Hypertrophic Cardiomyopathy Secondary to RAF1 Cysteine-Rich Domain Variants

Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy disproportionate to loading conditions.Changes in sarcomeric genes are commonly implicated in HCM pathology; however, non-sarcomeric genes can also cause HCM.One major contributor to non-sarcomeric HCM is the RASopathies, which often present with Noonan syndrome.1 RAF1, one RASopathy gene, encodes a Ras-activated serine/threonine kinase.Activated RAF1 stimulates the mitogen-activated protein kinase (MAPK) pathway through phosphorylation of MAPK/ERK kinase (MEK).RAF1 contains multiple regulatory domains, including the cysteine-rich domain (CRD) within conserved region1 (CR1), the conserved region 2 (CR2), and the C-terminal domain.RAF1 variants that associate with Noonan-spectrum disease and concomitant HCM mainly localize to the CR2 domain and C-terminus, and these variants correlate with increased RAF1 activity (Figure 1A). 2 The data that support the findings of this study are available from the corresponding author upon reasonable request.This study was approved by the Northwestern University IRB, and written informed consent was obtained from all human subjects included.Using broad cardiomyopathy genetic testing panels, we identified individuals from two unrelated HCM families with heterozygous RAF1 variants of uncertain significance in the CRD: RAF1 c.453C>A (p.F151L) and c.434C>T (p.T145M) (transcript NM_002880.3).The F151L RAF1 variant is not found in population databases (gnomAD v2.1.1 and v3.1.2),while the RAF1 T145M variant is ultrarare (not observed in gnomAD v2.1.1,and allele frequency 0.000013 in gnomAD v3.1.2).The proband in the F151L family presented at