Recurrent TTN missense variants in biallelic titinopathies: a focus on Proline changes

Elenco Abstract

Maria Francesca Di Feo

Recurrent TTN missense variants in biallelic titinopathies: a focus on Proline changes

Autori

MARIA FRANCESCA DI FEO (FOLKHÄLSAN RESEARCH CENTER, HELSINKI, FINLAND/ UNIVERSITY OF GENOVA, GENOVA, ITALY)
MARTIN REES (RANDALL CENTRE FOR CELL AND MOLECULAR BIOPHYSICS, MUSCLE BIOPHYSICS, KING’S COLLEGE LONDON BHF CENTRE OF RESEARCH EXCELLENCE, LONDON, UK – )
MATHIAS GAUTEL (RANDALL CENTRE FOR CELL AND MOLECULAR BIOPHYSICS, MUSCLE BIOPHYSICS, KING’S COLLEGE LONDON BHF CENTRE OF RESEARCH EXCELLENCE, LONDON, UK – )
HEINZ JUNGBLUTH (RANDALL CENTRE FOR CELL AND MOLECULAR BIOPHYSICS, MUSCLE BIOPHYSICS, KING’S COLLEGE LONDON BHF CENTRE OF RESEARCH EXCELLENCE, LONDON, UK – )
MRIDUL JOHARI ( HARRY PERKINS INSTITUTE OF MEDICAL RESEARCH, CENTRE FOR MEDICAL RESEARCH, UNIVERSITY OF WESTERN AUSTRALIA, NEDLANDS, WA, AUSTRALIA. – )
KATALIN SZAKSZON ( FACULTY OF MEDICINE, DEPARTAMENT OF PEDIATRICS, UNIVERSITY OF DEBRECEN, 4032 DEBRECEN, HUNGARY – )
ISTVÁN BALOGH (FACULTY OF MEDICINE, DEPARTAMENT OF PEDIATRICS, UNIVERSITY OF DEBRECEN, 4032 DEBRECEN, HUNGARY – )
CLAUDIO BRUNO (DEPARTMENT OF NEUROSCIENCE, REHABILITATION, OPHTALMOLOGY, GENETICS, MATERNAL AND CHILD HEALTH-DINOGMI, CENTER OF TRANSLATIONAL AND EXPERIMENTAL MYOLOGY, IRCCS ISTITUTO GIANNINA GASLINI IRCCS, UNIVERSITY OF GENOVA, GENOVA, ITALY – NEUROLOGIA)
CHIARA FIORILLO (DEPARTMENT OF NEUROSCIENCE, REHABILITATION, OPHTALMOLOGY, GENETICS, MATERNAL AND CHILD HEALTH-DINOGMI, CENTER OF TRANSLATIONAL AND EXPERIMENTAL MYOLOGY, IRCCS ISTITUTO GIANNINA GASLINI IRCCS, UNIVERSITY OF GENOVA, GENOVA, ITALY – NEUROLOGIA)
MARINA PEDEMONTE (CENTER OF MYOLOGY AND NEURODEGENERATIVE DISORDERS, IRCCS ISTITUTO GIANNINA GASLINI, GENOA, ITALY – NEUROLOGIA)
NOEMI BROLATTI (CENTER OF MYOLOGY AND NEURODEGENERATIVE DISORDERS, IRCCS ISTITUTO GIANNINA GASLINI, GENOA, ITALY – NEUROLOGIA)
CHIARA PANICUCCI (CENTER OF MYOLOGY AND NEURODEGENERATIVE DISORDERS, IRCCS ISTITUTO GIANNINA GASLINI, GENOA, ITALY – NEUROLOGIA)
MONICA TRAVERSO (CENTER OF MYOLOGY AND NEURODEGENERATIVE DISORDERS, IRCCS ISTITUTO GIANNINA GASLINI, GENOA, ITALY – GENETICA MEDICA)
FRANCESCA FARAVELLI (CLINICAL GENOMICS AND GENETICS UNIT, IRCCS ISTITUTO GIANNINA GASLINI, GENOA, ITALY – GENETICA MEDICA)
LUANA MANDARA’ (MEDICAL GENETICS UNIT, MARIA PATERNÒ AREZZO HOSPITAL, RAGUSA, ITALY – GENETICA MEDICA)
FRANZISKA SCHNABEL (INSTITUTE OF HUMAN GENETICS, UNIVERSITY MEDICAL CENTER GÖTTINGEN, HEINRICH-DÜKER-WEG 12, 37073, GÖTTINGEN, GERMANY – )
FEDERICA SILVIA RICCI (CHILD AND ADOLESCENT NEUROPSYCHIATRY DIVISION, DEPARTMENT OF PUBLIC HEALTH AND PEDIATRIC SCIENCES, UNIVERSITY OF TURIN, TURIN, ITALY – NEUROPSICHIATRIA INFANTILE)
ALESSANDRO MUSSA (DEPARTMENT OF PUBLIC HEALTH AND PEDIATRIC SCIENCES, UNIVERSITY OF TORINO, PIAZZA POLONIA 94, 10126 TORINO, ITALY – NEUROLOGIA)
EDOARDO MALFATTI (SERVICE NEUROLOGIE MÉDICALE, CENTRE DE RÉFÉRENCE MALADIES NEUROMUSCULAIRE PARIS-EST-ILE DE FRANCE, CHU RAYMOND-POINCARÉ PARIS OUEST, GARCHES, FRANCE – NEUROLOGIA)
ENRICO SILVIO BERTINI (UNIT OF NEUROMUSCULAR AND NEURODEGENERATIVE DISORDERS, BAMBINO GESU CHILDREN’S HOSPITAL, IRCCS, ROME, ITALY – NEUROLOGIA)
GINA RAVENSCROFT (HARRY PERKINS INSTITUTE OF MEDICAL RESEARCH, PERTH, WESTERN AUSTRALIA, AUSTRALIA – )
BJARNE UDD (FOLKHÄLSAN RESEARCH CENTER, HELSINKI, FINLAND – NEUROLOGIA)
SAVARESE MARCO (FOLKHÄLSAN RESEARCH CENTER, HELSINKI, FINLAND – NEUROLOGIA)

