RT Journal Article
SR Electronic
T1 Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP jmedgenet-2020-107595
DO 10.1136/jmedgenet-2020-107595
A1 Annie Laquerriere
A1 Dana Jaber
A1 Emanuela Abiusi
A1 Jérome Maluenda
A1 Dan Mejlachowicz
A1 Alexandre Vivanti
A1 Klaus Dieterich
A1 Radka Stoeva
A1 Loic Quevarec
A1 Flora Nolent
A1 Valerie Biancalana
A1 Philippe Latour
A1 Damien Sternberg
A1 Yline Capri
A1 Alain Verloes
A1 Bettina Bessieres
A1 Laurence Loeuillet
A1 Tania Attie-Bitach
A1 Jelena Martinovic
A1 Sophie Blesson
A1 Florence Petit
A1 Claire Beneteau
A1 Sandra Whalen
A1 Florent Marguet
A1 Jerome Bouligand
A1 Delphine Héron
A1 Géraldine Viot
A1 Jeanne Amiel
A1 Daniel Amram
A1 Céline Bellesme
A1 Martine Bucourt
A1 Laurence Faivre
A1 Pierre-Simon Jouk
A1 Suonavy Khung
A1 Sabine Sigaudy
A1 Anne-Lise Delezoide
A1 Alice Goldenberg
A1 Marie-Line Jacquemont
A1 Laetitia Lambert
A1 Valérie Layet
A1 Stanislas Lyonnet
A1 Arnold Munnich
A1 Lionel Van Maldergem
A1 Juliette Piard
A1 Fabien Guimiot
A1 Pierre Landrieu
A1 Pascaline Letard
A1 Fanny Pelluard
A1 Laurence Perrin
A1 Marie-Hélène Saint-Frison
A1 Haluk Topaloglu
A1 Laetitia Trestard
A1 Catherine Vincent-Delorme
A1 Helge Amthor
A1 Christine Barnerias
A1 Alexandra Benachi
A1 Eric Bieth
A1 Elise Boucher
A1 Valerie Cormier-Daire
A1 Andrée Delahaye-Duriez
A1 Isabelle Desguerre
A1 Bruno Eymard
A1 Christine Francannet
A1 Sarah Grotto
A1 Didier Lacombe
A1 Fanny Laffargue
A1 Marine Legendre
A1 Dominique Martin-Coignard
A1 André Mégarbané
A1 Sandra Mercier
A1 Mathilde Nizon
A1 Luc Rigonnot
A1 Fabienne Prieur
A1 Chloé Quélin
A1 Hanitra Ranjatoelina-Randrianaivo
A1 Nicoletta Resta
A1 Annick Toutain
A1 Helene Verhelst
A1 Marie Vincent
A1 Estelle Colin
A1 Catherine Fallet-Bianco
A1 Michèle Granier
A1 Romulus Grigorescu
A1 Julien Saada
A1 Marie Gonzales
A1 Anne Guiochon-Mantel
A1 Jean-Louis Bessereau
A1 Marcel Tawk
A1 Ivo Gut
A1 Cyril Gitiaux
A1 Judith Melki
YR 2021
UL http://jmg.bmj.com/content/early/2021/04/04/jmedgenet-2020-107595.abstract
AB 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.