@article {758, title = {Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy.}, journal = {Ann Clin Transl Neurol}, volume = {7}, year = {2020}, month = {2020 05}, pages = {610-627}, abstract = {

OBJECTIVE: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families.

METHODS: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory.

RESULTS: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2~years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood.

CONCLUSION: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

}, keywords = {Adolescent, Alleles, Atrophy, Child, Child, Preschool, Cohort Studies, Consanguinity, Epilepsy, Female, Humans, Infant, Male, Microcephaly, Neurodevelopmental Disorders, Pedigree, Phenotype, Receptors, Metabotropic Glutamate, Whole Exome Sequencing}, issn = {2328-9503}, doi = {10.1002/acn3.51003}, author = {Marafi, Dana and Mitani, Tadahiro and Isikay, Sedat and Hertecant, Jozef and Almannai, Mohammed and Manickam, Kandamurugu and Abou Jamra, Rami and El-Hattab, Ayman W and Rajah, Jaishen and Fatih, Jawid M and Du, Haowei and Karaca, Ender and Bayram, Yavuz and Punetha, Jaya and Rosenfeld, Jill A and Jhangiani, Shalini N and Boerwinkle, Eric and Akdemir, Zeynep C and Erdin, Serkan and Hunter, Jill V and Gibbs, Richard A and Pehlivan, Davut and Posey, Jennifer E and Lupski, James R} } @article {945, title = {Biallelic in-frame deletion in TRAPPC4 in a family with developmental delay and cerebellar atrophy.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 10 01}, pages = {e83}, keywords = {Atrophy, Cerebellar Diseases, Humans, Intellectual Disability, Sequence Deletion}, issn = {1460-2156}, doi = {10.1093/brain/awaa256}, author = {Saad, Ahmed K and Marafi, Dana and Mitani, Tadahiro and Jolly, Angad and Du, Haowei and Elbendary, Hasnaa M and Jhangiani, Shalini N and Akdemir, Zeynep C and Gibbs, Richard A and Hunter, Jill V and Carvalho, Claudia M B C and Pehlivan, Davut and Posey, Jennifer E and Zaki, MAH S and Lupski, James R} } @article {692, 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} }