Biallelic inherited SCN8A variants, a rare cause of SCN8A-related developmental and epileptic encephalopathy
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Biallelic inherited SCN8A variants, a rare cause of SCN8A-related developmental and epileptic encephalopathy. / Wengert, Eric R.; Tronhjem, Cathrine E.; Wagnon, Jacy L.; Johannesen, Katrine M.; Petit, Hayley; Krey, Ilona; Saga, Anusha U.; Panchal, Payal S.; Strohm, Samantha M.; Lange, Jörn; Kamphausen, Susanne B.; Rubboli, Guido; Lemke, Johannes R.; Gardella, Elena; Patel, Manoj K.; Meisler, Miriam H.; Møller, Rikke S.
I: Epilepsia, Bind 60, Nr. 11, 2019, s. 2277-2285.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Biallelic inherited SCN8A variants, a rare cause of SCN8A-related developmental and epileptic encephalopathy
AU - Wengert, Eric R.
AU - Tronhjem, Cathrine E.
AU - Wagnon, Jacy L.
AU - Johannesen, Katrine M.
AU - Petit, Hayley
AU - Krey, Ilona
AU - Saga, Anusha U.
AU - Panchal, Payal S.
AU - Strohm, Samantha M.
AU - Lange, Jörn
AU - Kamphausen, Susanne B.
AU - Rubboli, Guido
AU - Lemke, Johannes R.
AU - Gardella, Elena
AU - Patel, Manoj K.
AU - Meisler, Miriam H.
AU - Møller, Rikke S.
N1 - Publisher Copyright: Wiley Periodicals, Inc. © 2019 International League Against Epilepsy
PY - 2019
Y1 - 2019
N2 - Objective: Monoallelic de novo gain-of-function variants in the voltage-gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss-of-function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss-of-function are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders. In all three categories, the affected individuals are heterozygous for a SCN8A variant in combination with a wild-type allele. In the present study, we describe two unusual families with severely affected individuals who inherited biallelic variants of SCN8A. Methods: We identified two families with biallelic SCN8A variants by diagnostic gene panel sequencing. Functional analysis of the variants was performed using voltage clamp recordings from transfected ND7/23 cells. Results: We identified three probands from two unrelated families with DEE due to biallelic SCN8A variants. Each parent of an affected individual carried a single heterozygous SCN8A variant and exhibited mild cognitive impairment without seizures. In both families, functional analysis demonstrated segregation of one allele with complete loss-of-function, and one allele with altered biophysical properties consistent with partial loss-of-function. Significance: These studies demonstrate that SCN8A DEE may, in rare cases, result from inheritance of two variants, both of which exhibit reduced channel activity. In these families, heterozygosity for the dominant variants results in less severe disease than biallelic inheritance of two variant alleles. The clinical consequences of variants with partial and complete loss of SCN8A function are variable and likely to be influenced by genetic background.
AB - Objective: Monoallelic de novo gain-of-function variants in the voltage-gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss-of-function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss-of-function are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders. In all three categories, the affected individuals are heterozygous for a SCN8A variant in combination with a wild-type allele. In the present study, we describe two unusual families with severely affected individuals who inherited biallelic variants of SCN8A. Methods: We identified two families with biallelic SCN8A variants by diagnostic gene panel sequencing. Functional analysis of the variants was performed using voltage clamp recordings from transfected ND7/23 cells. Results: We identified three probands from two unrelated families with DEE due to biallelic SCN8A variants. Each parent of an affected individual carried a single heterozygous SCN8A variant and exhibited mild cognitive impairment without seizures. In both families, functional analysis demonstrated segregation of one allele with complete loss-of-function, and one allele with altered biophysical properties consistent with partial loss-of-function. Significance: These studies demonstrate that SCN8A DEE may, in rare cases, result from inheritance of two variants, both of which exhibit reduced channel activity. In these families, heterozygosity for the dominant variants results in less severe disease than biallelic inheritance of two variant alleles. The clinical consequences of variants with partial and complete loss of SCN8A function are variable and likely to be influenced by genetic background.
U2 - 10.1111/epi.16371
DO - 10.1111/epi.16371
M3 - Journal article
C2 - 31625145
AN - SCOPUS:85074099248
VL - 60
SP - 2277
EP - 2285
JO - Epilepsia
JF - Epilepsia
SN - 0013-9580
IS - 11
ER -
ID: 279117689