Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance.
Cilia
Congenital hydrocephalus
Exome sequencing
Mutation burden test
Oligogenic inheritance
Journal
Human genomics
ISSN: 1479-7364
Titre abrégé: Hum Genomics
Pays: England
ID NLM: 101202210
Informations de publication
Date de publication:
02 03 2023
02 03 2023
Historique:
received:
10
01
2023
accepted:
22
02
2023
entrez:
1
3
2023
pubmed:
2
3
2023
medline:
4
3
2023
Statut:
epublish
Résumé
Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH. We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test. In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls. Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.
Sections du résumé
BACKGROUND
Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH.
MATERIALS AND METHODS
We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test.
RESULTS
In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls.
CONCLUSION
Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.
Identifiants
pubmed: 36859317
doi: 10.1186/s40246-023-00464-w
pii: 10.1186/s40246-023-00464-w
pmc: PMC9979489
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
16Informations de copyright
© 2023. The Author(s).
Références
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12438-43
pubmed: 25114218
Ophthalmic Genet. 2017 Mar-Apr;38(2):127-132
pubmed: 27029556
Cell Rep. 2017 Jul 25;20(4):960-972
pubmed: 28746879
Dis Model Mech. 2019 Aug 2;12(8):
pubmed: 31383820
Nucleic Acids Res. 2016 Jan 4;44(D1):D710-6
pubmed: 26687719
Acta Radiol. 2005 Oct;46(6):645-51
pubmed: 16334849
Dev Biol. 2020 Dec 1;468(1-2):101-109
pubmed: 32979334
Childs Nerv Syst. 2021 Nov;37(11):3355-3364
pubmed: 33999288
Acta Neuropathol. 2013 Sep;126(3):427-42
pubmed: 23820807
J Appl Genet. 2018 Aug;59(3):253-268
pubmed: 29680930
Mol Syndromol. 2010 Sep;1(3):99-112
pubmed: 21031079
Hum Mol Genet. 2003 Mar 1;12(5):527-34
pubmed: 12588800
Nat Neurosci. 2010 Jun;13(6):700-7
pubmed: 20473291
Eur J Med Genet. 2012 Dec;55(12):753-7
pubmed: 23022981
Sci Rep. 2017 Aug 1;7(1):7056
pubmed: 28765568
Hum Mol Genet. 2001 Oct 1;10(20):2293-9
pubmed: 11673413
Arterioscler Thromb Vasc Biol. 2018 Jul;38(7):1562-1575
pubmed: 29724820
Proc Natl Acad Sci U S A. 2021 May 25;118(21):
pubmed: 34011608
Cell. 2007 Jun 15;129(6):1051-63
pubmed: 17574020
Mol Syndromol. 2023 Jan;13(6):522-526
pubmed: 36660028
BMC Biol. 2007 Aug 07;5:33
pubmed: 17683645
Circ Res. 2017 Mar 31;120(7):1084-1090
pubmed: 28223422
Nat Med. 2020 Nov;26(11):1754-1765
pubmed: 33077954
Nat Genet. 2014 Aug;46(8):818-25
pubmed: 24974849
Neuron. 2021 Jan 20;109(2):241-256.e9
pubmed: 33220177
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
EMBO J. 2004 Jun 16;23(12):2358-68
pubmed: 15167895
Hum Mol Genet. 2017 Oct 1;26(19):3792-3796
pubmed: 28934391
Artif Intell Med. 2019 Aug;99:101690
pubmed: 31606112
J Med Genet. 2012 Nov;49(11):708-12
pubmed: 23042809
Cell Tissue Res. 2003 Oct;314(1):61-8
pubmed: 12915980
Nucleic Acids Res. 2017 Sep 6;45(15):e140
pubmed: 28911095
J Neurosurg. 2005 Aug;103(2 Suppl):113-8
pubmed: 16370275
Am J Hum Genet. 2012 Oct 5;91(4):672-84
pubmed: 23022101
Pediatr Neurosurg. 2010;46(1):34-8
pubmed: 20516736
Eur J Hum Genet. 2019 Aug;27(8):1235-1243
pubmed: 30914828
Brain. 2019 Jan 1;142(1):35-49
pubmed: 30508070
Hum Mol Genet. 2021 Feb 4;29(23):3757-3764
pubmed: 33205811
Hum Mol Genet. 2015 Jul 1;24(13):3775-91
