Restrictive cardiomyopathy (RCM) is a rare cause of cardiomyopathy, the etiology of which remains poorly understood and may result from inherited or acquired predispositions to disease, or a combination thereof. Familial RCM 5 (OMIM 617047) usually has autosomal dominant inheritance with most of the identified genes encoding sarcomere or Z-disk proteins. The aim of this study was to determine the disease-causing variant in a South African family diagnosed with RCM. A South African family was screened at Groote Schuur Hospital, and the DNA of the affected individuals were investigated using next-generating sequencing methods with a custom cardiomyopathy panel of 38 genes. Possible RCM-causing variants were selected according to the ACMG/AMP guidelines. Primers were designed, and the Sanger sequencing method was used for variant validation. Segregation analysis was performed after the RCM-causing variant was identified. The family was initially diagnosed with Noonan syndrome-associated cardiomyopathy based on suggestive clinical findings; however, panel screening for Noonan’s found no causative gene. The diagnosis was revised, and an alternative cause of RCM was considered. A custom cardiomyopathy panel sequencing found a heterozygous missense NM₀01458. 5 (FLNC): c. 6031G > A (p. Gly2011Arg) variant in all affected individuals. The variant is located in the FLNC protein R18 Ig-loop of the rod 2 domain and has been associated with severe RCM. This case highlights the importance of considering a broader genetic differential diagnosis in patients presenting with Noonan syndrome-like features, particularly when cardiac abnormalities are present and initial genetic testing for common Noonan syndrome genes is negative. Mutations in genes like FLNC, while not typically associated with classic Noonan syndrome, can cause overlapping clinical presentations. Whole exome sequencing can be a valuable tool for identifying these alternative genetic etiologies and guiding appropriate clinical management and genetic counseling for families.
Ndibangwi et al. (Wed,) studied this question.