MYBPC3 c.2309-2A>G: exploring a founder variant in Italian hypertrophic cardiomyopathy patients

被引：0

作者：

Fabiani, Marco ^{[1
]}

Micolonghi, Caterina ^{[1
,2
]}

Caroselli, Silvia ^{[1
]}

Savio, Camilla ^{[2
]}

Petrucci, Simona ^{[2
,3
,4
]}

Tini, Giacomo ^{[2
,3
]}

Musumeci, Beatrice ^{[2
,3
]}

Pagannone, Erika ^{[2
]}

De Fazio, Ludovica ^{[2
]}

Germani, Aldo ^{[3
]}

Visco, Vincenzo ^{[2
,3
]}

Pizzuti, Antonio ^{[1
,4
]}

Veneziano, Liana ^{[5
]}

Marchionni, Enrica ^{[6
]}

Mango, Ruggiero ^{[7
,8
]}

Pezzoli, Laura ^{[9
]}

Bottillo, Irene ^{[10
]}

Lucca, Camilla ^{[9
]}

Scatigno, Agnese ^{[11
]}

Goisis, Lucrezia ^{[9
]}

Cappuccini, Francesca ^{[9
]}

Ciccone, Maria Pia ^{[10
]}

Ballerini, Adelaide ^{[12
]}

Gozzini, Alessia ^{[12
]}

Onofri, Valerio ^{[13
]}

Cristalli, Carlotta Pia ^{[14
]}

Latini, Andrea ^{[6
,15
]}

D'Angelantonio, Daniela ^{[16
]}

Gualandi, Francesca ^{[17
,18
]}

Tortora, Giada ^{[13
]}

Magliozzi, Monia ^{[16
]}

Novelli, Antonio ^{[16
]}

Rossi, Cesare ^{[14
]}

Grammatico, Paola ^{[10
]}

Sangiuolo, Federica ^{[6
,19
]}

Girolami, Francesca ^{[12
]}

Iascone, Maria ^{[9
]}

Olivotto, Iacopo ^{[12
,20
]}

Autore, Camillo ^{[21
]}

Rubattu, Speranza ^{[2
,3
,22
]}

Piane, Maria ^{[2
,3
]}

机构：

[1] Sapienza Univ Rome, Dept Expt Med, Rome, Italy

[2] St Andrea Univ Hosp, Rome, Italy

[3] Sapienza Univ Rome, Dept Clin & Mol Med, Rome, Italy

[4] Casa Sollievo Sofferenza Fdn, San Giovanni Rotondo, Italy

[5] Ist Ricovero & Cura Carattere Sci San Raffaele Rom, Human Funct Genom Lab, Rome, Italy

[6] Univ Roma Tor Vergata, Med Genet Unit, Policlin Tor Vergata, Rome, Italy

[7] Local Hlth Author Roma 2, House Care D4, Rome, Italy

[8] Policlin Tor Vergata, Dept Emergency & Crit Care, Cardiol Unit, Rome, Italy

[9] ASST Papa Giovanni XXIII, Lab Med Genet, Bergamo, Italy

[10] Sapienza Univ, San Camillo Forlanini Hosp, Dept Expt Med, Lab Med Genet, Rome, Italy

[11] ASST Papa Giovanni XXIII, Pediat Unit, Bergamo, Italy

[12] IRCCS, Meyer Childrens Hosp, Cardiol Unit, Florence, Italy

[13] Azienda Osped Univ Marche, Ancona, Italy

[14] IRCCS Azienda Osped Univ Bologna, Med Genet Unit, Bologna, Italy

[15] UniCamillus St Camillus Int Univ Hlth Sci, Rome, Italy

[16] IRCCS, Bambino Gesu Children Hosp, Translat Cytogen Res Unit, Lab Med Genet, Rome, Italy

