Abstract 13550: Genotype-Phenotype Mismatch of Val122Ile Transthyretin Mutation in Dilated Cardiomyopathy

Abstract

Introduction: An estimated 3.4% of African Americans carry the Valine 122 Isoleucine (Val122Ile) mutation associated with hereditary transthyretin (TTR) amyloidosis cardiomyopathy (hATTR-CM). Val122Ile is inherited in an autosomal dominant pattern, but penetrance of the clinical disease is variable and incompletely understood. Asymptomatic carriers therefore require screening for phenotypic manifestations of hATTR-CM before initiation of TTR-targeted therapies. Case Description: A 57-year-old African American male with non-ischemic dilated cardiomyopathy (DCM) presented in cardiogenic shock for advanced therapy evaluation. DCM was diagnosed 20 years prior, and family history was pertinent for cardiomyopathy in both parents. Echocardiography on admission revealed severely reduced left ventricular systolic function (EF 10%) with moderate cavitary dilation but no evidence of concentric or septal hypertrophy (LVeDd 6.1 cm, IVSd 0.9 cm, LVPWd 1.0 cm & LVMI 103 g/m 2 ). His family history prompted genetic testing to evaluate hereditary etiologies of DCM. However, his genetic test only revealed a heterozygous Val122Ile mutation. He underwent left ventricular assist device (LVAD) implantation, after which LV apical core biopsy was negative for Congo red staining. Discussion: This case illustrates a clear genotype (Val122Ile) - phenotype (DCM) mismatch. Although positive for the Val122Ile mutation, the lack of Congo red staining on his LV core biopsy rules out cardiac infiltration of mutated TTR amyloid fibrils and instead suggests an entirely independent, idiopathic DCM. The increasing ease and availability of genetic testing, combined with the known high prevalence of the Val122Ile mutation in the African American population will inevitably lead to more cases of genotype-phenotype mismatch. The variable penetrance of this pathogenic mutation (Val122Ile) may lead to inappropriate treatment with TTR-targeted therapies in patients without clear disease, potentially increasing patient and healthcare costs unnecessarily. Further research is needed to understand the variable penetrance of Val122Ile and factors that may predict development of clinical disease in the future.