TY - JOUR
T1 - Lack of evidence for a causal role of CALR3 in monogenic cardiomyopathy
AU - Verhagen, Judith M. A.
AU - Veldman, Job H.
AU - van der Zwaag, Paul A.
AU - von der Thusen, Jan H.
AU - Brosens, Erwin
AU - Christiaans, Mike
AU - Dooijes, Dennis
AU - Helderman-van den Enden, Apollonia T. J. M.
AU - Deprez, Ronald H. Lekanne
AU - Michels, Michelle
AU - van Mil, Anneke M.
AU - Oldenburg, Rogier A.
AU - van der Smagt, Jasper J.
AU - van den Wijngaard, Arthur
AU - Wessels, Marja W.
AU - Hofstra, Robert M. W.
AU - van Slegtenhorst, Marjon A.
AU - Jongbloed, Jan D. H.
AU - van de Laar, Ingrid M. B. H.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - The pathogenicity of previously published disease-associated genes and variants is sometimes questionable. Large-scale, population-based sequencing studies have uncovered numerous false assignments of pathogenicity. Misinterpretation of sequence variants may have serious implications for the patients and families involved, as genetic test results are increasingly being used in medical decision making In this study, we assessed the role of the calreticulin-3 gene (CALR3) in cardiomyopathy. CALR3 has been included in several cardiomyopathy gene panels worldwide. Its inclusion is based on a single publication describing two missense variants in patients with hypertrophic cardiomyopathy. In our national cardiomyopathy cohort (n = 6154), we identified 17 unique, rare heterozygous CALR3 variants in 48 probands. Overall, our patient cohort contained a significantly higher number of rare CALR3 variants compared to the ExAC population (p = 0.0036). However, after removing a potential Dutch founder variant, no statistically significant difference was found (p = 0.89). In nine probands, the CALR3 variant was accompanied by a disease-causing variant in another, well-known cardiomyopathy gene. In three families, the CALR3 variant did not segregate with the disease. Furthermore, we could not demonstrate calreticulin-3 protein expression in myocardial tissues at various ages. On the basis of these findings, it seems highly questionable that variants in CALR3 are a monogenic cause of cardiomyopathy.
AB - The pathogenicity of previously published disease-associated genes and variants is sometimes questionable. Large-scale, population-based sequencing studies have uncovered numerous false assignments of pathogenicity. Misinterpretation of sequence variants may have serious implications for the patients and families involved, as genetic test results are increasingly being used in medical decision making In this study, we assessed the role of the calreticulin-3 gene (CALR3) in cardiomyopathy. CALR3 has been included in several cardiomyopathy gene panels worldwide. Its inclusion is based on a single publication describing two missense variants in patients with hypertrophic cardiomyopathy. In our national cardiomyopathy cohort (n = 6154), we identified 17 unique, rare heterozygous CALR3 variants in 48 probands. Overall, our patient cohort contained a significantly higher number of rare CALR3 variants compared to the ExAC population (p = 0.0036). However, after removing a potential Dutch founder variant, no statistically significant difference was found (p = 0.89). In nine probands, the CALR3 variant was accompanied by a disease-causing variant in another, well-known cardiomyopathy gene. In three families, the CALR3 variant did not segregate with the disease. Furthermore, we could not demonstrate calreticulin-3 protein expression in myocardial tissues at various ages. On the basis of these findings, it seems highly questionable that variants in CALR3 are a monogenic cause of cardiomyopathy.
KW - HYPERTROPHIC CARDIOMYOPATHY
KW - GENETIC-VARIANTS
KW - CALRETICULIN
KW - PATHOGENICITY
KW - DIAGNOSTICS
KW - GUIDELINES
KW - PROTEIN
KW - ESC
U2 - 10.1038/s41431-018-0208-1
DO - 10.1038/s41431-018-0208-1
M3 - Article
C2 - 29988065
SN - 1018-4813
VL - 26
SP - 1603
EP - 1610
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 11
ER -