Federico Perfetto1, Sabrina Frusconi2, Franco Bergesio3, Elisa Grifoni4, Alessia Fabbri4, Costanza Giuliani2, Serena Falconi2, Stefania Bonifacio2, Francesco Cappelli5. 1. Regional Amyloid Center, Azienda Ospedaliero Universitaria Careggi, Florence, Italy, Department of Internal and Experimental Medicine, University of Florence, Florence, Italy; perfetto@unifi.it. 2. Genetic Diagnostics Unit, Laboratory Department, Careggi University Hospital, Florence, Italy. 3. Regional Amyloid Center, Azienda Ospedaliero Universitaria Careggi, Florence, Italy. 4. Department of Internal and Experimental Medicine, University of Florence, Florence, Italy. 5. Regional Amyloid Center, Azienda Ospedaliero Universitaria Careggi, Florence, Italy, Intensive Cardiac Care Unit, Department of Heart and Vessels, Azienda Ospedaliero Universitaria Careggi, Florence, Italy.
We read the case report (1) by Molina et al. with great interest. We believe that a few points need to be discussed in greater detail. Molina reported that this mutation is an important, though under-diagnosed, cause of heart failure in the elderly black community, with virtually undetectable prevalence in the white population (2). In fact, to date, only few and sporadic cases of Val142Ile (formerly known as Val122Ile) TTRamyloidosis in Caucasian patients have been described (2–6), and this variant has been reported in NHLBI Exome Sequencing Project with a frequency of 1.75% in the African American population while it has never been reported in the European American population (7). In the ExAC Browser (Beta)/Exome Aggregation Consortium (the data set provided on this website spans 61,486 unrelated individuals sequenced as part of various disease-specific and population-specific genetic studies), the Val142Ile variant is reported in the European population with a frequency of 0.004432%, while in the African population it is reported with a frequency of 1.5% (8). Nevertheless, in the past year, in our centre, we diagnosed two unrelated Caucasian patients with cardiac ATTR with Val142Ile pathogenic variant. Therefore, we have retrospectively evaluated all cases of TTR referred to our centre since 1998 to assess the frequency of this pathogenic variant. Among our 33 patients with ATTRm (18 families), we identified five Val142Ilepatients (15.5%) belonging to unrelated families of Caucasian origin. Furthermore, our data show that Caucasian patients with this pathogenic variant have phenotypic manifestations similar to that of African Americans, as previously reported in literature, and characterised by a late onset of severe restrictive cardiomyopathy with the absence of significant neurological involvement and the presence of increased values of NT-proBNP and troponin I at the time of diagnosis. This unexpected clustering of diagnosis in our centre could be caused either by a founder effect or by independent spontaneous events. The Val142Ile pathogenic variant occurs at a CpG dinucleotide. The dinucleotide CpG is a mutational ‘hotspot’ as a result of the modification of the 5’ cytosine by cellular DNA methyltransferases, and the consequent high frequency of spontaneous deamination of 5-methyl cytosine to thymidine on the coding strand as well as of guanine to adenine substitutions on the antisense strand (9). Therefore, it could be hypothesised that the frequency of Val142Ile in Caucasian patients could have been under-estimated with a consistent quote of under or misdiagnosis. In our opinion, irrespectively to a founder effect that, at present, it’s difficult to demonstrate due to the small number of available samples, the Val142Ile variant frequency could be greater than presumed till now. It could be due to an already known particular fragility of the dinucleotide CpG mutational hotspot that could lead to higher spontaneous mutation frequency.