TY - JOUR
T1 - Exome sequencing of ATP1A3-negative cases of alternating hemiplegia of childhood reveals SCN2A as a novel
causative gene
AU - Panagiotakaki, Eleni
AU - Tiziano, Francesco Danilo
AU - Mikati, Mohamad A.
AU - Vijfhuizen, Lisanne S.
AU - Nicole5, Sophie
AU - Lesca, Gaetan
AU - Abiusi, Emanuela
AU - Novelli, Agnese
AU - Di Pietro, Lorena
AU - Consortium, I. B. AHC
AU - Consortium, IAHCRC
AU - Harder, Aster V. E.
AU - Walley, Nicole M.
AU - Grandis, Elisa De
AU - Poulat, Anne-Lise
AU - Portes, Vincent Des
AU - Lépine, Anne
AU - Nassogne, Marie-Cecile
AU - Arzimanoglou, Alexis
AU - Vavassori, Rosaria
AU - Koenderink, Jan
AU - Thompson, Christopher H.
AU - Jr, Alfred L. George
AU - Gurrieri, Fiorella
AU - van den Maagdenberg, Arn M. J. M.
AU - Heinzen, Erin L.
PY - 2024
Y1 - 2024
N2 - Alternating hemiplegia of childhood (AHC) is a rare neurodevelopment disorder that is typically characterized by debilitating
episodic attacks of hemiplegia, seizures, and intellectual disability. Over 85% of individuals with AHC have a de novo missense
variant in ATP1A3 encoding the catalytic α3 subunit of neuronal Na+/K+ ATPases. The remainder of the patients are genetically
unexplained. Here, we used next-generation sequencing to search for the genetic cause of 26 ATP1A3-negative index patients with
a clinical presentation of AHC or an AHC-like phenotype. Three patients had affected siblings. Using targeted sequencing of exonic,
intronic, and flanking regions of ATP1A3 in 22 of the 26 index patients, we found no ultra-rare variants. Using exome sequencing,
we identified the likely genetic diagnosis in 9 probands (35%) in five genes, including RHOBTB2 (n = 3), ATP1A2 (n = 3), ANK3 (n = 1),
SCN2A (n = 1), and CHD2 (n = 1). In follow-up investigations, two additional ATP1A3-negative individuals were found to have rare
missense SCN2A variants, including one de novo likely pathogenic variant and one likely pathogenic variant for which inheritance
could not be determined. Functional evaluation of the variants identified in SCN2A and ATP1A2 supports the pathogenicity of the
identified variants. Our data show that genetic variants in various neurodevelopmental genes, including SCN2A, lead to AHC or
AHC-like presentation. Still, the majority of ATP1A3-negative AHC or AHC-like patients remain unexplained, suggesting that other
mutational mechanisms may account for the phenotype or that cases may be explained by oligo- or polygenic risk factors.
AB - Alternating hemiplegia of childhood (AHC) is a rare neurodevelopment disorder that is typically characterized by debilitating
episodic attacks of hemiplegia, seizures, and intellectual disability. Over 85% of individuals with AHC have a de novo missense
variant in ATP1A3 encoding the catalytic α3 subunit of neuronal Na+/K+ ATPases. The remainder of the patients are genetically
unexplained. Here, we used next-generation sequencing to search for the genetic cause of 26 ATP1A3-negative index patients with
a clinical presentation of AHC or an AHC-like phenotype. Three patients had affected siblings. Using targeted sequencing of exonic,
intronic, and flanking regions of ATP1A3 in 22 of the 26 index patients, we found no ultra-rare variants. Using exome sequencing,
we identified the likely genetic diagnosis in 9 probands (35%) in five genes, including RHOBTB2 (n = 3), ATP1A2 (n = 3), ANK3 (n = 1),
SCN2A (n = 1), and CHD2 (n = 1). In follow-up investigations, two additional ATP1A3-negative individuals were found to have rare
missense SCN2A variants, including one de novo likely pathogenic variant and one likely pathogenic variant for which inheritance
could not be determined. Functional evaluation of the variants identified in SCN2A and ATP1A2 supports the pathogenicity of the
identified variants. Our data show that genetic variants in various neurodevelopmental genes, including SCN2A, lead to AHC or
AHC-like presentation. Still, the majority of ATP1A3-negative AHC or AHC-like patients remain unexplained, suggesting that other
mutational mechanisms may account for the phenotype or that cases may be explained by oligo- or polygenic risk factors.
KW - ATP1A3
KW - SCN2A
KW - alternating hemiplegia of childhood
KW - ATP1A3
KW - SCN2A
KW - alternating hemiplegia of childhood
UR - https://publicatt.unicatt.it/handle/10807/260660
U2 - 10.1038/s41431-023-01489-4
DO - 10.1038/s41431-023-01489-4
M3 - Article
SN - 1476-5438
VL - 32
SP - 224
EP - 231
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 2
ER -