A new explanation for recessive myotonia congenita: exon deletions and duplications in CLCN1.
OBJECTIVE
To assess whether exon deletions or duplications in CLCN1 are associated with recessive myotonia congenita (MC).


METHODS
We performed detailed clinical and electrophysiologic characterization in 60 patients with phenotypes consistent with MC. DNA sequencing of CLCN1 followed by multiplex ligation-dependent probe amplification to screen for exon copy number variation was undertaken in all patients.


RESULTS
Exon deletions or duplications in CLCN1 were identified in 6% of patients with MC. Half had heterozygous exonic rearrangements. The other 2 patients (50%), with severe disabling infantile onset myotonia, were identified with both a homozygous mutation, Pro744Thr, which functional electrophysiology studies suggested was nonpathogenic, and a triplication/homozygous duplication involving exons 8-14, suggesting an explanation for the severe phenotype.


CONCLUSIONS
These data indicate that copy number variation in CLCN1 may be an important cause of recessive MC. Our observations suggest that it is important to check for exon deletions and duplications as part of the genetic analysis of patients with recessive MC, especially in patients in whom sequencing identifies no mutations or only a single recessive mutation. These results also indicate that additional, as yet unidentified, genetic mechanisms account for cases not currently explained by either CLCN1 point mutations or exonic deletions or duplications.
Medical Research Council Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, University College London, London, UK.
D L
DL
Raja Rayan
A
A
Haworth
R
R
Sud
E
E
Matthews
D
D
Fialho
J
J
Burge
S
S
Portaro
S
S
Schorge
K
K
Tuin
P
P
Lunt
M
M
McEntagart
A
A
Toscano
M B
MB
Davis
M G
MG
Hanna
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D018118:Chloride Channels / Q000235:genetics*; D056915:DNA Copy Number Variations; D005091:Exons; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D009224:Myotonia Congenita / Q000235:genetics*; D017384:Sequence Deletion
C086321:CLC-1 channel; D018118:Chloride Channels