Genetic Testing for Dilated Cardiomyopathy in Clinical Practice

Abstract

Background Familial involvement is common in dilated cardiomyopathy (DCM) and >40 genes have been implicated in causing disease. However, the role of genetic testing in clinical practice is not well defined. We examined the experience of clinical genetic testing in a diverse DCM population to characterize the prevalence and predictors of gene mutations. Methods and Results We studied 264 unrelated adult and pediatric DCM index patients referred to 1 reference lab for clinical genetic testing. Up to 10 genes were analyzed (MYH7, TNNT2, TNNI3, TPM1, MYBPC3, ACTC, LMNA, PLN, TAZ, and LDB3), and 70% of patients were tested for all genes. The mean age was 26.6 ± 21.3 years, and 52% had a family history of DCM. Rigorous criteria were used to classify DNA variants as clinically relevant (mutations), variants of unknown clinical significance (VUS), or presumed benign. Mutations were found in 17.4% of patients, commonly involving MYH7, LMNA, or TNNT2 (78%). An additional 10.6% of patients had VUS. Genetic testing was rarely positive in older patients without a family history of DCM. Conversely in pediatric patients, family history did not increase the sensitivity of genetic testing. Conclusions Using rigorous criteria for classifying DNA variants, mutations were identified in 17% of a diverse group of DCM index patients referred for clinical genetic testing. The low sensitivity of genetic testing in DCM reflects limitations in both current methodology and knowledge of DCM-associated genes. However, if mutations are identified, genetic testing can help guide family management.

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing

“…Our previous analyses indicated that the overall detection rate for pathogenic DCM variants across all genes tested did not differ among age groups. 26 In our current data set, detection rates did not differ among age groups except for those for the two most recent gene panels (24 and 46 genes; Supplementary Figure S2 online). Here, the higher detection rate in the adult and pediatric groups was driven mostly by TTN and DSP, although it should be noted that the numbers behind some of these detection rates are small (for confidence intervals, see Supplementary Table S2 online).…”

“…Interestingly, the clinical sensitivity for individuals with a family history of DCM was similar to that obtained for the entire cohort (with positive rates improving from 6.9-8.6% to 31-38%) and is consistent with our previous, smaller study. 26 This is different from what has been reported for HCM, for which a family history substantially increases the likelihood of detecting a clinically relevant variant. A second variable that is often suspected to correlate with detection rates is age.…”

Dilated Cardiomyopathy

“…These studies suggest that mutations in sarcomeric genes, including TTN (titin), MYH7 (myosin heavy chain), TNNT2 (cardiac troponin T) and TPM1 (α-tropomyosin) are the most common etiologies, collectively accounting for ~30% of cases. 8,16,[21][22][23] Mutations in LMNA, which encodes Lamin A/C, a nuclear envelope protein, have been shown to cause different phenotypes associated with DCM, including DCM with limb-girdle or Emery-Dreifuss muscular dystrophy. Patients with LMNA mutations and DCM also have electrical instability (DCM+E), with supraventricular arrhythmias and atrioventricular block (AVB) often present before systolic dysfunction.…”

“…16 However, the likelihood of finding a mutation appears less likely in older patients (> 40 years) with non-familial disease. 23 Ordering providers should be aware of the limitations of genetic testing for DCM, especially as they apply to indeterminate and "negative" test results in index patients. Importantly, not all genetic variation identified by genetic testing is pathogenic, and clinical decisions should not be predicated on genetic variants of uncertain or indeterminate clinical significance.…”

Recent Developments in the Genetics of Cardiomyopathies

“…For example, mutations in the myosin heavy chains, myosin-binding protein C, cardiac troponins and calcium handling protein genes are associated with more than one type of cardiomyopathy. DCM in particular, has been associated with a large number different genes [8]. Moreover, within the individual genes, multiple mutations and variants have been described and novel mutations private to individual families continue to be identified.…”