pubmed: 25859007
Dev Biol. 2019 Jun 1;450(1):47-62
pubmed: 30914320
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
RNA. 2018 Dec;24(12):1856-1870
pubmed: 30254136
Data Brief. 2015 Nov 27;6:121-3
pubmed: 26858976
Nat Genet. 1993 Aug;4(4):331
pubmed: 8401576
Eur J Med Genet. 2022 Feb;65(2):104407
pubmed: 34942405
Semin Cell Dev Biol. 2016 Jul;55:99-110
pubmed: 26994528
Curr Opin Cell Biol. 2010 Oct;22(5):597-604
pubmed: 20817501
Semin Cell Dev Biol. 2018 Jul;79:103-112
pubmed: 28965864
Mol Biol Cell. 2001 Mar;12(3):589-99
pubmed: 11251073
Childs Nerv Syst. 2020 Aug;36(8):1661-1668
pubmed: 32451664
Am J Hum Genet. 2015 Jul 2;97(1):153-62
pubmed: 26073779
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Ann Neurol. 2017 Jun;81(6):890-897
pubmed: 28556411
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3062-7
pubmed: 24516132
Int J Mol Sci. 2020 Sep 16;21(18):
pubmed: 32947856
Eur J Med Genet. 2014 Aug;57(8):359-68
pubmed: 24932902
Mol Genet Genomic Med. 2021 Sep;9(9):e1768
pubmed: 34402213
Exp Neurol. 2013 Sep;247:703-9
pubmed: 23518418
Nucleic Acids Res. 2019 Jul 2;47(W1):W93-W98
pubmed: 31147699
Am J Hum Genet. 2016 Nov 3;99(5):1117-1129
pubmed: 27773430
PLoS One. 2017 Mar 14;12(3):e0173258
pubmed: 28291836
Clin Genet. 2012 Aug;82(2):140-6
pubmed: 21815888
Development. 2018 Aug 28;145(17):
pubmed: 30093551
Cilia. 2013 May 31;2(1):7
pubmed: 23725226
Orphanet J Rare Dis. 2006 Aug 03;1:29
pubmed: 16887026
J Med Genet. 2013 Oct;50(10):641-52
pubmed: 23785127
Acta Neuropathol Commun. 2017 May 1;5(1):36
pubmed: 28460636
Fly (Austin). 2012 Apr-Jun;6(2):80-92
pubmed: 22728672
Hum Mol Genet. 2011 Oct 1;20(19):3725-37
pubmed: 21653639
J Clin Invest. 2020 Aug 3;130(8):4055-4068
pubmed: 32369453
Neuron. 2018 Jul 25;99(2):302-314.e4
pubmed: 29983323
Nature. 1996 Nov 28;384(6607):368-72
pubmed: 8934524
Am J Med Genet A. 2022 Sep;188(9):2701-2706
pubmed: 35792517
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
Eur J Med Genet. 2011 Nov-Dec;54(6):e542-7
pubmed: 21839187
Proc Natl Acad Sci U S A. 2019 Jun 11;116(24):11878-11887
pubmed: 31127050
J Med Genet. 2013 Jan;50(1):54-8
pubmed: 23240096
J Mol Cell Biol. 2019 May 1;11(5):383-394
pubmed: 30060180
Development. 2017 Jan 15;144(2):201-210
pubmed: 27993979
Nat Genet. 2014 Mar;46(3):310-5
pubmed: 24487276
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
J Med Genet. 2007 Nov;44(11):739-44
pubmed: 17617514
Nat Rev Mol Cell Biol. 2017 Jun;18(6):375-388
pubmed: 28293032
Clin Genet. 2005 Apr;67(4):281-9
pubmed: 15733261
Methods Enzymol. 2010;479:343-52
pubmed: 20816175
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Exp Anim. 2015;64(4):407-14
pubmed: 26156403
Cell. 2009 Apr 3;137(1):32-45
pubmed: 19345185
Hum Mol Genet. 2002 Mar 15;11(6):715-21
pubmed: 11912187
G3 (Bethesda). 2016 Aug 09;6(8):2479-87
pubmed: 27261005
Clin Genet. 2019 May;95(5):590-600
pubmed: 30811583
Development. 2005 Dec;132(23):5329-39
pubmed: 16284123
Fluids Barriers CNS. 2021 Jul 07;18(1):31
pubmed: 34233705
Vet Pathol. 2012 Jan;49(1):166-81
pubmed: 21746835
Dev Cell. 2001 Nov;1(5):717-24
pubmed: 11709191
J Neurosci. 2010 Feb 17;30(7):2600-10
pubmed: 20164345
Curr Biol. 2019 Jan 21;29(2):229-241.e6
pubmed: 30612902
PLoS Genet. 2018 Nov 26;14(11):e1007817
pubmed: 30475797
Hum Mutat. 2020 Feb;41(2):512-524
pubmed: 31696992
Am J Hum Genet. 2013 Nov 7;93(5):915-25
pubmed: 24140113