[17] Univ Hosp S Anna Ferrara, Dept Med Sci, Unit Med Genet, Ferrara, Italy

[18] Univ Hosp S Anna Ferrara, Dept Mother & Child, Ferrara, Italy

[19] Tor Vergata Univ, Dept Biomed & Prevent, Rome, Italy

[20] Univ Florence, Dept Expt & Clin Med, Florence, Italy

[21] San Raffaele, Dept Cardiol & Resp Sci, Cassino, Italy

[22] IRCCS Neuromed, Pozzilli, Italy

来源：

EUROPEAN JOURNAL OF HUMAN GENETICS | 2025年

关键词：

BINDING-PROTEIN-C; GENE; MUTATIONS; IDENTIFICATION; POPULATION; HCM; AGE;

D O I：

10.1038/s41431-025-01873-2

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

MYBPC3 pathogenic variants are the most common cause of hypertrophic cardiomyopathy (HCM) and are associated with significant phenotypic heterogeneity. Despite their pathogenic potential, MYBPC3 founder variants persist within specific populations. This study investigates the MYBPC3 c.2309-2 A > G splice variant hypothesizing its founder origin in central Italy. The aim was to confirm the presence of a common haplotype, assess its molecular and clinical impact, and compare the phenotype with that of other MYBPC3 founder variants. Among the 5251 HCM patients recruited at eight Italian referral centers, 1108 probands (21.1%) were identified as carriers of pathogenic or likely pathogenic MYBPC3 variants, and among these, 11.6% carried the c.2309-2 A > G variant. Haplotype reconstruction using short tandem repeats and tag-SNPs revealed a unique 5.2 Mb haplotype segregating with the c.2309-2 A > G variant in all carriers. Age estimation suggested that the variant originated approximately 481 years ago, likely in the Lazio region with clustering in Rome. Clinically, carriers exhibited variable expressivity with age-and sex-dependent penetrance. Males showed earlier onset, higher penetrance and greater disease severity compared to females. RNA analysis showed the retention of both introns 23 and 24, and significantly reduced MYBPC3 expression consistent with haploinsufficiency. Comparative analysis with other MYBPC3 founder variants highlighted differences in phenotypic expression, particularly in left ventricular wall thickness and clinical outcomes. This study establishes c.2309-2 A > G as an Italian MYBPC3 founder mutation, enhancing the understanding of HCM genetics and regional founder effects. These findings emphasize the importance of targeted genetic screening and personalized management for MYBPC3 c.2309-2 A > G carriers.

引用

页数：12

共 42 条

[1] ] Hypertrophic cardiomyopathy in myosin-binding protein C (MYBPC3) Icelandic founder mutation carriers [J].

Adalsteinsdottir, Berglind ;

Burke, Michael ;

Maron, Barry J. ;

Danielsen, Ragnar ;

Lopez, Begona ;

Diez, Javier ;

Jarolim, Petr ;

Seidman, Jonathan ;

Seidman, Christine E. ;

Ho, Carolyn Y. ;

Gunnarsson, Gunnar Th .

OPEN HEART, 2020, 7 (01)

[2] Nationwide Study on Hypertrophic Cardiomyopathy in Iceland Evidence of a MYBPC3 Founder Mutation [J].

Adalsteinsdottir, Berglind ;

Teekakirikul, Polakit ;

Maron, Barry J. ;

Burke, Michael A. ;

Gudbjartsson, Daniel F. ;

Holm, Hilma ;

Stefansson, Kari ;

DePalma, Steven R. ;

Mazaika, Erica ;

McDonough, Barbara ;

Danielsen, Ragnar ;

Seidman, Jonathan G. ;

Seidman, Christine E. ;

Gunnarsson, Gunnar T. .

CIRCULATION, 2014, 130 (14) :1158-1167

[3] The 2373insG mutation in the MYBPC3 gene is a founder mutation, which accounts for nearly one-fourth of the HCM cases in the Netherlands [J].

Alders, M ;

Jongbloed, R ;

Deelen, W ;

van den Wijngaard, A ;

Doevendans, P ;

Ten Cate, F ;

Regitz-Zagrosek, V ;

Vosberg, HP ;

van Langen, I ;

Wilde, A ;

Dooijes, D ;

Mannens, M .

