Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
26 Oct 2023
26 Oct 2023
Historique:
received:
04
05
2023
accepted:
11
09
2023
revised:
24
07
2023
medline:
26
10
2023
pubmed:
26
10
2023
entrez:
25
10
2023
Statut:
aheadofprint
Résumé
Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function.
Identifiants
pubmed: 37880421
doi: 10.1038/s41431-023-01461-2
pii: 10.1038/s41431-023-01461-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 469177153
Informations de copyright
© 2023. The Author(s).
Références
Di Donato N, Chiari S, Mirzaa GM, Aldinger K, Parrini E, Olds C, et al. Lissencephaly: expanded imaging and clinical classification. Am J Med Genet A. 2017;173:1473–88.
pubmed: 28440899
pmcid: 5526446
doi: 10.1002/ajmg.a.38245
Guerrini R, Dobyns WB. Malformations of cortical development: clinical features and genetic causes. Lancet Neurol. 2014;13:710–26.
pubmed: 24932993
pmcid: 5548104
doi: 10.1016/S1474-4422(14)70040-7
Koenig M, Dobyns WB, Di Donato N. Lissencephaly: update on diagnostics and clinical management. Eur J Paediatr Neurol. 2021;35:147–52.
pubmed: 34731701
doi: 10.1016/j.ejpn.2021.09.013
Parrini E, Conti V, Dobyns WB, Guerrini R. Genetic basis of brain malformations. Mol Syndromol. 2016;7:220–33.
pubmed: 27781032
pmcid: 5073505
doi: 10.1159/000448639
Jang TH, Park HH. PIDD mediates and stabilizes the interaction between RAIDD and caspase-2 for the PIDDosome assembly. BMB Rep. 2013;46:471–6.
pubmed: 24064063
pmcid: 4133880
doi: 10.5483/BMBRep.2013.46.9.021
Park HH, Logette E, Raunser S, Cuenin S, Walz T, Tschopp J, et al. Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell. 2007;128:533–46.
pubmed: 17289572
pmcid: 2908332
doi: 10.1016/j.cell.2007.01.019
Di Donato N, Jean YY, Maga AM, Krewson BD, Shupp AB, Avrutsky MI, et al. Mutations in CRADD result in reduced caspase-2-mediated neuronal apoptosis and cause megalencephaly with a rare lissencephaly variant. Am J Hum Genet. 2016;99:1117–29.
pubmed: 27773430
pmcid: 5097945
doi: 10.1016/j.ajhg.2016.09.010
Harripaul R, Vasli N, Mikhailov A, Rafiq MA, Mittal K, Windpassinger C, et al. Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol Psychiatry. 2018;23:973–84.
pubmed: 28397838
doi: 10.1038/mp.2017.60
Zaki MS, Accogli A, Mirzaa G, Rahman F, Mohammed H, Porras-Hurtado GL, et al. Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features. Eur J Hum Genet. 2021;29:1226–34.
pubmed: 34163010
pmcid: 8385073
doi: 10.1038/s41431-021-00910-0
Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–30.
pubmed: 26220891
pmcid: 4833888
doi: 10.1002/humu.22844
Lin YC, Niceta M, Muto V, Vona B, Pagnamenta AT, Maroofian R, et al. SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling. Am J Hum Genet. 2021;108:115–33.
pubmed: 33308444
doi: 10.1016/j.ajhg.2020.11.015
Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44:D862–8.
pubmed: 26582918
doi: 10.1093/nar/gkv1222
Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35:1978–80.
pubmed: 30376034
doi: 10.1093/bioinformatics/bty897
Robinson PN, Kohler S, Bauer S, Seelow D, Horn D, Mundlos S. The human phenotype ontology: a tool for annotating and analyzing human hereditary disease. Am J Hum Genet. 2008;83:610–5.
pubmed: 18950739
pmcid: 2668030
doi: 10.1016/j.ajhg.2008.09.017
Genomics England PanelApp; https://panelapp.genomicsengland.co.uk (03.23.2023) Id-masV.
de Sainte Agathe JM, Filser M, Isidor B, Besnard T, Gueguen P, Perrin A, et al. SpliceAI-visual: a free online tool to improve SpliceAI splicing variant interpretation. Hum Genom. 2023;17:7.
doi: 10.1186/s40246-023-00451-1
Ellard S, Baple EL, Berry I, Forrester N, Turnbull C, Owens M, et al. ACGS best practice guidelines for variant classification in rare disease 2020. Retrieved from https://www.acgs.uk.com/media/11631/uk-practice-guidelines-for-variant-classificationv4-01-2020.pdf .
Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, et al. ClinGen–the clinical genome resource. N Engl J Med. 2015;372:2235–42.
pubmed: 26014595
pmcid: 4474187
doi: 10.1056/NEJMsr1406261
Quinodoz M, Peter VG, Bedoni N, Royer Bertrand B, Cisarova K, Salmaninejad A, et al. AutoMap is a high performance homozygosity mapping tool using next-generation sequencing data. Nat Commun. 2021;12:518.
pubmed: 33483490
pmcid: 7822856
doi: 10.1038/s41467-020-20584-4
Tompson SW, Young TL. Assaying the effects of splice site variants by exon trapping in a mammalian cell line. Bio Protoc. 2017;7:e2281.
pubmed: 28758139
pmcid: 5528174
doi: 10.21769/BioProtoc.2281
Rad A, Schade-Mann T, Gamerdinger P, Yanus GA, Schulte B, Muller M, et al. Aberrant COL11A1 splicing causes prelingual autosomal dominant nonsyndromic hearing loss in the DFNA37 locus. Hum Mutat. 2021;42:25–30.
pubmed: 33169910
doi: 10.1002/humu.24136
Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, Darbandi SF, Knowles D, Li YI, et al. Predicting splicing from primary sequence with deep learning. Cell. 2019;176:535–48.
pubmed: 30661751
doi: 10.1016/j.cell.2018.12.015
Gudmundsson S, Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, et al. Addendum: the mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2021;597:E3–4.
pubmed: 34373650
pmcid: 8410591
doi: 10.1038/s41586-021-03758-y
Halldorsson BV, Eggertsson HP, Moore KHS, Hauswedell H, Eiriksson O, Ulfarsson MO, et al. The sequences of 150,119 genomes in the UK Biobank. Nature. 2022;607:732–40.
pubmed: 35859178
pmcid: 9329122
doi: 10.1038/s41586-022-04965-x
Baliga BC, Read SH, Kumar S. The biochemical mechanism of caspase-2 activation. Cell Death Differ. 2004;11:1234–41.
pubmed: 15297885
doi: 10.1038/sj.cdd.4401492
Tinel A, Tschopp J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science. 2004;304:843–6.
pubmed: 15073321
doi: 10.1126/science.1095432
Sheikh TI, Vasli N, Pastore S, Kharizi K, Harripaul R, Fattahi Z, et al. Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability. Transl Psychiatry. 2021;11:1.
pubmed: 33414379
pmcid: 7791037
doi: 10.1038/s41398-020-01158-w
Koprulu M, Shabbir RMK, Zaman Q, Nalbant G, Malik S, Tolun A. CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental delay, strabismus, behavioural problems and skeletal anomalies. Eur J Med Genet. 2021;64:104181.
pubmed: 33647455
doi: 10.1016/j.ejmg.2021.104181
Harel T, Hacohen N, Shaag A, Gomori M, Singer A, Elpeleg O, et al. Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated with lissencephaly. Am J Med Genet A. 2017;173:2539–44.
pubmed: 28686357
doi: 10.1002/ajmg.a.38347
Polla DL, Rahikkala E, Bode MK, Maatta T, Varilo T, Loman T, et al. Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population. Eur J Hum Genet. 2019;27:1235–43.
pubmed: 30914828
pmcid: 6777631
doi: 10.1038/s41431-019-0383-8
Avela K, Toiviainen-Salo S, Karttunen-Lewandowski P, Kauria L, Valanne L, Salonen-Kajander R. Frontotemporal pachygyria-two new patients. Eur J Med Genet. 2012;55:753–7.
