This study sheds light on the genetic causes of dilated cardiomyopathy by finding a strong link between the nebulin-related anchoring protein gene (NRAP) and autosomal recessive dilated cardiomyopathy. Inclusion of this gene in cardiology gene panels is key for diagnosing individuals with a clinical suspicion of this condition.
Dilated cardiomyopathy (DCM) affects between 1:500 to 1:3000 in the general population. As much as 30% to 50% of DCM is thought to be genetic or familial with over 40 genes linked to the disorder.
“Although knowledge about the genetic etiology of DCM has developed rapidly over the past 10 years, we still encounter familial cases in which conventional genetic testing is negative, especially in families compatible with an autosomal recessive form of DCM,” said cardiologist Tiina Heliö, MD, PhD, from Helsinki University Hospital Heart and Lung Center. “Our study adds to the diagnostic tool kit in the search for a patient’s molecular diagnosis. A molecular genetic diagnosis allows for risk stratification among family members: those who are at risk of developing of DCM can be followed-up whereas those not at risk, are discharged from long-term follow-up and lifestyle modifications.”
In the study, a total of 11 out of 577 patients with either clinically diagnosed DCM or suspected DCM were identified to have two NRAP variants. None of the 11 individuals had an alternative molecular diagnosis. The study found that biallelic NRAP variants could explain up to 2.46% of all DCM cases.
This clinically significant finding was possible given the availability of both comprehensive clinical information in addition to large amounts of genetic data. Segregation studies and clinical characterization of family members were key in establishing the link between NRAP and DCM.
“The results of this study provide valuable information, suggesting NRAP is the most common cause of autosomal recessive dilated cardiomyopathy,” said Blueprint Genetics Executive Director of Medical and Laboratory Director, Juha Koskenvuo, MD, PhD. “Considering the link between NRAP variants and a more severe DCM presentation, this information is critical for clinicians caring for patients with suspected dilated cardiomyopathy. NRAP should become available for testing of DCM at a large scale to gain the full benefit for diagnostics.”
The study in short:
- Analyzed the frequency of rare NRAP variants in a cohort of 577 patients with either a confirmed or suspected DCM diagnosis, and 31,062 control patients
- All variant calls from the NRAP gene were queried from the internal variant database in 31,639 individuals who underwent genetic testing using NGS-panels or direct WES approach
- Focused on variants in NRAP with the highest potential to cause disease, specifically protein-truncating variants (PTVs) and missense variants
- Identified two NRAP variants in 11 out of 577 unrelated probands with DCM (1.9%), but none of the controls
- Data obtained from family member testing supports segregation
Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy Koskenvuo J, Saarinen I, Ahonen S, Tommiska J, Weckström S, Seppälä E, Tuupanen S, Kangas-Kontio T, Schleit J, Heliö K, Hathaway J, Gummesson A, Dahlberg P, Ojala T, Vepsäläinen V, Kytölä V, Muona M, Sistonen J, Salmenperä P, Gentile M, Paananen J, Myllykangas S, Alastalo T, Heliö T. (2021) Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy. PLOS ONE 16(2): e0245681. https://doi.org/10.1371/journal.pone.0245681
Executive Director, Medical & Lab Director, Juha Koskenvuo, MD, PhD, firstname.lastname@example.org
HUS Helsinki University Hospital
Cardiologist Tiina Heliö, email@example.com