title: Significance of sarcomere gene mutations analysis in the end-stage phase of hypertrophic cardiomyopathy.
abstract: End-stage hypertrophic cardiomyopathy (ES-HC) has an ominous prognosis. Whether genotype can influence ES-HC occurrence is unresolved. We assessed the spectrum and clinical correlates of HC-associated mutations in a large multicenter cohort with end-stage ES-HC. Sequencing analysis of 8 sarcomere genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1) and 2 metabolic genes (PRKAG2 and LAMP2) was performed in 156 ES-HC patients with left ventricular (LV) ejection fraction (EF) <50%. A comparison among mutated and negative ES-HC patients and a reference cohort of 181 HC patients with preserved LVEF was performed. Overall, 131 mutations (36 novel) were identified in 104 ES-HC patients (67%) predominantly affecting MYH7 and MYBPC3 (80%). Complex genotypes with double or triple mutations were present in 13% compared with 5% of the reference cohort (p = 0.013). The distribution of mutations was otherwise indistinguishable in the 2 groups. Among ES-HC patients, those presenting at first evaluation before the age of 20 had a 30% prevalence of complex genotypes compared with 19% and 21% in the subgroups aged 20 to 59 and ≥60 years (p = 0.003). MYBPC3 mutation carriers with ES-HC were older than patients with MYH7, other single mutations, or multiple mutations (median 41 vs 16, 26, and 28 years, p ≤0.001). Outcome of ES-HC patients was severe irrespective of genotype. In conclusion, the ES phase of HC is associated with a variable genetic substrate, not distinguishable from that of patients with HC and preserved EF, except for a higher frequency of complex genotypes with double or triple mutations of sarcomere genes.
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Alma Mater Studiorum, Universita di Bologna, Italy. Electronic address: elena.biagini73@gmail.com.
authors.forename: Elena
authors.initials: E
authors.lastname: Biagini
authors.affiliation: Centro di Riferimento per le Cardiomiopatie, Azienda Ospedaliero-Universitaria Careggi, Firenze Italy.
authors.forename: Iacopo
authors.initials: I
authors.lastname: Olivotto
authors.affiliation: USSD Laboratorio Genetica Medica, Ospedali Riuniti, Bergamo, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Iascone
authors.affiliation: S.C. Laboratorio di Genetica Umana, E.O. Ospedali Galliera, Genova, Italy.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Parodi
authors.affiliation: SOD Diagnostica Genetica, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Girolami
authors.affiliation: CEINGE-Biotecnologie Avanzate s.c.ar.l. Napoli e Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", IRCCS-Fondazione SDN, Napoli, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Frisso
authors.affiliation: Divisione di Cardiologia, Dipartimento di Medicina Clinica e Molecolare, Università La Sapienza, Roma, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Autore
authors.affiliation: Dipartimento di Cardiologia, Seconda Università degli Studi, Napoli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Limongelli
authors.affiliation: S.C. Laboratorio di Genetica Umana, E.O. Ospedali Galliera, Genova, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cecconi
authors.affiliation: Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Maron
authors.affiliation: Tufts Medical Center, Hypertrophic Cardiomyopathy Center, Boston, Massachusetts.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Maron
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Alma Mater Studiorum, Universita di Bologna, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rosmini
authors.affiliation: S.C. Cardiologia, E.O. Ospedali Galliera, Genova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Formisano
authors.affiliation: Divisione di Cardiologia, Dipartimento di Medicina Clinica e Molecolare, Università La Sapienza, Roma, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Musumeci
authors.affiliation: Centro di Riferimento per le Cardiomiopatie, Azienda Ospedaliero-Universitaria Careggi, Firenze Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Cecchi
authors.affiliation: Dipartimento Cardiovascolare, Ospedali Riuniti, Bergamo, Italy.
authors.forename: Attilio
authors.initials: A
authors.lastname: Iacovoni
authors.affiliation: Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota.
authors.forename: Tammy S
authors.initials: TS
authors.lastname: Haas
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Alma Mater Studiorum, Universita di Bologna, Italy.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Bacchi Reggiani
authors.affiliation: Policlinico di Monza, Monza, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferrazzi
authors.affiliation: CEINGE-Biotecnologie Avanzate s.c.ar.l. Napoli e Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", IRCCS-Fondazione SDN, Napoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvatore
authors.affiliation: S.C. Cardiologia, E.O. Ospedali Galliera, Genova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Spirito
authors.affiliation: Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Alma Mater Studiorum, Universita di Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Rapezzi
mesh_terms: D000328:Adult; D000368:Aged; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D003430:Cross-Sectional Studies; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D015995:Prevalence; D012189:Retrospective Studies; D012518:Sarcomeres / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: D002352:Carrier Proteins; D004247:DNA; D018995:Myosin Heavy Chains