Background: Episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are autosomal dominant disorders characterised by paroxysmal ataxia and migraine, respectively. Point mutations in CACNA1A, which encodes the neuronal P/Q-type calcium channel, have been detected in many cases of EA2 and FHM1. The genetic basis of typical cases without CACNA1A point mutations is not fully known. Standard DNA sequencing methods may miss large scale genetic rearrangements such as deletions and duplications. The authors investigated whether large scale genetic rearrangements in CACNA1A can cause EA2 and FHM1.
Methods: The authors used multiplex ligation dependent probe amplification (MLPA) to screen for intragenic CACNA1A rearrangements.
Results: The authors identified five previously unreported large scale deletions in CACNA1A in seven families with episodic ataxia and in one case with hemiplegic migraine. One of the deletions (exon 6 of CACNA1A) segregated with episodic ataxia in a four generation family with eight affected individuals previously mapped to 19p13. In addition, the authors identified the first pathogenic duplication in CACNA1A in an index case with isolated episodic diplopia without ataxia and in a first degree relative with episodic ataxia.
Conclusions: Large scale deletions and duplications can cause CACNA1A associated channelopathies. Direct DNA sequencing alone is not sufficient as a diagnostic screening test.
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▸ Additional figure is published online only at http://jmg.bmj.com/content/vol46/issue11
RWL and SR contributed equally to this work.
Funding SR holds a Clinical Training Fellowship from the Wellcome Trust. TDG was funded by an Action Medical Research Training Fellowship and the Guarantors of Brain. SR, TDG and MGH belong to the Consortium for Clinical Investigation of Neurological Channelopathies (CINCH) supported by NIH RU54 RR019482 (NINDS/ORD). The work of RWL, SR, MGS, MBD, LHE, TDG and MGH is undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. MGH is supported by an MRC Centre grant (G0601943).
Competing interests None.
Patient consent Not required.
Provenance and Peer review Not commissioned; externally peer reviewed.