Biallelic truncating variants in children with titinopathy represent a recognizable condition with distinctive muscular and cardiac characteristics: a report on five patients

Abstract

Background: Monoallelic and biallelic TTN truncating variants (TTNtv) may be responsible for a wide spectrum of musculoskeletal and cardiac disorders with different age at onset. Although the prevalence of heterozygous TTNtv is relatively high in the general population, cardiac phenotyping (mainly cardiomyopathies, CMPs) in biallelic titinopathy has rarely been described in children.

Methods: We reviewed the medical records of pediatric patients with biallelic TTNtv and cardiac involvement. Clinical exome sequencing excluded pathogenic/likely pathogenic variants in major CMP genes.

Results: Five pediatric patients (four male) with biallelic TTNtv were included. Major arthrogryposis multiplex was observed in four patients; no patient showed intellectual disability. At a cardiac level, congenital heart defects (atrial and ventricular septal defects, n = 3) and left ventricular non-compaction (n = 1) were reported. All patients had dilated cardiomyopathy (DCM) diagnosed at birth in one patient and at the age of 10, 13, 14, and 17 years in the other four patients. Heart rhythm monitoring showed tachyarrhythmias (premature ventricular contractions, n = 2; non-sustained ventricular tachycardia, n = 2) and nocturnal first-degree atrio-ventricular block (n = 2). Cardiac magnetic resonance (CMR) imaging was performed in all patients and revealed a peculiar late gadolinium enhancement distribution in three patients. HyperCKemia was present in two patients and end-stage heart failure in four. End-organ damage requiring heart transplantation (HT) was indicated in two patients, who were operated on successfully.

Conclusion: Biallelic TTNtv should be considered when evaluating children with severe and early-onset DCM, particularly if skeletal and muscular abnormalities are present, e.g., arthrogryposis multiplex and congenital progressive myopathy. End-stage heart failure is common and may require HT.

Keywords: children; dilated cardiomyopathy; heart failure; neuromuscular disease; titin (TTN); titinopathy; truncating variant.

Figure 1

Schematic structure of titin: principal cardiac long isoform N2BA (NM_001256850.1) and schematic representation of the variants presented in our cohort. Patient 1, with very mild musculoskeletal phenotype, carries variants that are located beyond the second half of the I-band and the most distal part of the M-band. All other patients, with remarkable extracardiac involvement, show more proximally located variants.

Figure 2

Panel 1 shows skeletal muscular magnetic resonance imaging with diffuse fibrofatty infiltration of different degree. Minimal changes are observed in patient 1, while changes in almost each muscular segment are present in patient 4. Panel 2 includes major cardiac studies including cardiac magnetic resonance imaging in patients 2–5 with variable degree of late gadolinium enhancement of different intensity in three out of five patients, mainly in the subepicardial region. Specific histological specimens from extracted hearts of patients 1 and 3 are included: (A) in patient 1, the myocardium is characterized by polymetric and polymorphic nuclei of cardiomyocytes (HE, 10×). (B) Masson trichrome staining shows mild fibrotic expansion of the interstitium (10×), while in patient 3, (C) eccentric hypertrophy of the left ventricular free wall can be seen (HE, 1.25×). (D) In the insert, at higher magnification, large areas with loss of myocardium replaced by fibrosis (HE, 40×). The lower panel shows the ECG changes, including non-sustained ventricular tachycardia and premature ventricular contractions in patients 2, 3, and 4, respectively.

Figure 3

Wide phenotypic variability was noticed in the study cohort ranging from apparently no major skeletal or multisystemic involvement (patient 1) to major arthrogryposis, muscular rigidity, and craniofacial changes in patient 4. Moreover, in the latter, panoramic coronal curved multiplanar reconstructions (A,B) show diffuse, severe, end-stage fatty infiltration of all muscular groups, including intercostal ones (white arrows). Coronal and reformatted axial VIBE T1 DIXON of pelvis and thighs (C,D) revealed a less evident (moderate) bilateral fatty infiltration of adductor longus muscles (yellow arrows). Diffuse severe fatty infiltration of all muscular groups of the pelvis, thighs, and legs. Coronal and reformatted axial VIBE T1 DIXON (E,F) of the legs shows diffuse end-stage fatty infiltration of all muscular groups.

Figure 4

Family pedigrees of the study cohort showing phenotype-negative individuals with heterozygous variants and phenotype positive individuals with biallelic variants.