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DOI 10.1038/s41591-020-1090-2

Медицинская библиотека · Nature medicine · 2020

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Jin Sheng Chih, Dong Weilai, Kundishora Adam J, Panchagnula Shreyas, Moreno-De-Luca Andres, Furey Charuta G, Allocco August A, Walker Rebecca L, Nelson-Williams Carol, Smith Hannah, Dunbar Ashley, Conine Sierra, Lu Qiongshi, Zeng Xue, Sierant Michael C, Knight James R, Sullivan William, Duy Phan Q, DeSpenza Tyrone, Reeves Benjamin C, Karimy Jason K, Marlier Arnaud, Castaldi Christopher, Tikhonova Irina R, Li Boyang, Peña Helena Perez, Broach James R, Kabachelor Edith M, Ssenyonga Peter, Hehnly Christine, Ge Li, Keren Boris, Timberlake Andrew T, Goto June, Mangano Francesco T, Johnston James M, Butler William E, Warf Benjamin C, Smith Edward R, Schiff Steven J, Limbrick David D, Heuer Gregory, Jackson Eric M, Iskandar Bermans J, Mane Shrikant, Haider Shozeb, Guclu Bulent, Bayri Yasar, Sahin Yener, Duncan Charles C, Apuzzo Michael L J, DiLuna Michael L, Hoffman Ellen J, Sestan Nenad, Ment Laura R, Alper Seth L, Bilguvar Kaya, Geschwind Daniel H, Günel Murat, Lifton Richard P, Kahle Kristopher T

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод в очереди

Аннотация

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.

Для цитирования: Jin Sheng Chih, Dong Weilai, Kundishora Adam J, Panchagnula Shreyas, Moreno-De-Luca Andres, Furey Charuta G, Allocco August A, Walker Rebecca L, Nelson-Williams Carol, Smith Hannah, Dunbar Ashley, Conine Sierra, Lu Qiongshi, Zeng Xue, Sierant Michael C, Knight James R, Sullivan William, Duy Phan Q, DeSpenza Tyrone, Reeves Benjamin C, Karimy Jason K, Marlier Arnaud, Castaldi Christopher, Tikhonova Irina R, Li Boyang, Peña Helena Perez, Broach James R, Kabachelor Edith M, Ssenyonga Peter, Hehnly Christine, Ge Li, Keren Boris, Timberlake Andrew T, Goto June, Mangano Francesco T, Johnston James M, Butler William E, Warf Benjamin C, Smith Edward R, Schiff Steven J, Limbrick David D, Heuer Gregory, Jackson Eric M, Iskandar Bermans J, Mane Shrikant, Haider Shozeb, Guclu Bulent, Bayri Yasar, Sahin Yener, Duncan Charles C, Apuzzo Michael L J, DiLuna Michael L, Hoffman Ellen J, Sestan Nenad, Ment Laura R, Alper Seth L, Bilguvar Kaya, Geschwind Daniel H, Günel Murat, Lifton Richard P, Kahle Kristopher T. Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.. Nature medicine. 2020. DOI: 10.1038/s41591-020-1090-2.

Предметные рубрики MeSH

BrainCerebral VentriclesExomeFemaleGenetic Predisposition to DiseaseHumansHydrocephalusMaleMutationNeural Stem CellsNeurogenesisNeurogliaTranscription FactorsTripartite Motif ProteinsUbiquitin-Protein LigasesExome Sequencing
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