Novel, complex configurations of the <i>MARCHF6</i> repeat expansion associated with progressive myoclonic epilepsy and familial adult myoclonic epilepsy

Repeat expansions are a known cause of progressive myoclonic epilepsy (PME) and familial adult myoclonic epilepsy (FAME). We hypothesized that PME and FAME may have an overlapping phenotypic spectrum and searched for pathogenic repeat expansions in 18 individuals from 15 families with later-onset PME or FAME. We generated whole genome sequencing data by short-read sequencing and searched for known and novel repeat expansions. No known, pathogenic repeat expansions were identified. Instead, we discovered a novel TTGTA expansion in the gene <i>MARCHF6</i> at the same location as the known, pathogenic FAME3 expansion in a PME family. Targeted long-read sequencing of this locus revealed a large, complex repeat structure harbouring an expansion of the pathogenic TTTCA repeat that causes FAME, surrounded by TTTTA and TTGTA expansions. Motivated by this discovery, we developed a new bioinformatic approach, mixSTR, to search for evidence of such complex expansions and discovered an additional novel configuration of the FAME3 expansion containing hidden pathogenic TTTCA expansions embedded within a TTTTA expansion in a second family clinically diagnosed with FAME. Both families had initially tested negative for the FAME3 expansion with standard RP-PCR and short-read genome sequencing analysis. We searched large epilepsy and population cohorts but did not identify any additional new individuals with complex FAME3 expansions. These findings have two important implications. Firstly, known repeat expansion loci with unusual repeat expansions, even if not known to be pathogenic, warrant further investigation as they may contain hidden pathogenic repeat expansions. Secondly, they provide molecular support for the clinical idea that PME and FAME have an overlapping phenotypic spectrum, and that the known FAME repeat expansions should be part of the diagnostic assessment of unsolved PMEs.

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Journal
Brain Communications
Published
2025-01-01
DOI
https://doi.org/10.1093/braincomms/fcaf433
Primary Topic
Glycogen Storage Diseases and Myoclonus
Type
article
Field-Weighted Citation Impact
0.00

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article

Novel, complex configurations of the MARCHF6 repeat expansion associated with progressive myoclonic epilepsy and familial adult myoclonic epilepsy

Kristina Ibáñez, Jillian M. Cameron, Jozef Gécz, Loretta Giuliano et al.
Brain Communications
Glycogen Storage Diseases and Myoclonus
article

Novel, complex configurations of the MARCHF6 repeat expansion associated with progressive myoclonic epilepsy and familial adult myoclonic epilepsy

Kristina Ibáñez, Jillian M. Cameron, Jozef Gécz, Loretta Giuliano, Giuseppe Didato, Karen Oliver, Laura Canafoglia, Ingrid Eileen Scheffer, Michael S. Hildebrand, Anna‐Elina Lehesjoki, Silvana Franceschetti, Samuel F. Berkovic, Liam G. Fearnley, Thessa Kroes, Melanie Bahlo, Jacob E. Munro, Mark F. Bennett, Carolina Courage, Sanjay M. Sisodiya, Mark Corbett, Neblina Sikta, Arianna Tucci
article en

Abstract

Repeat expansions are a known cause of progressive myoclonic epilepsy (PME) and familial adult myoclonic epilepsy (FAME). We hypothesized that PME and FAME may have an overlapping phenotypic spectrum and searched for pathogenic repeat expansions in 18 individuals from 15 families with later-onset PME or FAME. We generated whole genome sequencing data by short-read sequencing and searched for known and novel repeat expansions. No known, pathogenic repeat expansions were identified. Instead, we discovered a novel TTGTA expansion in the gene <i>MARCHF6</i> at the same location as the known, pathogenic FAME3 expansion in a PME family. Targeted long-read sequencing of this locus revealed a large, complex repeat structure harbouring an expansion of the pathogenic TTTCA repeat that causes FAME, surrounded by TTTTA and TTGTA expansions. Motivated by this discovery, we developed a new bioinformatic approach, mixSTR, to search for evidence of such complex expansions and discovered an additional novel configuration of the FAME3 expansion containing hidden pathogenic TTTCA expansions embedded within a TTTTA expansion in a second family clinically diagnosed with FAME. Both families had initially tested negative for the FAME3 expansion with standard RP-PCR and short-read genome sequencing analysis. We searched large epilepsy and population cohorts but did not identify any additional new individuals with complex FAME3 expansions. These findings have two important implications. Firstly, known repeat expansion loci with unusual repeat expansions, even if not known to be pathogenic, warrant further investigation as they may contain hidden pathogenic repeat expansions. Secondly, they provide molecular support for the clinical idea that PME and FAME have an overlapping phenotypic spectrum, and that the known FAME repeat expansions should be part of the diagnostic assessment of unsolved PMEs.

Brain CommunicationsVol. 7(6)
Royal Children's Hospital (AU), University of Helsinki (FI), The University of Melbourne (AU), Walter and Eliza Hall Institute of Medical Research (AU), Florey Institute of Neuroscience and Mental Health (AU), University of Catania (IT), South Australian Health and Medical Research Institute (AU), William Harvey Research Institute (GB), Murdoch Children's Research Institute (AU), National Hospital for Neurology and Neurosurgery (GB), Austin Health (AU), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Folkhälsans Forskningscentrum (FI), University College London (GB), Epilepsy Society (GB), The University of Adelaide (AU)
Citizens United for Research in Epilepsy, Helsingin Yliopisto, Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, Epilepsy Society, Medical Research Council, National Health and Medical Research Council
Openalex Percentile: Top 54%
Glycogen Storage Diseases and Myoclonus
DOIOpen Access PDFOpenAlex
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