@article {Laquerriere559, author = {Annie Laquerriere and Dana Jaber and Emanuela Abiusi and J{\'e}rome Maluenda and Dan Mejlachowicz and Alexandre Vivanti and Klaus Dieterich and Radka Stoeva and Loic Quevarec and Flora Nolent and Valerie Biancalana and Philippe Latour and Damien Sternberg and Yline Capri and Alain Verloes and Bettina Bessieres and Laurence Loeuillet and Tania Attie-Bitach and Jelena Martinovic and Sophie Blesson and Florence Petit and Claire Beneteau and Sandra Whalen and Florent Marguet and Jerome Bouligand and Delphine H{\'e}ron and G{\'e}raldine Viot and Jeanne Amiel and Daniel Amram and C{\'e}line Bellesme and Martine Bucourt and Laurence Faivre and Pierre-Simon Jouk and Suonavy Khung and Sabine Sigaudy and Anne-Lise Delezoide and Alice Goldenberg and Marie-Line Jacquemont and Laetitia Lambert and Val{\'e}rie Layet and Stanislas Lyonnet and Arnold Munnich and Lionel Van Maldergem and Juliette Piard and Fabien Guimiot and Pierre Landrieu and Pascaline Letard and Fanny Pelluard and Laurence Perrin and Marie-H{\'e}l{\`e}ne Saint-Frison and Haluk Topaloglu and Laetitia Trestard and Catherine Vincent-Delorme and Helge Amthor and Christine Barnerias and Alexandra Benachi and Eric Bieth and Elise Boucher and Valerie Cormier-Daire and Andr{\'e}e Delahaye-Duriez and Isabelle Desguerre and Bruno Eymard and Christine Francannet and Sarah Grotto and Didier Lacombe and Fanny Laffargue and Marine Legendre and Dominique Martin-Coignard and Andr{\'e} M{\'e}garban{\'e} and Sandra Mercier and Mathilde Nizon and Luc Rigonnot and Fabienne Prieur and Chlo{\'e} Qu{\'e}lin and Hanitra Ranjatoelina-Randrianaivo and Nicoletta Resta and Annick Toutain and Helene Verhelst and Marie Vincent and Estelle Colin and Catherine Fallet-Bianco and Mich{\`e}le Granier and Romulus Grigorescu and Julien Saada and Marie Gonzales and Anne Guiochon-Mantel and Jean-Louis Bessereau and Marcel Tawk and Ivo Gut and Cyril Gitiaux and Judith Melki}, title = {Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita}, volume = {59}, number = {6}, pages = {559--567}, year = {2022}, doi = {10.1136/jmedgenet-2020-107595}, publisher = {BMJ Publishing Group Ltd}, abstract = {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.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/59/6/559}, eprint = {https://jmg.bmj.com/content/59/6/559.full.pdf}, journal = {Journal of Medical Genetics} }