Presentatore

MARIA FRANCESCA DI FEO (FOLKHÄLSAN RESEARCH CENTER, HELSINKI, FINLAND/ UNIVERSITY OF GENOVA, GENOVA, ITALY)

Modalità

Oral Communication

Abstract

“Assessing the clinical significance of missense variants in large genes like TTN poses a formidable challenge in the genomic era. Despite some pathogenic missense variants published in the last few years, there remain over 200,000 potential amino acid changes in the titin protein, many classified as “variants of unknown significance” (VUS). Our international cohort study focused on unresolved cases with compatible phenotypes carrying a TTN truncating variant (TTNtv) in compound heterozygosity (comp het) with a proline missense variant.

We identified 4 recurrent missense variants in 9 families exhibiting muscular phenotypes consistent with a titinopathy. These patients all carried a TTNtv in comp het with a proline missense variant, predicted to be deleterious according to Alphamissense.

Patients with the same missense variant in comp het with a TTNtv in a constitutively expressed exon (PSI > 85-90% in pre and postnatal skeletal muscles) displayed very similar phenotypes. Notably, all cases carrying the same missense variant located in the proximal I-band region (Ig-domains, affecting beta-sheet structure) have respiratory involvement, prompting further investigations on TTN isoforms in specific muscles.

Our ongoing study aims to possibly identify new pathogenic missense variants, establish new genotype-phenotype correlations in titinopathies, and confirm the destabilizing effect of proline changes on the titin protein. Functional studies will be essential for comprehensively understanding the biochemical and biophysical impacts of the variants.”