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Nat Commun. 2019 Oct 29;10(1):4920. doi: 10.1038/s41467-019-12671-y.

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2.

Author information

1
Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, 5005, SA, Australia.
2
Institute of Translational Pharmacology, National Research Council, Rome, Italy.
3
Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, VIC, Australia.
4
Department of Medical Biology, the University of Melbourne, Melbourne, 3010, VIC, Australia.
5
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, 3084, VIC, Australia.
6
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
7
Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, Napoli, Italy.
8
IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
9
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
10
Neurophysiopathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
11
Member of the European Reference Network on Rare and Complex epilepsies, ERN EpiCARE, London, UK.
12
Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università, 30, 00185, Rome, Italy.
13
IRCCS Neuromed, Pozzilli, IS, Italy.
14
Pacific Biosciences, Menlo Park, CA, USA.
15
Neuroscience and Neurogenetics Department, Meyer Children's Hospital, Florence, Italy.
16
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.
17
Department of Biotechnology, University of Verona, Strada le Grazie 15, 37134, Verona, Italy.
18
Institute of Pediatric Neurology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
19
Tel Aviv University Medical School, 69978, Tel Aviv, Israel.
20
Personal Genomics, Strada le Grazie 15, 37134, Verona, Italy.
21
Department of Neurology, Northern Health, Melbourne, VIC, Australia.
22
Amsterdam UMC, University of Amsterdam, Department of Neurology and Clinical Neurophysiology, Amsterdam Neuroscience, Amsterdam, The Netherlands.
23
Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
24
Kinghorn Centre for Clinical Genomics, Garvan Institute for Medical Research, Darlinghurst, NSW, 2010, Australia.
25
St-Vincent's Clinical School, Faulty of Medicine, UNSW Sydney, Darlinghurst, NSW, 2010, Australia.
26
Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel.
27
Laboratory of Neurogenetics, IRCCS Istituto "G. Gaslini", Genova, Italy.
28
Department of Neurology, Federico II University, Napoli, Italy.
29
AP-HP, Hôpital Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France.
30
INSERM, U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
31
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
32
Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France.
33
Université de Strasbourg, Illkirch, France.
34
Department of Neurology, Strasbourg University Hospital, Strasbourg, France.
35
Centre National de la Recherche Scientifique, U7104, Illkirch, France.
36
MS Unit, Montpellier University Hospital, Montpellier, France.
37
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
38
Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK.
39
Division of Neurology Children's Hospital of Philadelphia, Philadelphia, PA, USA.
40
Department of Neurology, the University of Tokyo Hospital, Tokyo, Japan.
41
Medical Genome Center, the University of Tokyo Hospital, Tokyo, Japan.
42
International University of Health and Welfare, Chiba, Japan.
43
TIGEM - Telethon Institute of Genetics and Medicine, Naples, and San Raffaele University, Milan, Italy.
44
Department of Paediatrics and Child Health, University of Otago, Wellington, Wellington, New Zealand.
45
University of Pretoria, Pretoria, South Africa.
46
Department of Neurology, University of Groningen, Groningen, The Netherlands.
47
Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Goethe University, Frankfurt am Main, Frankfurt, Germany.
48
Department of Neurology, Epilepsy Center Hessen, Philipps University, Marburg, Marburg, Germany.
49
Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute & Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
50
Departments of Human Genetics & Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
51
Medical Genetics Unit, Sant'Orsola-Malpighi University Hospital, Bologna, Italy.
52
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto "G. Gaslini", Genova, Italy.
53
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy.
54
Royal Children's Hospital, Murdoch Children's Research Institute and Florey Institute, Melbourne, VIC, Australia.
55
Medical Genetics, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
56
Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Rome, Italy.
57
Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, 5005, SA, Australia. jozef.gecz@adelaide.edu.au.
58
South Australian Health and Medical Research Institute, Adelaide, 5000, SA, Australia. jozef.gecz@adelaide.edu.au.

Abstract

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.

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