@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 {691, title = {Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities.}, journal = {Am J Med Genet A}, volume = {179}, year = {2019}, month = {2019 Oct}, pages = {2056-2066}, abstract = {

Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < -3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier-Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel-like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral-Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel-like phenotype and FFS, the last of which has not been associated with any disease gene to date.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61315}, author = {Karaca, Ender and Posey, Jennifer E and Bostwick, Bret and Liu, Pengfei and Gezdirici, Alper and Yesil, G{\"o}zde and Coban Akdemir, Zeynep and Bayram, Yavuz and Harms, Frederike L and Meinecke, Peter and Alawi, Malik and Bacino, Carlos A and Sutton, V Reid and Kort{\"u}m, Fanny 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} } @article {573, title = {Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 02 12}, pages = {708}, abstract = {

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.

}, keywords = {Alleles, Animals, Brain Diseases, Cell Line, Disease Models, Animal, Epilepsy, Female, Fibroblasts, Gene Knockout Techniques, Genetic Predisposition to Disease, Humans, Loss of Function Mutation, Male, Microcephaly, Models, Molecular, Neurodevelopmental Disorders, Pedigree, Prosencephalon, Valine-tRNA Ligase, Zebrafish}, issn = {2041-1723}, doi = {10.1038/s41467-018-07953-w}, author = {Siekierska, Aleksandra and Stamberger, Hannah and Deconinck, Tine and Oprescu, Stephanie N and Partoens, Mich{\`e}le and Zhang, Yifan and Sourbron, Jo and Adriaenssens, Elias and Mullen, Patrick and Wiencek, Patrick and Hardies, Katia and Lee, Jeong-Soo and Giong, Hoi-Khoanh and Distelmaier, Felix and Elpeleg, Orly and Helbig, Katherine L and Hersh, Joseph and Isikay, Sedat and Jordan, Elizabeth and Karaca, Ender and Kecskes, Angela and Lupski, James R and Kovacs-Nagy, Reka and May, Patrick and Narayanan, Vinodh and Pendziwiat, Manuela and Ramsey, Keri and Rangasamy, Sampathkumar and Shinde, Deepali N and Spiegel, Ronen and Timmerman, Vincent and von Spiczak, Sarah and Helbig, Ingo and Weckhuysen, Sarah and Francklyn, Christopher and Antonellis, Anthony and de Witte, Peter and De Jonghe, Peter} } @article {562, title = {Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 11 01}, pages = {794-807}, abstract = {

Ca signaling is vital for various cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, gene transcription, and cellular proliferation. The endoplasmic reticulum (ER) is the largest intracellular Ca store, and dysregulation of ER Ca signaling and homeostasis contributes to the pathogenesis of various complex disorders and Mendelian disease traits. We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. Through whole-exome sequencing and family-based genomics, we identified bi-allelic variants in CCDC47 that encodes the Ca-binding ER transmembrane protein CCDC47. CCDC47, also known as calumin, has been shown to bind Ca with low affinity and high capacity. In mice, loss of Ccdc47 leads to embryonic lethality, suggesting that Ccdc47 is essential for early development. Characterization of cells from individuals with predicted likely damaging alleles showed decreased CCDC47 mRNA expression and protein levels. In~vitro cellular experiments showed decreased total ER Ca storage, impaired Ca signaling mediated by the IPR Ca release channel, and reduced ER Ca refilling via store-operated Ca entry. These results, together with the previously described role of CCDC47 in Ca signaling and development, suggest that bi-allelic loss-of-function variants in CCDC47 underlie the pathogenesis of this multisystem disorder.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.014}, author = {Morimoto, Marie and Waller-Evans, Helen and Ammous, Zineb and Song, Xiaofei and Strauss, Kevin A and Pehlivan, Davut and Gonzaga-Jauregui, Claudia and Puffenberger, Erik G and Holst, Charles R and Karaca, Ender and Brigatti, Karlla W and Maguire, Emily and Coban-Akdemir, Zeynep H and Amagata, Akiko and Lau, C Christopher and Chepa-Lotrea, Xenia and Macnamara, Ellen and Tos, Tulay and Isikay, Sedat and Nehrebecky, Michele and Overton, John D and Klein, Matthew and Markello, Thomas C and Posey, Jennifer E and Adams, David R and Lloyd-Evans, Emyr and Lupski, James R and Gahl, William A and Malicdan, May Christine V} }