7 research outputs found
Intelligenza Artificiale in Cardiogenetica: utilizzo dell’algoritmo predittivo Mutscore in 15 anni di pratica clinica
Background.
Negli ultimi decenni, l'introduzione delle tecnologie di sequenziamento genetico di nuova
generazione (NGS) ha cambiato profondamente la pratica della genetica medica. Se da un lato l'analisi
dell'intero genoma, ha permesso un più ampio accesso all’analisi genetica nella pratica di routine, dall’altro ha sollevato nuove e
difficili sfide nell'interpretazione dei risultati. A causa infatti dell'aumentato numero di test genetici,
è divenuto sempre più frequente il riscontro di nuove varianti di sequenza che rimangono di significato incerto.
Obiettivi.
Lo studio attuale presenta l'esperienza quindicinale della consultazione congiunta di cardiogenetica
dei servizi di Cardiologia e di Medicina Genetica dell'Ospedale Universitario di Losanna, relativa alla
coorte di pazienti indirizzati per sospetto di malattia ereditaria cardiaca e arruolati nel registro
prospettico delle malattie cardiache ereditarie del Servizio di Genetica Medica. Previa identificazione
e analisi delle varianti probabilmente patogene/patogene e di significato incerto riscontrate, lo studio
prevede l’applicazione del nuovo algoritmo computazionale predittivo Mutscore, basato su un
approccio di apprendimento automatico (“machine learning”), al fine di testare, su un nuovo set di
dati, la performance predittiva dell’algoritmo e la capacità di riclassificazione delle varianti di
significato incerto.
Metodi.
Il nostro studio ha comportato l’analisi retrospettiva dei risultati di sequenziamento del DNA dei
pazienti testati per sospetta malattia ereditaria cardiaca e indirizzati al nostro centro dal 1° luglio 2007
al 31 dicembre 2021. Per ogni variante probabilmente patogena/patogena e per le varianti di
significato incerto abbiamo quindi applicato l'algoritmo Mutscore precedentemente descritto,
utilizzando un approccio random forest.
Risultati.
Sui 488 pazienti testati, l’indicazione clinica più frequente è rappresentata dallo screening
presintomatico (37,3%) in caso di variante familiare conosciuta, seguita dall’indicazione per sospetta
sindrome aritmica (28,3%) e per cardiomiopatia ereditaria diagnosticata o sospetta (26,8%). Una
variante patogena/probabilmente patogena è stata riscontrata in 198 pazienti per una resa diagnostica
globale del 40,6% e del 23,6% nei soli casi indice. Il tasso di mutation-carriers identificati è risultato
maggiore (45,8%) nei pazienti con cardiomiopatia rispetto a quelli (37%) affetti da sindromi
aritmiche ereditarie. Le varianti patogene sono state identificate principalmente nei geni con chiara
evidenza scientifica di associazione causale alla malattia. Abbiamo dimostrato l’ottima capacità
predittiva del Mutscore sul nostro set di dati, come attestato da una AUC (Area Under the Curve) di
0,895 e dalla correlazione positiva statisticamente significativa (r= 0,65, p-value = 0.000) tra il
Mutscore e l’interpretazione della variante annotata in ClinVar. Abbiamo infine documentato, sulla
base del Mutscore, la possibile riclassificazione in varianti probabilmente benigne/patogene per il
47,2% delle varianti di significato incerto.
Conclusione.
Lo studio ha permesso di dimostrare, attraverso l’esperienza di 15 anni di consultazioni specializzate
congiunte in Cardiogenetica, il ruolo fondamentale dell’analisi genetica nella conferma diagnostica
(nel 40% dei pazienti testati) e nella presa in carico dei pazienti con sospetta malattia cardiaca
ereditaria. Sulla base di questa solida esperienza clinica, abbiamo inoltre dimostrato, nella nostra
coorte di pazienti, l’ottima performance predittiva dell’algoritmo computazionale Mutscore e la sua
accuratezza nell’aiutare a riclassificare le varianti di significato incerto. Sebbene ulteriori studi di
validazione siano ancora necessari, il Mutscore sembra essere un valido strumento ed una potente
risorsa in grado di contribuire alla riclassificazione delle varianti di significato incerto.Backgroud.
In the last decades, the implementation of high-throughput next-generation (NGS) technologies has
profoundly changed the landscape of human genome sequencing. The analysis of whole genome,
exomes or deputed genes in the context of multigene panels, while being rapidly and extensively
available in the routine practice, has raised new and difficult challenges in result interpretation.
Among others, due to the increase of genetic specimen testing, novel sequence variants have become
an increasingly frequent finding which, differing from the standard sequence of the referenced general
population, remain of unknown/uncertain significance.
Objective.
We present hereby our single center experience over a 15-year period on a cohort of consecutive
patients addressed for suspicion of cardiac hereditary disease to the specialized cardiogenetic
outpatient clinic of the University Hospital of Lausanne and enrolled in the prospective registry of
hereditary cardiac diseases of the Service of Medical Genetics. After the identification and careful
analysis of likely pathogenic/pathogenic variants and of variants of uncertain significance, we applied
the new computational predictive algorithm Mutscore, based on a machine-learning approach, to test,
in a new dataset, Mutscore performance as well as its ability in reclassifying variants of uncertain
significance.
Methods.
Our study implied a retrospective review of DNA sequencing results of patients tested for suspected
cardiac hereditary disease and addressed at our center from July 1st 2007 through December 31st 2021.
For each likely pathogenic/pathogenic variants and for variants of uncertain significance we then
applied the previously described Mutscore algorithm using a random forest approach.
Results.
Among the 488 tested patients, the most frequent clinical indications were presymptomatic screening
(37.3%) proposed in case of a known familial variant, followed by suspected arrhythmic syndrome
(28.3%) and hereditary cardiomyopathy (26.8%). A likely pathogenic/pathogenic variant was found
in 198 patients for an overall diagnostic yield of 40.6% and of 23.6% considering only index cases.
The rate of identified mutation-carriers was higher among patients with cardiomyopathy (45.8%) than
among those with inherited arrhythmic syndromes (37%). The pathogenic variants were mainly
identified in genes with definitive scientific evidence of causal association with the disease. We
demonstrated the excellent predictive performance of the Mutscore in our dataset, as attested by an
AUC (Area Under the Curve) of 0.895 and by the statistically significant positive correlation (r =
0.65, p-value = 0.000) between the Mutscore and the variant interpretation reported in ClinVar. We
finally documented, according to Mutscore, the possible reclassification into likely benign/pathogenic
variants for the 47.2% of the variants of uncertain significance.
Conclusions.
The 15-year experience of our specialized cardiogenetic outpatient clinic has demonstrated the pivotal
role of the genetic analysis in diagnostic confirmation (in 40% of the patients tested) and in
therapeutic management of patients with suspected cardiac hereditary diseases. Based on this solid
clinical experience, we have also demonstrated in our dataset the excellent predictive performance of
the Mutscore computational algorithm and its accuracy in reclassifying variants of uncertain
significance. Although further validation studies are still needed, the Mutscore algorithm seems to be
a valuable tool and a powerful resource contributing to disambiguation of variants of uncertain
significance and to the further build the pathway towards precision medicine
Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry
AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator
Clinical presentation of calmodulin mutations:the International Calmodulinopathy Registry
Aims: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms.
Methods and results: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing.
Conclusion: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator