Severe Epileptic Encephalopathy in Siblings due to a Novel Heterozygous CACNA1A Gene Mutation

Mammadova, Dilbar; Kraus, Cornelia; Leis, Thomas; Trollmann, Regina

doi:10.1055/s-0039-1698222

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“…In general, missense gain of function variants are mainly associated with familial hemiplegic migraine (FHM1, #141500), LOF variants with EA2 (#108500) and the gain of toxicity expansions of CAG repeats with spinocerebellar ataxia (SCA6, #183086) [19][20][21][22]. However, both gain and LOF heterozygous variants have also been associated with cognitive/behavioral impairments [17,21,23,24], with epileptic encephalopathy [18,[25][26][27] and with congenital ataxia [28], suggesting that the neuropsychological disturbances are caused by the channel dysfunction. Indeed, no major cognitive deficits have been described in SCA6 patients, probably because polyglutamine expansions do not alter the calcium current of the channel [19].…”

Section: Results and Discussion Familymentioning

confidence: 99%

Biallelic variants in genes previously associated with dominant inheritance: CACNA1A, RET and SLC20A2

et al. 2021

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A subset of families with co-dominant or recessive inheritance has been described in several genes previously associated with dominant inheritance. Those recessive families displayed similar, more severe, or even completely different phenotypes to their dominant counterparts. We report the first patients harboring homozygous disease-related variants in three genes that were previously associated with dominant inheritance: a loss-of-function variant in the CACNA1A gene and two missense variants in the RET and SLC20A2 genes, respectively. All patients presented with a more severe clinical phenotype than the corresponding typical dominant form. We suggest that co-dominant or recessive inheritance for these three genes could explain the phenotypic differences from those documented in their cognate dominant phenotypes. Our results reinforce that geneticists should be aware of the possible different forms of inheritance in genes when WES variant interpretation is performed. We also evidence the need to refine phenotypes and inheritance patterns associated with genes in order to avoid failures during WES analysis and thus, raising the WES diagnostic capacity in the benefit of patients.

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