Whole-exome sequencing revealed a likely pathogenic variant in NF1 causing neurofibromatosis type I and Arrhythmogenic Cardiomyopathy

Neurofibromatosis (NF), with an incidence of 1 to 5 per 10 000 live births worldwide, is a genetic disorder that causes tumors in nerve tissue [1, 2]. The inheritance pattern of NF is autosomal dominant [2] and is divided into 3 categories: NF1, NF2, and schwannomatosis [3]. NF1, also called “von Recklinghausen’s disease”, is caused by germ-line mutations in tumor suppressor genes [4], with symptoms including pigmentary lesions (brown macules, freckles, skin folds, and Lisch nodules), skin neurofibromas, skeletal abnormalities (scoliosis, tibia pseudarthrosis, and orbital dysplasia), brain tumors (gliomas of the visual pathway and glioblastomas), and peripheral nerve tumors (spinal neurofibromas, plexiform neurofibromas, and malignant peripheral nerve sheath tumors) [4]. It typically manifests during childhood, although it can appear in adulthood as well. NF1 sometimes causes cardiovascular diseases [5], such as congenital heart diseases [6] and cardiomyopathies [7]. In a study by Ibarrola et al., left ventricular non-compaction and orthodromic atrioventricular tachycardia were observed in a patient with NF1 [8]. Moreover, a patient with NF1 and hypertrophic cardiomyopathy (HCM) was described by Jurko et al. [9]. Nguyen et al. [10] concluded that in patients with sizeable deletions of the NF1 gene, HCM was more common. NF1 gene, located on chromosome 17q11.2 and encodes a large cytoplasmic protein known as neurofibromin. Neurofibromin serves as a tumor suppressor and plays a critical role in the regulation of cellular signaling pathways, particularly the Ras/mitogen-activated protein kinase (MAPK) pathway. Treatment for NF1 focuses on managing symptoms and complications rather than curing the condition. In the present study, we performed whole-exome sequencing (WES) on an Iranian family with a son suffering from NF1 and arrhythmogenic cardiomyopathy (ACM) to identify the genetic cause(s). ACM is a genetic disorder characterized by the replacement of heart muscle tissue with fibrous or fatty tissue. It typically manifests in adolescence or young adulthood, although it can present at any age. Arrhythmias and chest pain are the common features of ACM. Genetic counseling and testing for affected NF1 and/or ACM individuals and their families to identify the mutation and assess the risk of passing it on to future generations. To our knowledge, this is the first report of ACM manifestation in a patient with NF1.

In our present study, we found a missense variant, c.3277G > A, in exon 25 of the NF1 gene in the proband, probably responsible for his NF1 condition0. To our knowledge, our investigation is the first to report the association between the NF1 variant and ACM. Previous studies have reported other cardiovascular manifestations secondary to NF1 mutations, including congenital heart diseases, vasculopathy, and hypertension [15]. Dunning-Davies et al. [16] concluded that congenital heart diseases, especially pulmonary stenosis, were associated with, with frequencies ranging from 0.4 to 6.4%. NF1-associated vasculopathy, comprises stenosis, aneurysms, and arteriovenous malformations, the second cause of death worldwide, renal artery stenosis is the most common appearance, occurring in at least 1% of patients with NF1. Nonetheless, the clinical investigation of the proband did not detect vasculopathy. Hypertension is strongly associated with increased mortality in NF1 patients and should be screened annually [15]. Prior to our current study, hypertension was not observed in similar investigations, although this complication may occur in older age. In 2019, Ritter et al. [17] described a patient with isolated fetal HCM as the presenting feature of NF1. Left ventricular hypertrophy, a rare finding in NF1, is primarily reported in patients with 1.4 Mb NF1 deletion. The loss of neurofibromin in cardiomyocytes causes cardiac hypertrophy and progressive HCM in NF1 homozygous null mouse models, suggesting that adults with NF1 who have a normal heart structure in childhood might be at risk of cardiomyopathy later in life. Most likely, fetal cardiomyopathy, asymmetric septal hypertrophy, and subsequent diagnosis of NF1 are not coincidental. Nevertheless, given that the patient’s cardiac dysfunction in the study by Ritter et al. had no other causes, the most likely explanation is that cardiomyopathy was an early manifestation of left ventricular hypertrophy associated with NF1. The authors posited that adding NF1 to diagnostic panels could allow early diagnosis of patients with NF1. In 2012, Alkindy et al. [18] assessed a 71-year-old father and his 29-year-old son who had symptoms of echocardiographically diagnosed HCM manifesting as cardiovascular-related complications of NF1. Echocardiographic findings of a ratio of the free wall of the septum to the left ventricular posterior wall of greater than 1.5 (indicative of HCM) are seen in at least 4% of patients with NF1. Cardiac hypertrophy is the most common risk factor in mortality and cardiovascular complications in these patients. Congenital heart diseases and cardiomyopathy are also common concomitants of several growth and development syndromes that affect RASopathies. In these syndromes, increased signaling through Erk1/2 and mTOR complex 1 causes cardiomyopathy. Neurofibromin regulates Ras signaling, and Ras activation causes progressive cardiac hypertrophy in adult mice. Our study patient was also suffering from cardiomyopathy, ACM. All such patients show NF1 pigmentary changes with very few NF1-related complications milder in terms of clinical phenotypes. Our patient had more than 6 light brown spots on the skin of his legs and upper body. In 2016, Jurko et al. [9] described an 18-year-old boy suffering from NF1 and HCM with forward systolic movements of the anterior leaflet of the mitral valve. The authors concluded that one of the common causes of severe arrhythmias and sudden deaths was HCM and that cardiac involvement caused significant problems in patients with NF, although relevant information was scarce. Patients with NF can develop progressive cardiomyopathy, hence the need for follow-ups in cardiology clinics to swiftly identify any change in the electrocardiogram or the chest X-ray. Additionally, the follow-up of HCM is necessary as it may require surgery [9]. This study holds significance in several aspects, clinical Correlation: The study found that the patient exhibited signs consistent with ACM, which is a significant complication associated with NF1. This correlation between the genetic variant and clinical presentation highlights the importance of genetic testing in diagnosing and managing NF1 patients, as it can help predict potential complications and guide appropriate medical interventions. Family screening and counseling: by identifying the genetic variant in the affected individual, the study demonstrates the utility of genetic testing in identifying asymptomatic family members who may be at risk of developing NF1-related complications. This has implications for genetic counseling and family planning, as it allows for informed decision-making and proactive management of the condition within the family.

The proband in the current study had NF1 and ACM. This investigation is the first to report ACM in a patient with NF1. Although there is no cure for NF1, genetic tests, such as WES, can identify asymptomatic family members at risk. In addition, cardiac evaluation could assist in helping these patients before cardiac problems develop.

The accession number of the variant in ClinVar is as follows:

NM_001042492.3 (NF1): c.3277G > A (p.Val1093Met): VCV000457638.5.