@article {77, title = {Biallelic CACNA2D2 variants in epileptic encephalopathy and cerebellar atrophy.}, journal = {Ann Clin Transl Neurol}, volume = {6}, year = {2019}, month = {2019 Aug}, pages = {1395-1406}, abstract = {

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.

}, issn = {2328-9503}, doi = {10.1002/acn3.50824}, author = {Punetha, Jaya and Karaca, Ender and Gezdirici, Alper and Lamont, Ryan E and Pehlivan, Davut and Marafi, Dana and Appendino, Juan P and Hunter, Jill V and Akdemir, Zeynep C and Fatih, Jawid M and Jhangiani, Shalini N and Gibbs, Richard A and Innes, A Micheil and Posey, Jennifer E and Lupski, James R} } @article {48, title = {The phenotypic spectrum of Xia-Gibbs syndrome.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 06}, pages = {1315-1326}, abstract = {

Xia-Gibbs syndrome (XGS: OMIM $\#$ 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38699}, author = {Jiang, Yunyun and Wangler, Michael F and McGuire, Amy L and Lupski, James R and Posey, Jennifer E and Khayat, Michael M and Murdock, David R and Sanchez-Pulido, Luis and Ponting, Chris P and Xia, Fan and Hunter, Jill V and Meng, Qingchang and Murugan, Mullai and Gibbs, Richard A} }