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

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

doi:10.1038/s41591-020-1090-2

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

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

School of Medicine

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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.

Original language	English (US)
Pages (from-to)	1754-1765
Number of pages	12
Journal	Nature medicine
Volume	26
Issue number	11
DOIs	https://doi.org/10.1038/s41591-020-1090-2
State	Published - Nov 2020

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/s41591-020-1090-2

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Jin, S. C., Dong, W., Kundishora, A. J., Panchagnula, S., Moreno-De-Luca, A., Furey, C. G., Allocco, A. A., Walker, R. L., Nelson-Williams, C., Smith, H., Dunbar, A., Conine, S., Lu, Q., Zeng, X., Sierant, M. C., Knight, J. R., Sullivan, W., Duy, P. Q., DeSpenza, T., ... Kahle, K. T. (2020). Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus. Nature medicine, 26(11), 1754-1765. https://doi.org/10.1038/s41591-020-1090-2

Jin, SC, Dong, W, Kundishora, AJ, Panchagnula, S, Moreno-De-Luca, A, Furey, CG, Allocco, AA, Walker, RL, Nelson-Williams, C, Smith, H, Dunbar, A, Conine, S, Lu, Q, Zeng, X, Sierant, MC, Knight, JR, Sullivan, W, Duy, PQ, DeSpenza, T, Reeves, BC, Karimy, JK, Marlier, A, Castaldi, C, Tikhonova, IR, Li, B, Peña, HP, Broach, JR, Kabachelor, EM, Ssenyonga, P, Hehnly, C, Ge, L, Keren, B, Timberlake, AT, Goto, J, Mangano, FT, Johnston, JM, Butler, WE, Warf, BC, Smith, ER, Schiff, SJ, Limbrick, DD, Heuer, G, Jackson, EM, Iskandar, BJ, Mane, S, Haider, S, Guclu, B, Bayri, Y, Sahin, Y, Duncan, CC, Apuzzo, MLJ, DiLuna, ML, Hoffman, EJ, Sestan, N, Ment, LR, Alper, SL, Bilguvar, K, Geschwind, DH, Günel, M, Lifton, RP & Kahle, KT 2020, 'Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus', Nature medicine, vol. 26, no. 11, pp. 1754-1765. https://doi.org/10.1038/s41591-020-1090-2

@article{b4a6dc0337ab4efdbe7e027ad5012ae0,

title = "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.",

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

note = "Funding Information: We are grateful to the patients and their families who participated in this research. We thank the Hydrocephalus Association (HA) for their support. We also thank J. Koschnitzky (HA), J. Rockefeller (Yale), J. Freeman (Yale) and J. Nicolleli (Yale) for their help and support. This work is supported by the Yale–National Institutes of Health (NIH) Center for Mendelian Genomics (5U54HG006504); NIH Director{\textquoteright}s Pioneer Award DP1HD086071 and NIH Director{\textquoteright}s Transformative Award 1R01AI145057 (S.J.S.); R01 NS111029-01A1, R01 NS109358, K12 228168 and the Rudi Schulte Research Institute (K.K.); NIH Medical Scientist Training Program (NIH/National Institute of General Medical Sciences Grant T32GM007205); NIH Clinical and Translational Science Award from the National Center for Advancing Translational Science (TL1 TR001864); James Hudson Brown – Alexander B. Coxe Fellowship at Yale School of Medicine, the American Heart Association Postdoctoral Fellowship (18POST34060008), the K99/ R00 Pathway to Independence Award (K99HL143036 and R00HL143036-02) (S.C.J.); the American Heart Association Predoctoral Fellowship (19PRE34380842, W.D.); the Pediatric Hydrocephalus Foundation (P.H.F.). We thank M. C. Kruer at Phoenix Children{\textquoteright}s Hospital and H. Zhao at Yale School of Public Health for critical discussion. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

month = nov,

doi = "10.1038/s41591-020-1090-2",

language = "English (US)",

volume = "26",

pages = "1754--1765",

journal = "Nature medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "11",

}

TY - JOUR

T1 - Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus

AU - Jin, Sheng Chih

AU - Dong, Weilai

AU - Kundishora, Adam J.

