TY - JOUR
T1 - Identification of known and unknown genes associated with mitral valve prolapse using an exome slice methodology
AU - van Wijngaarden, Aniek L.
AU - Hiemstra, Yasmine L.
AU - Koopmann, Tamara T.
AU - Ruivenkamp, Claudia A. L.
AU - Aten, Emmelien
AU - Schalij, Martin J.
AU - Bax, Jeroen J.
AU - Delgado, Victoria
AU - Barge-Schaapveld, Daniela Q. C. M.
AU - Ajmone Marsan, Nina
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Purpose: Although a familial distribution has been documented, the genetic aetiology of mitral valve prolapse (MVP) is largely unknown, with only four genes identified so far: FLNA, DCHS1, DZIP1 and PLD1. The aim of this study was to evaluate the genetic yield in known causative genes and to identify possible novel genes associated with MVP using a heart gene panel based on exome sequencing. Methods: Patients with MVP were referred for genetic counselling when a positive family history for MVP was reported and/or Barlow's disease was diagnosed. In total, 101 probands were included to identify potentially pathogenic variants in a set of 522 genes associated with cardiac development and/or diseases. Results: 97 (96%) probands were classified as Barlow's disease and 4 (4%) as fibroelastic deficiency. Only one patient (1%) had a likely pathogenic variant in the known causative genes (DCHS1). However, an interesting finding was that 10 probands (11%) had a variant that was classified as likely pathogenic in six different, mostly cardiomyopathy genes: DSP (1×), HCN4 (1×), MYH6 (1×), TMEM67 (1×), TRPS1 (1×) and TTN (5×). Conclusion: Exome slice sequencing analysis performed in MVP probands reveals a low genetic yield in known causative genes but may expand the cardiac phenotype of other genes. This study suggests for the first time that also genes related to cardiomyopathy may be associated with MVP. This highlights the importance to screen these patients and their family for the presence of arrhythmias and of â - disproportionate' LV remodelling as compared with the severity of mitral regurgitation, unravelling a possible coexistent cardiomyopathy.
AB - Purpose: Although a familial distribution has been documented, the genetic aetiology of mitral valve prolapse (MVP) is largely unknown, with only four genes identified so far: FLNA, DCHS1, DZIP1 and PLD1. The aim of this study was to evaluate the genetic yield in known causative genes and to identify possible novel genes associated with MVP using a heart gene panel based on exome sequencing. Methods: Patients with MVP were referred for genetic counselling when a positive family history for MVP was reported and/or Barlow's disease was diagnosed. In total, 101 probands were included to identify potentially pathogenic variants in a set of 522 genes associated with cardiac development and/or diseases. Results: 97 (96%) probands were classified as Barlow's disease and 4 (4%) as fibroelastic deficiency. Only one patient (1%) had a likely pathogenic variant in the known causative genes (DCHS1). However, an interesting finding was that 10 probands (11%) had a variant that was classified as likely pathogenic in six different, mostly cardiomyopathy genes: DSP (1×), HCN4 (1×), MYH6 (1×), TMEM67 (1×), TRPS1 (1×) and TTN (5×). Conclusion: Exome slice sequencing analysis performed in MVP probands reveals a low genetic yield in known causative genes but may expand the cardiac phenotype of other genes. This study suggests for the first time that also genes related to cardiomyopathy may be associated with MVP. This highlights the importance to screen these patients and their family for the presence of arrhythmias and of â - disproportionate' LV remodelling as compared with the severity of mitral regurgitation, unravelling a possible coexistent cardiomyopathy.
KW - clinical genetics
KW - valvar diseases
UR - http://www.scopus.com/inward/record.url?scp=85083293127&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/jmedgenet-2019-106715
DO - https://doi.org/10.1136/jmedgenet-2019-106715
M3 - Article
C2 - 32277046
SN - 0022-2593
VL - 57
SP - 843
EP - 850
JO - Journal of medical genetics
JF - Journal of medical genetics
IS - 12
M1 - 2019106715
ER -