Novel CAPN3 variant associated with an autosomal dominant calpainopathy

Mathieu Cerino (1, 2) , Emmanuelle Salort-Campana (1, 3) , Alexandra Salvi (1) , P Cintas (4) , D. Renard (5) , R Juntas Morales (6) , C Tard (7) , F. Leturcq (8) , T Stojkovic (9) , Nathalie Bonello-Palot (1, 2) , Svetlana Gorokhova (1, 2) , Jeremie Mortreux (2, 1) , André Maues de Paula (1, 3) , Nicolas Levy (1, 3) , M. Cossée (10, 11) , Marc Bartoli (1) , Martin Krahn (1, 3) , Shahram Attarian (2, 1)

1 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
2 TIMONE - Hôpital de la Timone [CHU - APHM]
3 Département de génétique médicale [Hôpital de la Timone - APHM]
4 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
5 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
6 CHU Montpellier
7 CHU de Lille - Centre Hospitalier Universitaire de Lille
8 Hôpital Cochin [AP-HP]
9 CHU Pitié-Salpêtrière [AP-HP]
10 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
11 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]

Aims The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies. Methods Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance. Results We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice. Conclusions We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in‐frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well‐documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re‐assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.

Mots clés: dominant; calpainopathy; NGS; myopathy; CAPN3

Domaines: Sciences du Vivant [q-bio]; Génétique humaine

Mathieu Cerino, Emmanuelle Salort-Campana, Alexandra Salvi, P Cintas, D. Renard, et al.. Novel CAPN3 variant associated with an autosomal dominant calpainopathy. Neuropathology and Applied Neurobiology, 2020, ⟨10.1111/nan.12624⟩. ⟨hal-02901906⟩