De novo mutations in FLNC leading to early‐onset restrictive cardiomyopathy and congenital myopathy

• Published in: Human mutation Vol. 39; no. 9; pp. 1161 - 1172
• Main Authors: Kiselev, Artem, Vaz, Raquel, Knyazeva, Anastasia, Khudiakov, Aleksandr, Tarnovskaya, Svetlana, Liu, Jiao, Sergushichev, Alexey, Kazakov, Sergey, Frishman, Dmitrij, Smolina, Natalia, Pervunina, Tatiana, Jorholt, John, Sjoberg, Gunnar, Vershinina, Tatiana, Rudenko, Dmitriy, Arner, Anders, Sejersen, Thomas, Lindstrand, Anna, Kostareva, Anna
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01.09.2018
• Subjects: Arthrogryposis; Cardiomyopathy; Children; Differential diagnosis; Electromyography; filamin C; Heart; Immunoglobulins; Medicin och hälsovetenskap; Morphology; Mutation; Myopathy; Neuromuscular diseases; Pathogenicity; Phenotypes; zebrafish model; zebrafish model; mutation; cardiomyopathy; filamin C; myopathy
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.23559

Mutations in FLNC for a long time are known in connection to neuromuscular disorders and only recently were described in association with various cardiomyopathies. Here, we report a new clinical phenotype of filaminopathy in four unrelated patients with early‐onset restrictive cardiomyopathy (RCM) in combination with congenital myopathy due to FLNC mutations (NM_001458.4:c.3557C>T, p.A1186V, rs1114167361 in three probands and c.[3547G>C; 3548C>T], p.A1183L, rs1131692185 in one proband). In all cases, concurrent myopathy was confirmed by neurological examination, electromyography, and morphological studies. Three of the patients also presented with arthrogryposis. The pathogenicity of the described missense variants was verified by cellular and morphological studies and by in vivo modeling in zebrafish. Combination of in silico and experimental approaches revealed that FLNC missense variants localized in Ig‐loop segments often lead to development of RCM. The described FLNC mutations associated with early‐onset RCMP extend cardiac spectrum of filaminopathies and facilitate the differential diagnosis of restrictive cardiac phenotype associated with neuromuscular involvement in children. We report a new clinical phenotype of filaminopathy with early—onset restrictive cardiomyopathy in combination with congenital myopathy and arthrogryposisdue to de novoFLNC mutations. Described FLNC mutations in combination with functional studies extend cardiac spectrum of filaminopathies and facilitate the differential diagnosis of restrictive cardiac phenotype associated with neuromuscular involvement in children.