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

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.