TY - JOUR T1 - Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2020-107595 SP - jmedgenet-2020-107595 AU - Annie Laquerriere AU - Dana Jaber AU - Emanuela Abiusi AU - Jérome Maluenda AU - Dan Mejlachowicz AU - Alexandre Vivanti AU - Klaus Dieterich AU - Radka Stoeva AU - Loic Quevarec AU - Flora Nolent AU - Valerie Biancalana AU - Philippe Latour AU - Damien Sternberg AU - Yline Capri AU - Alain Verloes AU - Bettina Bessieres AU - Laurence Loeuillet AU - Tania Attie-Bitach AU - Jelena Martinovic AU - Sophie Blesson AU - Florence Petit AU - Claire Beneteau AU - Sandra Whalen AU - Florent Marguet AU - Jerome Bouligand AU - Delphine Héron AU - Géraldine Viot AU - Jeanne Amiel AU - Daniel Amram AU - Céline Bellesme AU - Martine Bucourt AU - Laurence Faivre AU - Pierre-Simon Jouk AU - Suonavy Khung AU - Sabine Sigaudy AU - Anne-Lise Delezoide AU - Alice Goldenberg AU - Marie-Line Jacquemont AU - Laetitia Lambert AU - Valérie Layet AU - Stanislas Lyonnet AU - Arnold Munnich AU - Lionel Van Maldergem AU - Juliette Piard AU - Fabien Guimiot AU - Pierre Landrieu AU - Pascaline Letard AU - Fanny Pelluard AU - Laurence Perrin AU - Marie-Hélène Saint-Frison AU - Haluk Topaloglu AU - Laetitia Trestard AU - Catherine Vincent-Delorme AU - Helge Amthor AU - Christine Barnerias AU - Alexandra Benachi AU - Eric Bieth AU - Elise Boucher AU - Valerie Cormier-Daire AU - Andrée Delahaye-Duriez AU - Isabelle Desguerre AU - Bruno Eymard AU - Christine Francannet AU - Sarah Grotto AU - Didier Lacombe AU - Fanny Laffargue AU - Marine Legendre AU - Dominique Martin-Coignard AU - André Mégarbané AU - Sandra Mercier AU - Mathilde Nizon AU - Luc Rigonnot AU - Fabienne Prieur AU - Chloé Quélin AU - Hanitra Ranjatoelina-Randrianaivo AU - Nicoletta Resta AU - Annick Toutain AU - Helene Verhelst AU - Marie Vincent AU - Estelle Colin AU - Catherine Fallet-Bianco AU - Michèle Granier AU - Romulus Grigorescu AU - Julien Saada AU - Marie Gonzales AU - Anne Guiochon-Mantel AU - Jean-Louis Bessereau AU - Marcel Tawk AU - Ivo Gut AU - Cyril Gitiaux AU - Judith Melki Y1 - 2021/04/04 UR - http://jmg.bmj.com/content/early/2021/04/04/jmedgenet-2020-107595.abstract N2 - Background Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.Methods Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.Results We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).Conclusion New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included. ER -