Novel, Complex Configurations of the MARCHF6 Repeat Expansion Associated with Progressive Myoclonic Epilepsy and Familial Adult Myoclonic Epilepsy
Abstract number :
2.041
Submission category :
12. Genetics / 12A. Human Studies
Year :
2024
Submission ID :
1162
Source :
www.aesnet.org
Presentation date :
12/8/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Mark Bennett, PhD – The Walter and Eliza Hall Institute of Medical Research
Mark Corbett, PhD – University of Adelaide
Thessa Kroes, BSc – University of Adelaide
Laura Canafoglia, MD, PhD – Fondazione IRCCS Istituto Neurologico Carlo Besta
Karen Oliver, PhD – University of Melbourne
Jillian Cameron, MBBS – University of Melbourne
Neblina Sikta, BCS – University of Melbourne
Jacob Munro, MIT – The Walter and Eliza Hall Institute of Medical Research
Liam Fearnley, PhD – The Walter and Eliza Hall Institute of Medical Research
Kristina Ibañez, PhD – Queen Mary University of London
Arianna Tucci, MD, PhD – Queen Mary University of London
Sanjay Sisodiya, MD – University College of London (UCL) Queen Square Institute of Neurology
Michael Hildebrand, PhD – University of Melbourne
Ingrid Scheffer, MBBS, PhD, FRACP, FRS – University of Melbourne, Austin Hospital and Royal Children's Hospital, Florey and Murdoch Children’s Research Institutes
Carolina Courage, MD – Folkhälsan Research Center
Anna-Elina Lehesjoki, MD, PhD – Folkhälsan Research Center
Loretta Giuliano, MD – University of Catania
Giuseppe Didato, MD – Fondazione IRCCS Istituto Neurologico Carlo Besta
Silvana Franceschetti, MD, PhD – Fondazione IRCCS Istituto Neurologico Carlo Besta
Jozef Gecz, PhD – University of Adelaide
Samuel Berkovic, MD, FRS – University of Melbourne
Melanie Bahlo, PhD – The Walter and Eliza Hall Institute of Medical Research
Rationale: Repeat expansions cause over 50 human disorders, including eight forms of epilepsy. Pentanucleotide TTTCA expansions in seven different genes are associated with familial adult myoclonic epilepsy (FAME) and a dodecamer expansion causes Unverricht-Lundborg disease, a form of progressive myoclonic epilepsy (PME). We hypothesised that PME and FAME may have an overlapping phenotypic spectrum and searched for pathogenic repeat expansions in individuals with later-onset PME or FAME.
Methods: We generated whole genome sequencing data and searched for known and novel repeat expansions. Targeted long read sequencing was performed to characterize repeat expansions identified. Motivated by our discovery of a novel complex repeat expansion, we developed a new bioinformatic approach and searched 18 individuals with later-onset PME or suspected FAME for evidence of similar complex expansions. We also interrogated >5000 individuals with mixed epilepsy diagnoses or controls to search for additional carriers and estimate the population frequency of novel repeat expansions identified.
Results: No known pathogenic repeat expansions were identified. We discovered a novel TTGTA expansion in a father-son duo with later-onset PME in the gene MARCHF6 at the same locus as the pathogenic TTTCA expansion that causes FAME3. Targeted long-read sequencing of this locus revealed a large, complex repeat structure, harbouring TTTCA expansions buried within it. We discovered a second, different, complex configuration of the FAME3 expansion containing a hidden pathogenic TTTCA expansion surrounded by TTTTA expansions in one of the 18 individuals searched, who had a diagnosis of suspected FAME. No other carriers of complex FAME3 expansions were identified. Both families had initially tested negative for the FAME3 expansion with standard RP-PCR testing and genome sequencing analysis.
Conclusions: We identified two novel, complex configurations of the FAME3 repeat expansion in families with PME and FAME, expanding the diversity of repeat expansions associated with epilepsy and further supporting the idea that PME and FAME have an overlapping phenotypic spectrum, which may lead to misdiagnoses. Loci with unusual repeat expansions warrant further investigation as they may contain hidden pathogenic repeat expansions, which can only be revealed by long read sequencing.
Funding: This work was supported by the National Health and Medical Research Council (NHMRC) Australia, the Medical Research Future Fund Australia, Victorian State Government Operational Infrastructure Support, the Australian Government NHMRC IRIISS, CURE Epilepsy, the Epilepsy Society, the Folkhälsan Research Foundation, and the Italian Ministry of Health (RRC). This research was made possible through access to data in the National Genomic Research Library, which is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure.
Genetics