Fully penetrant genetic mutation results in wide familial variability: a cardiac magnetic resonance focused report

Dilated cardiomyopathy (DCM) is a progressive and often irreversible disease of the myocardium characterized by left ventricular (LV) or biventricular dilation alongside systolic dysfunction. While non-genetic causes are numerous and of great importance, up to 35% of the patients diagnosed with DCM have genetic alterations which contribute to or cause the development of genetic DCM. The genes suffering mutations are encoding mainly for structural proteins of the cytoskeleton, the cardiomyocytic sarcomeres and nuclear envelope proteins. Although inheritance in an X-linked, autosomal recessive or mitochondrial pattern is possible, most of the genetic anomalies are inherited as an autosomal dominant trait. This report aims to highlight cardiac magnetic resonance imaging in a DCM family¹.

A 37-year-old man, who had presented dyspnea and had undergone a cardiological check-up, was sent to our department in order to evaluate the diagnosis of dilated cardiomyopathy through cardiac magnetic resonance (CMR), which was performed on a 3.0 Tesla machine. Long axis SSFP Cine imaging showed dilation of the left ventricle, while also demonstrating apical hypertrabeculation meeting the criteria for non-compaction (Figure 1; Video file 1).

Figure 1

Using short axis SSFP Cine imaging, ventricular volumes and function were computed showing mild LV dilation, with a left ventricular end-diastolic volume (LVEDV) of 222 ml (117 ml/m²) and moderate systolic dysfunction (left ventricular ejection fraction – LVEF of 42%) due to generalized hypokinesia. Right ventricular (RV) dimension and function were normal. While, T2-weighted imaging showed no sign of myocardial edema, T1 mapping sequences revealed high T1 in the basal and mid inferior part of the interventricular septum (T1 = 1350 ms) (Figure 2).

Figure 2

Late gadolinium enhancement PSIR images reveal myocardial mid-wall fibrosis in the inferior IVS the partially extends towards the anterior IVS – incomplete „septal stripe” (Figure 3).

Figure 3

Thus, we concluded that the CMR aspect is that of typical non-ischemic DCM and followed-up with complete family history (including drawing a 2-generation pedigree – Figure 4).

Figure 4

Family history revealed that the patient’s mother (B1) was actually herself diagnosed with DCM 7 years before and had a cardiac defibrillator implanted for primary prevention of sudden cardiac death due to reduced LVEF. She also had a CMR exam 6 years prior which demonstrated severe LV dilation (LVEDV = 202 ml; 121 ml/m²) and reduced LVEF (23%), lateral LV non-compaction and mid-wall IVS fibrosis (Figure 5; Video file 2).

Figure 5

Moreover, the maternal grandfather (C1) had also been diagnosed with DCM, however he had very mild symptoms and had died at 87. Positive family history made it very likely that a genetic test would reveal a causing mutation for DCM and, indeed, the index patient’s test revealed a pathogenic mutation in the TTN (titin) gene (c.79273A>T). Cascade genetic testing followed, firstly for the mother (B1), sister (A2) and uncle (B2), which all came back positive for the same mutation, followed by testing of the 2 cousins (A3, A4) which also came back positive. (Updated pedigree in Figure 6).

Figure 6

The uncle and two cousins underwent CMR examinations, while the sister (A2) is scheduled to have a CMR in the following months. The uncle (B2) had normal LV volume and function, no LV non-compaction, but had focal mid-wall fibrosis in the inferior IVS. The male cousin (A3), had normal LV volume and function, no myocardial fibrosis, but had LV non-compaction, while the female cousin (A4) had a completely normal exam. The different CMR findings of all the family members are summarized in Figure 7 – the central illustration of this report.

Figure 7

This case report underlines the fact that the effects of mutations on the mechanisms of disease expression are still an unresolved issue of research. In this family, there was substantial difference in phenotypic expression of the disease, even though the mutation they carried was the same. On one hand, we have the paternal grandfather of the proband who had a mild form of DCM, with a normal lifespan, no major cardiovascular events or repeated hospitalizations for heart failure. On the other hand, the mother of the proband suffers from a severe form of DCM, diagnosed at the age of 54, and underwent an ICD implantation procedure for primary prevention of sudden cardiac death, while the index patient, at the age of 37, already has moderate systolic dysfunction. Moreover, on the other side of the family, the uncle, at the age of 55, has no dilation or dysfunction of the LV, only presenting focal myocardial fibrosis, while his son has LV non-compaction as a sign of cardiomyopathy. Whether genetic modulators or non-genetic triggers had contributed to the development of DCM is an issue that still needs to be addressed². Another particularity of this family is that, despite and autosomal genetic inheritance pattern (50% chance of transmission to any child), the penetrance was complete.

TTN mutations are the most frequent cause of genetic DCM. Titin is the largest protein in the human body, encoded by 364 exons in the TTN gene, and represents an essential component of the sarcomere. The impact of titin mutations in the development of cardiac disease highlights our only partial understanding of its properties and function. Initially, titin was thought to be related mostly to sarcomeric integrity and passive stiffness, but recent evidence suggests that titin may contribute significantly to the length-dependent activation through structural rearrangements of both thin- and thick-filament proteins³. These complex findings partially explain how the heterogeneity of pathogenicity of TTN influences cardiac phenotypes⁴.

Finally, our findings are in accordance with an excellent recent CMR study on the specific fibrosis patterns of different DCM-causing gene mutations⁵. Indeed, basal inferior IVS fibrosis is reported to be found in TTN mutations, among others. This confirms that CMR plays an important role in guiding the etiologic diagnosis in DCM.

Through extended CMR and genetic evaluation, this report illustrates the phenotypic heterogenicity of a completely penetrant TTN mutation within one family, suggesting a possible influence of other genetic or non-genetic factors and potential compensatory mechanisms. Moreover, we highlight the importance of CMR evaluation in DCM, showing that alterations such as myocardial fibrosis or LV non-compaction can be present in cases without LV dilation or dysfunction.