The Malta BioBank investigates mitochondrial disorders through a collaborative BBMRI-LPC project

Abstract

Introduction: The Malta BioBank (BBMRI.mt) participated in the Biobanking and BioMolecular resources Research Infrastructure-Large Prospective Cohort (BBMRI-LPC) whole exome sequencing (WES) call, jointly organised by BBMRI-LPC, EuroBioBank, RD-Connect and Centro Nacional de Análisis Genómico (CNAG-CRG). The goal was to sequence 50 exomes from patients with genetically undiagnosed mitochondrial disorders whose samples were banked at the EuroBioBank network. Methods: The Maltese cohort included 13 probands. WES and data processing were carried out at CNAG- CRG. Phenotypic data were recorded in the RD-Connect PhenoTips instance, and variant filtration and prioritisation was undertaken using the RD-Connect Genome-Phenome Analysis Platform. Results: A mis-sense mutation c.308C>T (rs749249430) in NDUFAF3 that caused Mitochondrial Complex 1 deficiency (MC1d) was detected in patient A. Patient B was a carrier for a splice donor and two mis- sense variants: c.207+2T>G (rs782792601), c.206A>G (rs781909386) and c.205A>G (rs782503581) in NDUFB11 that affected the exon-splice site and are thought to cause MC1d. Patient C had the mitochondrial m.3243A>G mutation (rs199474657) that caused Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke- like episodes (MELAS), and another variant m.4336T>C (rs41456348) that caused the splice site and sensinueronal deafness and migraine. It was observed that a number of patients were carriers for more than one rare variant but no clear candidates were always present. Conclusion: Critical analysis of rare nuclear and mitochondrial gene mutations identified from exome sequence data served to establish a genetic diagnosis in 3 of 13 undiagnosed patients with rare disease. Disclosure: The research work in this publication was partially funded by the Malta Government Scholarship Scheme grant, BBMRI-LPC project BBMRI_03 MITOMUTWES, RD-Connect and EuroBioBank.