes %A van Beusekom, Ellen %A Bloemen, Marjon %A Vankeirsbilck, Bruno %A Bergé, Stefaan %A Hens, Greet %A Schoenaers, Joseph %A Poorten, Vincent Vander %A Roosenboom, Jasmien %A Verdonck, An %A Devriendt, Koen %A Roeleveldt, Nel %A Jhangiani, Shalini N %A Vissers, Lisenka E L M %A Lupski, James R %A de Ligt, Joep %A Von den Hoff, Johannes W %A Pfundt, Rolph %A Brunner, Han G %A Zhou, Huiqing %A Dixon, Jill %A Mangold, Elisabeth %A van Bokhoven, Hans %A Dixon, Michael J %A Kleefstra, Tjitske %A Hoischen, Alexander %A Carels, Carine E L %K Adolescent %K Anodontia %K Child %K Exome %K Female %K Frameshift Mutation %K Genetic Predisposition to Disease %K Humans %K Low Density Lipoprotein Receptor-Related Protein-6 %K Male %K Mutation, Missense %K Pedigree %K Sequence Analysis, DNA %K Wnt Signaling Pathway %X

PURPOSE: We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.

METHODS: WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.

RESULTS: We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo.

CONCLUSION: Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.

%B Genet Med %V 18 %P 1158-1162 %8 2016 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/26963285?dopt=Abstract %R 10.1038/gim.2016.10