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Biallelic CACNA1A variants – review of literature and report of a child with drug-resistant epilepsy and developmental delay
Authors:
Wong-Spracklen, V.M.Y., Kolesnik, A., Eck, J., Sabanthan, S., Spasic-Boskovic, O., Maw, A., BAKER, K.
Reference:
American Journal of Medical Genetics Part A, 188(11), 3306-3311
Year of publication:
2022
CBU number:
8838
Abstract:
Biallelic variants in CACNA1A have previously been reported in nine individuals (four families) presenting with epilepsy and cognitive impairments of variable severity and age-of-onset. Here, we describe a child who presented at six months of age with drug-resistant epilepsy and developmental delay. At ten years of age she has profound impairments in motor function and communication. MRI was initially unremarkable, but progressed to severe cerebellar atrophy by age 3 years. Next Generation Sequencing and panel analysis identified a maternally-inherited truncating variant c.2042_2043delAG, p.(Gln681ArgfsTer100) and paternally-inherited missense variant c.1693G>A, p.(Glu565Lys). In contrast to previously reported biallelic cases, parents carrying these monoallelic variants did not display clear signs of a CACNA1A-associated syndrome. In conclusion, we provide further evidence that biallelic CACNA1A variants can cause a severe epileptic and developmental encephalopathy with progressive cerebellar atrophy, and highlight complexities of genetic counselling in such situations
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