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. 2022 Jun;59(6):559-567.
doi: 10.1136/jmedgenet-2020-107595. Epub 2021 Apr 5.

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita

Annie Laquerriere  1 , Dana Jaber  2 , Emanuela Abiusi  2   3 , Jérome Maluenda  2 , Dan Mejlachowicz  2 , Alexandre Vivanti  2 , Klaus Dieterich  4 , Radka Stoeva  2   5 , Loic Quevarec  2 , Flora Nolent  2 , Valerie Biancalana  6 , Philippe Latour  7 , Damien Sternberg  8 , Yline Capri  9 , Alain Verloes  9 , Bettina Bessieres  10 , Laurence Loeuillet  10 , Tania Attie-Bitach  10 , Jelena Martinovic  2   11 , Sophie Blesson  12 , Florence Petit  13 , Claire Beneteau  14 , Sandra Whalen  15 , Florent Marguet  1 , Jerome Bouligand  16 , Delphine Héron  17 , Géraldine Viot  18 , Jeanne Amiel  19 , Daniel Amram  20 , Céline Bellesme  21 , Martine Bucourt  22 , Laurence Faivre  23 , Pierre-Simon Jouk  4 , Suonavy Khung  24 , Sabine Sigaudy  25 , Anne-Lise Delezoide  24 , Alice Goldenberg  26 , Marie-Line Jacquemont  27 , Laetitia Lambert  28 , Valérie Layet  29 , Stanislas Lyonnet  30 , Arnold Munnich  30 , Lionel Van Maldergem  31 , Juliette Piard  31 , Fabien Guimiot  24 , Pierre Landrieu  21 , Pascaline Letard  22 , Fanny Pelluard  32 , Laurence Perrin  9 , Marie-Hélène Saint-Frison  24 , Haluk Topaloglu  33 , Laetitia Trestard  34 , Catherine Vincent-Delorme  13 , Helge Amthor  35 , Christine Barnerias  36 , Alexandra Benachi  2   37 , Eric Bieth  38 , Elise Boucher  31 , Valerie Cormier-Daire  19 , Andrée Delahaye-Duriez  22   39 , Isabelle Desguerre  36 , Bruno Eymard  40 , Christine Francannet  41 , Sarah Grotto  42 , Didier Lacombe  43 , Fanny Laffargue  41 , Marine Legendre  43 , Dominique Martin-Coignard  5 , André Mégarbané  44 , Sandra Mercier  14 , Mathilde Nizon  14 , Luc Rigonnot  45 , Fabienne Prieur  46 , Chloé Quélin  47 , Hanitra Ranjatoelina-Randrianaivo  27 , Nicoletta Resta  48 , Annick Toutain  49 , Helene Verhelst  50 , Marie Vincent  14 , Estelle Colin  51 , Catherine Fallet-Bianco  52 , Michèle Granier  53 , Romulus Grigorescu  54 , Julien Saada  37 , Marie Gonzales  10 , Anne Guiochon-Mantel  16 , Jean-Louis Bessereau  55 , Marcel Tawk  2 , Ivo Gut  56 , Cyril Gitiaux  57 , Judith Melki  58   59
Affiliations

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita

Annie Laquerriere et al. J Med Genet. 2022 Jun.

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.

Keywords: genomics; human genetics; nervous system malformations; neuromuscular diseases.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Genomic approaches including genetic mapping, TES or WES. n: number of unrelated patients and in brackets the percentage of index patients with disease gene identification (Gene Id.). Other approaches (n=4) included CMA, SMN1, MTM1 or NIPBL analyses. TES, targeted exome sequencing; WES, whole exome sequencing.
Figure 2
Figure 2
Comparative analysis of the percentage of patients with unrelated AMC in whom the disease gene was identified depending on whether the AMC was (i) familial (at least two affected patients) or sporadic (section ‘All’), (ii) in sporadic patients born to either CSG parents or not, (iii) familial AMC born to CSG parents or not. Statistical analysis was performed using Fisher’s exact test two tailed. In sporadic or familial patients, the consanguinity was unknown in 30 or 5 families, respectively. AMC, arthrogryposis multiplex congenita; CSG, consanguineous; ns, not significant.
Figure 3
Figure 3
Genes in which pathogenic variants were identified in our cohort of AMC index patients. The percentage indicates the ratio of patients with unrelated AMC carrying pathogenic variant(s) in a given gene to 166, the total number of index patients with an identified disease gene. The blue colour indicates new genes identified in AMC within the last 6 years. AMC, arthrogryposis multiplex congenita.
Figure 4
Figure 4
Pathogenic mechanisms in AMC. This study allowed an evaluation of the pathogenic mechanism through the function of the identified gene. The percentage indicates the ratio of patients carrying a mutation in a group of genes involved in a given function to 165, the total number of index patients with an identified disease gene (without the patient carrying the chromosomal translocation). AMC, arthrogryposis multiplex congenita; NMJ, neuromuscular junction.
Figure 5
Figure 5
Modes of inheritance based on disease gene identification. The percentage indicates the ratio of patients carrying pathogenic variants (s) with a given mode of inheritance (n) to 166, the total number of index patients with an identified disease gene.
Figure 6
Figure 6
Modes of inheritance of sporadic patients with AMC based on disease gene identification. De novo mutations include AD, AD with parental imprinting or X linked modes of inheritance. The percentage indicates the ratio of AMC with autosomal recessive or de novo mutation to the total number of CSG (n=29) or non-CSG index patients (n=60) with an identified disease gene. Statistical analysis was performed using Fisher’s exact test two tailed. AD, autosomal dominant; AMC, arthrogryposis multiplex congenita; CSG, consanguineous.
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