Testing for LMNA Mutations Called ‘Woefully Underutilized'

Medscape

15-07-2025

People with mutated copies of the LMNA gene are at high risk for cardiac laminopathies, including atrioventricular block and atrial or ventricular arrhythmias (VAs) leading to dilated cardiomyopathy.
These autosomal dominant mutations have a high penetrance, meaning that a high percentage of persons with a pathogenic or likely pathogenic variant will develop health problems related to the gene. For those with cardiac manifestations, about 90% of carriers of LMNA mutations older than 30 years have a high risk for sudden death from arrhythmia — even patients with minimal left ventricular dilation and mild systolic impairment — well before the onset of heart failure. A long-term follow-up study from 122 consecutive carriers of LMNA mutations with cardiac conditions showed that most had experienced arrhythmia, heart block, embolic events, or heart failure within 7 years of diagnosis.
Could some outcomes, such as sudden cardiac death, be averted with a more precise view of LMNA mutations? New research published in JAMA Cardiology shows pinpointing the type and location of the LMNA mutation may guide clinicians toward earlier treatment approaches to improve prognosis for these high-risk patients. These interventions might include earlier placement of implantable cardioverter-defibrillator (ICD) devices and family testing to detect the mutation before the onset of symptoms.
'Genetic testing for dilated cardiomyopathy is woefully underutilized,' said the paper's senior author, Neal Lakdawala, MD, an associate professor of medicine at Harvard Medical School and a cardiologist in the Heart and Vascular Center at Brigham and Women's Hospital, in Boston.
In fact, claims data showed that fewer than 2% of patients with dilated cardiomyopathy undergo genetic testing. 'Prior research has established the prognostic power of a genetic diagnosis,' Lakdawala told Medscape Medical News . 'We took it one step further within a specific genetic etiology, to show that the type of gene variant and the location of a gene variant also matter.'
The retrospective cohort study examined international registry data from 718 patients (mean age, 41.3 ± 14.3 years) with pathogenic or likely pathogenic variants of LMNA . The participants in the study had no prior history of malignant VA. The primary outcome was time to malignant VA, defined as sudden cardiac death, placement of an ICD, or other manifestations of hemodynamically unstable VA. The secondary outcome, advanced heart failure, was defined as nonsudden cardiac death, implantation of a left ventricular assist device, or heart transplant.
Reflecting the high risk associated with LMNA mutations, Lakdawala said, nearly one third of the study participants experienced sudden cardiac death, hemodynamically unstable VA, or an ICD procedure during the 4.2-year follow-up period. In addition, 15% developed advanced heart failure, defined as the implantation of a left ventricular assist device, heart transplant, or nonsudden cardiac death. These outcomes occurred despite many patients having a baseline left ventricular ejection fraction (EF) in the normal range (mean EF was 56%, well above guideline-recommended thresholds of 35%-45% for ICD placement, the researchers reported).
Looking deeper into the genes, Lakdawala and his colleagues found participants who had truncating LMNA variants — an abbreviated version of the protein — had worse arrhythmic outcomes, regardless of the position of this genetic mutation on the DNA sequence. On the other hand, those who exhibited missense variants of the LMNA gene — an altered amino acid on the DNA sequence — had a lower risk for harmful arrhythmias and better overall outcomes.
Taken together, the location and nature of the gene variants could lead to specific predictions of cardiac risk, according to the researchers. A man with an EF of 50% and a truncating LMNA gene variant, for example, would have a 12% risk for VA within 5 years, but a 7.2% risk if a missense variant were present. For a woman with EF 50%, this risk would be 7.5% for a truncating variant vs 4.5% for a missense variant, if no other risk factors were present.
Why Genetic Testing Is Key
In an editorial accompanying the journal article, Sharlene M. Day, MD, a cardiomyopathy specialist and presidential professor at the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia, wrote 'the data from this study can also inform risk stratification even in healthy populations with incidental or secondary findings.' Integrating genetic findings into cardiomyopathy management should be 'a priority for all practicing cardiologists,' she wrote.
'The knowledge gap appears to be narrowing with respect to the importance of genetic testing in patients with cardiomyopathies,' Day told Medscape Medical News . 'But there's still opportunity to improve recommendations and referrals by cardiologists for genetic counseling and testing.'
Testing typically consists of a broad panel identifying multiple gene variants, including LMNA , she said. If a gene variant is found in an individual patient, cascade testing of family members for that variant is often recommended.
'The current research study nicely highlights the impact of identifying not only the specific gene involved but the type of variation within that gene in terms of risk stratifying patients for adverse outcomes,' she said.
Impact on Future Cardiology Guidelines
Future clinical practice guidelines should emphasize the value of a genetic diagnosis for risk stratification in patients with dilated cardiomyopathy, especially for predicting sudden death and heart failure, Lakdawala said. The most recent guidelines on heart failure from the American College of Cardiology and the American Heart Association list a class 2A recommendation for placement of an ICD in patients with high-risk genes for dilated cardiomyopathy and an EF of 45% or lower, adding that primary preventive ICD may be considered for those with higher EF.
The 2023 European Cardiomyopathy Guideline recommends placement of ICDs in patients with LMNA variants and an EF above 35% (class 2A if risk factors are present and class 2B if no risk factors are present). 'For updated guidelines, I think the most immediate impact would be to refine the LMNA risk score for ventricular arrhythmias to include the type and location of the LMNA variant,' Day told Medscape Medical News .
'Genetic testing has clinical ramifications that will help cardiologists take better care of their patients,' Lakdawala added. 'The take-home message is that they should order these tests!'
Lakdawala reported receiving personal fees from Alexion, Bayer, Bristol Myers Squibb, Cytokinetics, Lexeo Therapeutics, Nuevocor, Pfizer, and Tenaya Therapeutics and grants from Bristol Myers Squibb and Pfizer.
Day reported serving as chair of the steering committee for Lexicon Pharmaceuticals, on the data monitoring committee for Cytokinetics, and receiving grants from Bristol Myers Squibb.