Novel FHL1 mutation variant identified in a patient with nonobstructive hypertrophic cardiomyopathy and myopathy – a case report

Abstract

Background Hypertrophic cardiomyopathy (HCM) is a genetic disorder mostly caused by sarcomeric gene mutations, but almost 10% of cases are attributed to inherited metabolic and neuromuscular disorders. First described in 2008 in an American-Italian family with scapuloperoneal myopathy, FHL1 gene encodes four-and-a-half LIM domains 1 proteins which are involved in sarcomere formation, assembly and biomechanical stress sensing both in cardiac and skeletal muscle, and its mutations are responsible for a large spectrum of neuromuscular disorders (mostly myopathies) and cardiac disease, represented by HCM, either isolated, or in conjunction with neurologic and skeletal muscle impairment. We thereby report a novel mutation variant in FHL1 structure, associated with HCM and type 6 Emery-Dreifuss muscular dystrophy (EDMD). Case presentation We describe the case of a 40 year old male patient, who was referred to our department for evaluation in the setting of NYHA II heart failure symptoms and was found to have HCM. The elevated muscular enzymes raised the suspicion of a neuromuscular disease. Rigid low spine and wasting of deltoidus, supraspinatus, infraspinatus and calf muscles were described by the neurological examination. Electromyography and muscle biopsy found evidence of chronic myopathy. Diagnosis work-up was completed by next-generation sequencing genetic testing which found a likely pathogenic mutation in the FHL1 gene (c.157-1G > A, hemizygous) involved in the development of X-linked EDMD type 6. Conclusion This case report highlights the importance of multimodality diagnostic approach in a patient with a neuromuscular disorder and associated hypertrophic cardiomyopathy by identifying a novel mutation variant in FHL1 gene. Raising awareness of non-sarcomeric gene mutations which can lead to HCM is fundamental, because of diagnostic and clinical risk stratification challenges.

System-wide hematopoietic and immune signaling aberrations in COVID-19 revealed by deep proteome and phosphoproteome analysis

“…S9). Collectively, the JAK-STAT pathway may signal to reduce the transcriptional activity of EP300 (i.e., increased S1038 phosphorylation) and the expression of FHL1/SLIM, a protein implicated in protein turnover and cardiomyopathy 51,52 . JAK2/3 may also regulate cell proliferation through the SHP2-GRB2-SOS-RAS-RAF-MEK1/2 pathway and survival through the PI3K-AKT2 pathway.…”

Kinome and phosphoproteome reprogramming underlies the aberrant immune responses in critically ill COVID-19 patients

“…STAT1 activation may underlie the significant changes in expression of proteins involved in regulating inflammation, complement, metabolism, and T cell signaling while the activation of STAT3, STAT5, and STAT6 may contribute to immune suppression. Collectively, the JAK-STAT pathway may signal to reduce the transcriptional activity of EP300 (i.e., increased T887 phosphorylation) and the expression of FHL1/SLIM, which is implicated in protein turnover and cardiomyopathy [ 59 , 60 ]. JAK2/3 may also regulate cell proliferation through the SHP2-GRB2-SOS-RAS-RAF-MEK1/2 signaling pathway and survival through the PI3K-AKT2 pathway.…”

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

“…We detected variant c.764G>C in an HCM patient in the FHL1 gene, which is classifiable as a VUS according to ACMG criteria. However, it is reported as pathogenic by HGMD database, showing strong evidence for a primary pathogenic role in HCM [ 73 , 76 ]. The FHL1 gene was classified without evidence for a HCM association by ClinGen.…”