AU - Panchagnula, Shreyas

AU - Moreno-De-Luca, Andres

AU - Furey, Charuta G.

AU - Allocco, August A.

AU - Walker, Rebecca L.

AU - Nelson-Williams, Carol

AU - Smith, Hannah

AU - Dunbar, Ashley

AU - Conine, Sierra

AU - Lu, Qiongshi

AU - Zeng, Xue

AU - Sierant, Michael C.

AU - Knight, James R.

AU - Sullivan, William

AU - Duy, Phan Q.

AU - DeSpenza, Tyrone

AU - Reeves, Benjamin C.

AU - Karimy, Jason K.

AU - Marlier, Arnaud

AU - Castaldi, Christopher

AU - Tikhonova, Irina R.

AU - Li, Boyang

AU - Peña, Helena Perez

AU - Broach, James R.

AU - Kabachelor, Edith M.

AU - Ssenyonga, Peter

AU - Hehnly, Christine

AU - Ge, Li

AU - Keren, Boris

AU - Timberlake, Andrew T.

AU - Goto, June

AU - Mangano, Francesco T.

AU - Johnston, James M.

AU - Butler, William E.

AU - Warf, Benjamin C.

AU - Smith, Edward R.

AU - Schiff, Steven J.

AU - Limbrick, David D.

AU - Heuer, Gregory

AU - Jackson, Eric M.

AU - Iskandar, Bermans J.

AU - Mane, Shrikant

AU - Haider, Shozeb

AU - Guclu, Bulent

AU - Bayri, Yasar

AU - Sahin, Yener

AU - Duncan, Charles C.

AU - Apuzzo, Michael L.J.

AU - DiLuna, Michael L.

AU - Hoffman, Ellen J.

AU - Sestan, Nenad

AU - Ment, Laura R.

AU - Alper, Seth L.

AU - Bilguvar, Kaya

AU - Geschwind, Daniel H.

AU - Günel, Murat

AU - Lifton, Richard P.

AU - Kahle, Kristopher T.

N1 - Funding Information: We are grateful to the patients and their families who participated in this research. We thank the Hydrocephalus Association (HA) for their support. We also thank J. Koschnitzky (HA), J. Rockefeller (Yale), J. Freeman (Yale) and J. Nicolleli (Yale) for their help and support. This work is supported by the Yale–National Institutes of Health (NIH) Center for Mendelian Genomics (5U54HG006504); NIH Director’s Pioneer Award DP1HD086071 and NIH Director’s Transformative Award 1R01AI145057 (S.J.S.); R01 NS111029-01A1, R01 NS109358, K12 228168 and the Rudi Schulte Research Institute (K.K.); NIH Medical Scientist Training Program (NIH/National Institute of General Medical Sciences Grant T32GM007205); NIH Clinical and Translational Science Award from the National Center for Advancing Translational Science (TL1 TR001864); James Hudson Brown – Alexander B. Coxe Fellowship at Yale School of Medicine, the American Heart Association Postdoctoral Fellowship (18POST34060008), the K99/ R00 Pathway to Independence Award (K99HL143036 and R00HL143036-02) (S.C.J.); the American Heart Association Predoctoral Fellowship (19PRE34380842, W.D.); the Pediatric Hydrocephalus Foundation (P.H.F.). We thank M. C. Kruer at Phoenix Children’s Hospital and H. Zhao at Yale School of Public Health for critical discussion. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2020/11

Y1 - 2020/11

N2 - 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.

AB - 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.

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U2 - 10.1038/s41591-020-1090-2

DO - 10.1038/s41591-020-1090-2

M3 - Article

C2 - 33077954

AN - SCOPUS:85092731366

SN - 1078-8956

VL - 26

SP - 1754

EP - 1765

JO - Nature medicine

JF - Nature medicine

IS - 11

ER -

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

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