Microchromosomal deletions involving SCN1A and adjacent genes in severe myoclonic epilepsy in infancy.
OBJECTIVE
Genetic abnormalities of the gene encoding alpha1 subunit of the sodium channel (SCN1A), which can be detected by direct sequencing, are present in more than 60% of patients with severe myoclonic epilepsy in infancy (SMEI) or its borderline phenotype (SMEB). Microchromosomal deletions have been recently reported as additional causes of SMEI. This study examines whether such microdeletions are associated with SMEI as well as with SMEB.


METHODS
We recruited patients with SMEI (n = 35) and SMEB (n = 34), who were confirmed previously to have no mutations of SCN1A by direct sequencing. Microdeletions were sought by multiplex ligation-dependent probe amplification (MLPA), and then confirmed and characterized by fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (aCGH), respectively.


RESULTS
Heterozygous multiple exonic deletions were identified in 7/35 SMEI patients (20%) and 0/34 SMEB patients (0%), with a net frequency of 10.1% (7/69 patients). Deletions were confirmed by FISH and aCGH analysis. The concomitant deletions of adjacent genes were revealed by aCGH. None of the parents who agreed to undergo the analysis had such deletions suggesting that the deletions were de novo. The phenotypes of patients with the deletions were indistinguishable from those of SMEI resulting from point mutations.


CONCLUSIONS
Our findings indicate that microchromosomal deletion, often involving not only SCN1A but also several adjacent genes, is associated with core SMEI. As microchromosomal deletion cannot be anticipated by the phenotypes or detected by conventional methods, genetic abnormalities in SMEI should be carefully sought by techniques that can detect microdeletions.
Wang
Ji-wen
JW
Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan.
Kurahashi
Hirokazu
H
Ishii
Atsushi
A
Kojima
Toshio
T
Ohfu
Masaharu
M
Inoue
Takahito
T
Ogawa
Atsushi
A
Yasumoto
Sawa
S
Oguni
Hirokazu
H
Kure
Shigeo
S
Fujii
Tatsuya
T
Ito
Masatoshi
M
Okuno
Takehiko
T
Shirasaka
Yukiyoshi
Y
Natsume
Jun
J
Hasegawa
Aki
A
Konagaya
Akihiko
A
Kaneko
Sunao
S
Hirose
Shinichi
S
D001921:Brain / Q000503:physiopathology; D002648:Child; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D004831:Epilepsies, Myoclonic / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007438:Introns / Q000235:genetics; D008297:Male; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics*
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels