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

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.

SUBMITTER: Jin SC

PROVIDER: S-EPMC7871900 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Jin Sheng Chih SC Dong Weilai W Kundishora Adam J AJ Panchagnula Shreyas S Moreno-De-Luca Andres A Furey Charuta G CG Allocco August A AA Walker Rebecca L RL Nelson-Williams Carol C Smith Hannah H Dunbar Ashley A Conine Sierra S Lu Qiongshi Q Zeng Xue X Sierant Michael C MC Knight James R JR Sullivan William W Duy Phan Q PQ DeSpenza Tyrone T Reeves Benjamin C BC Karimy Jason K JK Marlier Arnaud A Castaldi Christopher C Tikhonova Irina R IR Li Boyang B Peña Helena Perez HP Broach James R JR Kabachelor Edith M EM Ssenyonga Peter P Hehnly Christine C Ge Li L Keren Boris B Timberlake Andrew T AT Goto June J Mangano Francesco T FT Johnston James M JM Butler William E WE Warf Benjamin C BC Smith Edward R ER Schiff Steven J SJ Limbrick David D DD Heuer Gregory G Jackson Eric M EM Iskandar Bermans J BJ Mane Shrikant S Haider Shozeb S Guclu Bulent B Bayri Yasar Y Sahin Yener Y Duncan Charles C CC Apuzzo Michael L J MLJ DiLuna Michael L ML Hoffman Ellen J EJ Sestan Nenad N Ment Laura R LR Alper Seth L SL Bilguvar Kaya K Geschwind Daniel H DH Günel Murat M Lifton Richard P RP Kahle Kristopher T KT

Nature medicine 20201019 11

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 ...[more]

PMID: 33077954

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Project description:BackgroundThe cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear.MethodsWe evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited.ResultsIn 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases.ConclusionsIn this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.).

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

Publications

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

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