Low mutation rate in the TTN gene in paediatric patients with dilated cardiomyopathy – a pilot study

Abstract

Idiopathic dilated cardiomyopathy (DCM) is a common cardiomyopathy with the prevalence of 1:250, and at least one-third of all the cases are inherited. Mutations in the TTN gene are considered as the most frequent cause of inherited DCM and cover 10–30% of the cases. The studies were mainly focused on the adult or mixed age group of patients with DCM. The mutation rate in the TTN gene, the characteristics of manifestations and their prognostic significance in childhood have not been studied. To determine TTN mutation rate in children with DCM and the relevance of including this gene in the DNA diagnostic protocol for paediatric DCM, complete clinical and instrumental examination of 36 DCM patients (up to 18 years) with the manifestation of the disease was conducted in specialised cardiology centres. Molecular genetic testing included sequencing of coding and adjacent regulatory regions of the major cardiac TTN isoform N2BA using IonTorrent ™ semiconductor sequencing (for 25 isolated cases) and trio whole exome sequencing (trio WES)on the Illumina platform (for 11 family cases). Our pilot group included 36 probands with DCM diagnosis first established on the basis of the generally accepted criteria at the age of 5 days to 18 years(average age: 6.5 years). The sex ratio (M:F) was 23: 8. There were 25 sporadic DCM cases and 11 cases of familial DCM (at least one of the parents and/or siblings were also diagnosed with DCM). The only likely pathogenic truncating variant p.Arg33703*in the TTN gene (TTNtv) was found in a 16-year-oldmale proband out of 36 (3%). Apparently, TTN-dependent forms of DCMs manifest later at a young (but older than 18 years) or more mature age, and TTN gene cannot be considered as the first-line genetic testing for DCM in the paediatric group, despite several studies have reported a generally high mutation rate in this gene with DCM. Further research is needed to compare the representation of mutations in the TTN gene in different age groups of DCM patients.

The genetic architecture of pediatric cardiomyopathy

“…In children, reports of TTNtv are primarily from smaller studies and vary from $2%-13% with authors reaching different conclusions about the importance of TTN testing in younger children. 22,[49][50][51][52][53] Pugh et al identified causative TTN variants in a cohort of children but not infants (age 0-2), and TTN variants are the largest cause of DCM in 2-18 year olds. 49 They reported 10% (95% CI, 5.5%-30.6%) P/LP variants in TTN, though their sample size was small (n ¼ 29).…”

Targeted Sequencing of 242 Clinically Important Genes in the Russian Population From the Ivanovo Region

“…Moreover, this whole-exome study demonstrated the overrepresentation of several disease-causing variants for Mendelian disorders, such as phenylketonuria (PAH, rs5030858), Wilson's disease (ATP7B, rs76151636), factor VII deficiency (F7, rs36209567), and the kyphoscoliosis type of Ehlers-Danlos syndrome (FKBP14, rs542489955). For the Russian population, however, pathogenic variant frequencies were reported mostly for relatively small cohorts including patients and their families and targeted at specific genes and disorders, for example, familial hypercholesterolemia (Meshkov et al, 2021;Miroshnikova et al, 2021); cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss (Kiseleva et al, 2020;Petrova et al, 2020); cardiomyopathy (Marakhonov et al, 2019;Zaklyazminskaya et al, 2019;Kulikova et al, 2021;Shestak et al, 2021); and breast and ovarian cancer (Brovkina et al, 2018;Solodskikh et al, 2019).…”

Genotype and Cardiac Outcomes in Pediatric Dilated Cardiomyopathy

“… 23 Others have reported TTN variants associated with DCM in childhood. 19 , 20 One important note from our study is that P/LP TTN variants determined by cardiac genetic testing in infancy may still be associated with life‐threatening cardiac outcomes.…”