EUROPEAN HEART JOURNAL, 2003, 24 (20) :1848-1853

[4] 2023 ESC Guidelines for the management of cardiomyopathies Developed by the task force on the management of cardiomyopathies of the European Society of Cardiology (ESC) [J].

Arbelo, Elena ;

Protonotarios, Alexandros ;

Gimeno, Juan R. ;

Arbustini, Eloisa ;

Barriales-Villa, Roberto ;

Basso, Cristina ;

Bezzina, Connie R. ;

Biagini, Elena ;

Blom, Nico A. ;

de Boer, Rudolf A. ;

De Winter, Tim ;

Elliott, Perry M. ;

Flather, Marcus ;

Garcia-Pavia, Pablo ;

Haugaa, Kristina H. ;

Ingles, Jodie ;

Jurcut, Ruxandra Oana ;

Klaassen, Sabine ;

Limongelli, Giuseppe ;

Loeys, Bart ;

Mogensen, Jens ;

Olivotto, Iacopo ;

Pantazis, Antonis ;

Sharma, Sanjay ;

Van Tintelen, J. Peter ;

Ware, James S. ;

Kaski, Juan Pablo .

EUROPEAN HEART JOURNAL, 2023, 44 (37) :3503-3626

[5] Identification of Myocardial Disarray in Patients With Hypertrophic Cardiomyopathy and Ventricular Arrhythmias [J].

Ariga, Rina ;

Tunnicliffe, Elizabeth M. ;

Manohar, Sanjay G. ;

Mahmod, Masliza ;

Raman, Betty ;

Piechnik, Stefan K. ;

Francis, Jane M. ;

Robson, Matthew D. ;

Neubauer, Stefan ;

Watkins, Hugh .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2019, 73 (20) :2493-2502

[6]

Barrett Jeffrey C, 2009, Cold Spring Harb Protoc, V2009, DOI 10.1101/pdb.ip71

[7] Phenotypic spectrum of the first Belgian MYBPC3 founder: a large multi-exon deletion with a varying phenotype [J].

Boen, Hanne M. ;

Alaerts, Maaike ;

Van Laer, Lut ;

Saenen, Johan B. ;

Goovaerts, Inge ;

Bastianen, Jarl ;

Koopman, Pieter ;

Vanduynhoven, Philippe ;

De Vuyst, Elke ;

Rosseel, Michael ;

Heidbuchel, Hein ;

Van Craenenbroeck, Emeline M. ;

Loeys, Bart .

FRONTIERS IN GENETICS, 2024, 15

[8] A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life [J].

Calore, Chiara ;

De Bortoli, Marzia ;

Romualdi, Chiara ;

Lorenzon, Alessandra ;

Angelini, Annalisa ;

Basso, Cristina ;

Thiene, Gaetano ;

Iliceto, Sabino ;

Rampazzo, Alessandra ;

Melacini, Paola .

JOURNAL OF MEDICAL GENETICS, 2015, 52 (05) :338-347

[9] Reanalysis of Next-generation Sequencing Data in Patients With Hypertrophic Cardiomyopathy : Contribution of Spliceogenic MYBPC3 Variants in an Italian Cohort [J].

Caroselli, Silvia ;

Fabiani, Marco ;

Micolonghi, Caterina ;

Savio, Camilla ;

Tini, Giacomo ;

Musumeci, Beatrice ;

Pagannone, Erika ;

Germani, Aldo ;

Libi, Fabio ;

Visco, Vincenzo ;

Pizzuti, Antonio ;

Autore, Camillo ;

Petrucci, Simona ;

Rubattu, Speranza ;

Piane, Maria .

ANNALS OF LABORATORY MEDICINE, 2025, 45 (01) :96-100

[10] Targeting the population for gene therapy with MYBPC3 [J].

Carrier, Lucie .

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2021, 150 :101-108

← 1 2 3 4 5 →