Biallelic CACNA2D2 variants in epileptic encephalopathy and cerebellar atrophy.

TitleBiallelic CACNA2D2 variants in epileptic encephalopathy and cerebellar atrophy.
Publication TypeJournal Article
Year of Publication2019
AuthorsPunetha, J, Karaca, E, Gezdirici, A, Lamont, RE, Pehlivan, D, Marafi, D, Appendino, JP, Hunter, JV, Akdemir, ZC, Fatih, JM, Jhangiani, SN, Gibbs, RA, A Innes, M, Posey, JE, Lupski, JR
JournalAnn Clin Transl Neurol
Date Published2019 Aug

OBJECTIVE: To characterize the molecular and clinical phenotypic basis of developmental and epileptic encephalopathies caused by rare biallelic variants in CACNA2D2.

METHODS: Two affected individuals from a family with clinical features of early onset epileptic encephalopathy were recruited for exome sequencing at the Centers for Mendelian Genomics to identify their molecular diagnosis. GeneMatcher facilitated identification of a second family with a shared candidate disease gene identified through clinical gene panel-based testing.

RESULTS: Rare biallelic CACNA2D2 variants have been previously reported in three families with developmental and epileptic encephalopathy, and one family with congenital ataxia. We identified three individuals in two unrelated families with novel homozygous rare variants in CACNA2D2 with clinical features of developmental and epileptic encephalopathy and cerebellar atrophy. Family 1 includes two affected siblings with a likely damaging homozygous rare missense variant c.1778G>C; p.(Arg593Pro) in CACNA2D2. Family 2 includes a proband with a homozygous rare nonsense variant c.485_486del; p.(Tyr162Ter) in CACNA2D2. We compared clinical and molecular findings from all nine individuals reported to date and note that cerebellar atrophy is shared among all.

INTERPRETATION: Our study supports the candidacy of CACNA2D2 as a disease gene associated with a phenotypic spectrum of neurological disease that include features of developmental and epileptic encephalopathy, ataxia, and cerebellar atrophy. Age at presentation may affect apparent penetrance of neurogenetic trait manifestations and of a particular clinical neurological endophenotype, for example, seizures or ataxia.

Alternate JournalAnn Clin Transl Neurol
PubMed ID31402629
PubMed Central IDPMC6689679
Grant List / HL / NHLBI NIH HHS / United States
/ / American Brain Foundation /
/ NH / NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
T32 NS043124-17 / NS / NINDS NIH HHS / United States
#512848 / / Muscular Dystrophy Association /
T32 GM007526 / GM / NIGMS NIH HHS / United States