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

Mark Corbett ,Aaron M Wenger ,Sanjay M Sisodiya ,Giorgio Casari ,Massimo Delledonne ,Marina A J Tijssen ,Samuel F Berkovic ,Renzo Guerrini ,Rachel Straussberg ,Manuela Pendziwiat ,Shreyasee Chakraborty ,Douglas E Crompton ,Thessa Kroes ,Shoji Tsuji ,Josemir W Sander ,Mark F Bennett ,Ingo Helbig ,Davide Mei ,Karl Martin Klein ,Laura Canafoglia ,A.f Van Rootselaar ,Rahel T Florian ,Eric Leguern ,Paolo Tinuper ,Julien Buratti ,Édouard Hirsch ,Lynette G Sadleir ,Sylvie Forlani ,Rachael Catford ,Francesco Brancati ,Christel Depienne ,Renée Carroll ,Carlo Di Bonaventura ,Riaan Van Coller ,Antonio Suppa ,Amy Schneider ,Giangennaro Coppola ,Martin A Smith ,Ilan Blatt ,Sara Baldassari ,Sabine Kaya ,Shaun Carswell ,Tommaso Pippucci ,Melanie Bahlo ,Gabrielle Rudolf ,Luciano Xumerle ,Brigid M Regan ,Salvatore Striano ,Caroline Nava ,Kirston Barton ,Hiroyuki Ishiura ,Pasquale Striano ,Federico Zara ,Ingrid E Scheffer ,Zaid Afawi ,Francesca Bisulli ,Kathryn Friend ,Simona Balestrini ,Arn M J M Van Den Maagdenberg ,Alison Gardner ,Pierre Labauge ,Michele Iacomino ,Silvana Franceschetti ,Anthony Correll ,Liana Veneziano ,Boris Keren ,Jozef Gécz

doi:10.1038/s41467-019-12671-y

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.

Highlights

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
The endogenous ATTTT repeat in intron 1 of STARD7 was found to be variable in length in the normal population but not expanded to the same extent as repeats found in individuals with FAME
The pathogenic ATTTC insertion and expansion was always accompanied by the endogenous ATTTT pentanucleotide repeat in all cases of FAME2 that we describe here, replicating the findings in the cases of FAME with expansions in SAMD12, TNRC6A, RAPGEF210,11,19 and the report of a similar expansion in MARCH6 causing chr5-linked FAME20

Summary

Introduction

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. 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. The cause of FAME1, which is linked to chr[8] (OMIM:601068), has recently been shown to be a complex repeat expansion of pentameric TTTTA and inserted TTTCA repeats into the fourth intron of the SAMD12 gene[10,11]. TNRC6A (chr16) and RAPGEF2 (chr4) were implicated as FAME genes within single families, respectively, found via direct detection of the same repeated TTTTA and TTTCA sequences[11]

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Conclusion