@article {914, title = {Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.}, journal = {Nat Med}, volume = {26}, year = {2020}, month = {2020 11}, pages = {1754-1765}, abstract = {

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17\% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22\% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

}, keywords = {Brain, Cerebral Ventricles, Exome, Female, Genetic Predisposition to Disease, Humans, Hydrocephalus, Male, Mutation, Neural Stem Cells, Neurogenesis, Neuroglia, Transcription Factors, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, Whole Exome Sequencing}, issn = {1546-170X}, doi = {10.1038/s41591-020-1090-2}, author = {Jin, Sheng Chih and Dong, Weilai and Kundishora, Adam J and Panchagnula, Shreyas and Moreno-De-Luca, Andres and Furey, Charuta G and Allocco, August A and Walker, Rebecca L and Nelson-Williams, Carol and Smith, Hannah and Dunbar, Ashley and Conine, Sierra and Lu, Qiongshi and Zeng, Xue and Sierant, Michael C and Knight, James R and Sullivan, William and Duy, Phan Q and DeSpenza, Tyrone and Reeves, Benjamin C and Karimy, Jason K and Marlier, Arnaud and Castaldi, Christopher and Tikhonova, Irina R and Li, Boyang and Pe{\~n}a, Helena Perez and Broach, James R and Kabachelor, Edith M and Ssenyonga, Peter and Hehnly, Christine and Ge, Li and Keren, Boris and Timberlake, Andrew T and Goto, June and Mangano, Francesco T and Johnston, James M and Butler, William E and Warf, Benjamin C and Smith, Edward R and Schiff, Steven J and Limbrick, David D and Heuer, Gregory and Jackson, Eric M and Iskandar, Bermans J and Mane, Shrikant and Haider, Shozeb and Guclu, Bulent and Bayri, Yasar and Sahin, Yener and Duncan, Charles C and Apuzzo, Michael L J and DiLuna, Michael L and Hoffman, Ellen J and {\v S}estan, Nenad and Ment, Laura R and Alper, Seth L and Bilguvar, Kaya and Geschwind, Daniel H and G{\"u}nel, Murat and Lifton, Richard P and Kahle, Kristopher T} } @article {925, title = {Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.}, journal = {iScience}, volume = {23}, year = {2020}, month = {2020 Oct 23}, pages = {101552}, abstract = {

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated mutation (p.Cys188Trp) in the GABA receptor Cl channel γ-1 subunit () exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na and Ca channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca channel Ca3.2 (). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2020.101552}, author = {Dong, Weilai and Jin, Sheng Chih and Allocco, August and Zeng, Xue and Sheth, Amar H and Panchagnula, Shreyas and Castonguay, Annie and Lorenzo, Louis-{\'E}tienne and Islam, Barira and Brindle, Genevi{\`e}ve and Bachand, Karine and Hu, Jamie and Sularz, Agata and Gaillard, Jonathan and Choi, Jungmin and Dunbar, Ashley and Nelson-Williams, Carol and Kiziltug, Emre and Furey, Charuta Gavankar and Conine, Sierra and Duy, Phan Q and Kundishora, Adam J and Loring, Erin and Li, Boyang and Lu, Qiongshi and Zhou, Geyu and Liu, Wei and Li, Xinyue and Sierant, Michael C and Mane, Shrikant and Castaldi, Christopher and L{\'o}pez-Gir{\'a}ldez, Francesc and Knight, James R and Sekula, Raymond F and Simard, J Marc and Eskandar, Emad N and Gottschalk, Christopher and Moliterno, Jennifer and G{\"u}nel, Murat and Gerrard, Jason L and Dib-Hajj, Sulayman and Waxman, Stephen G and Barker, Fred G and Alper, Seth L and Chahine, Mohamed and Haider, Shozeb and De Koninck, Yves and Lifton, Richard P and Kahle, Kristopher T} } @article {590, title = {EphrinB2-EphB4-RASA1 Signaling in Human Cerebrovascular Development and Disease.}, journal = {Trends Mol Med}, volume = {25}, year = {2019}, month = {2019 04}, pages = {265-286}, abstract = {

Recent whole exome sequencing studies in humans have provided novel insight into the importance of the ephrinB2-EphB4-RASA1 signaling axis in cerebrovascular development, corroborating and extending previous work in model systems. Here, we aim to review the human cerebrovascular phenotypes associated with ephrinB2-EphB4-RASA1 mutations, including those recently discovered in Vein of Galen malformation: the most common and severe brain arteriovenous malformation in neonates. We will also discuss emerging paradigms of the molecular and cellular pathophysiology of disease-causing ephrinB2-EphB4-RASA1 mutations, including the potential role of somatic mosaicism. These observations have potential diagnostic and therapeutic implications for patients with rare congenital cerebrovascular diseases and their families.

}, issn = {1471-499X}, doi = {10.1016/j.molmed.2019.01.009}, author = {Zeng, Xue and Hunt, Ava and Jin, Sheng Chih and Duran, Daniel and Gaillard, Jonathan and Kahle, Kristopher T} }