pubmed: 23022981
doi: 10.1016/j.ejmg.2012.09.007
Hu H, Kahrizi K, Musante L, Fattahi Z, Herwig R, Hosseini M, et al. Genetics of intellectual disability in consanguineous families. Mol Psychiatry. 2019;24:1027–39.
pubmed: 29302074
doi: 10.1038/s41380-017-0012-2
Baptiste-Okoh N, Barsotti AM, Prives C. A role for caspase 2 and PIDD in the process of p53-mediated apoptosis. Proc Natl Acad Sci USA. 2008;105:1937–42.
pubmed: 18238895
pmcid: 2538861
doi: 10.1073/pnas.0711800105
Park HH, Wu H. Crystallization and preliminary X-ray crystallographic studies of the oligomeric death-domain complex between PIDD and RAIDD. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007;63:229–32.
pubmed: 17329820
pmcid: 2330181
doi: 10.1107/S1744309107007889
Manzl C, Fava LL, Krumschnabel G, Peintner L, Tanzer MC, Soratroi C, et al. Death of p53-defective cells triggered by forced mitotic entry in the presence of DNA damage is not uniquely dependent on caspase-2 or the PIDDosome. Cell Death Dis. 2013;4:e942.
pubmed: 24309929
pmcid: 3877543
doi: 10.1038/cddis.2013.470
Andersson S, Persson EK, Aring E, Lindquist B, Dutton GN, Hellstrom A. Vision in children with hydrocephalus. Dev Med Child Neurol. 2006;48:836–41.
pubmed: 16978464
doi: 10.1017/S0012162206001794
Ahmed Z, Kalinski H, Berry M, Almasieh M, Ashush H, Slager N, et al. Ocular neuroprotection by siRNA targeting caspase-2. Cell Death Dis. 2011;2:e173.
pubmed: 21677688
pmcid: 3168996
doi: 10.1038/cddis.2011.54
Thomas CN, Bernardo-Colon A, Courtie E, Essex G, Rex TS, Blanch RJ, et al. Effects of intravitreal injection of siRNA against caspase-2 on retinal and optic nerve degeneration in air blast induced ocular trauma. Sci Rep. 2021;11:16839.
pubmed: 34413361
pmcid: 8377143
doi: 10.1038/s41598-021-96107-y
Thomas CN, Thompson AM, McCance E, Berry M, Logan A, Blanch RJ, et al. Caspase-2 mediates site-specific retinal ganglion cell death after blunt ocular injury. Invest Ophthalmol Vis Sci. 2018;59:4453–62.
pubmed: 30193318
doi: 10.1167/iovs.18-24045
Dorstyn L, Kumar S. Caspase-2 protocols. Methods Mol Biol. 2014;1133:71–87.
pubmed: 24567095
doi: 10.1007/978-1-4939-0357-3_4
Tang Y, Wells JA, Arkin MR. Structural and enzymatic insights into caspase-2 protein substrate recognition and catalysis. J Biol Chem. 2011;286:34147–54.
pubmed: 21828056
pmcid: 3190824
doi: 10.1074/jbc.M111.247627
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419.
pubmed: 25613900
doi: 10.1126/science.1260419
Carlsson Y, Schwendimann L, Vontell R, Rousset CI, Wang X, Lebon S, et al. Genetic inhibition of caspase-2 reduces hypoxic-ischemic and excitotoxic neonatal brain injury. Ann Neurol. 2011;70:781–9.
pubmed: 21674587
doi: 10.1002/ana.22431
Shapiro LE, Katz CP, Wasserman SH, DeFesi CR, Surks MI. Heat stress and hydrocortisone are independent stimulators of triiodothyronine-induced growth hormone production in cultured rat somatotrophic tumour cells. Acta Endocrinol. 1991;124:417–24.
Miller JA, Ding SL, Sunkin SM, Smith KA, Ng L, Szafer A, et al. Transcriptional landscape of the prenatal human brain. Nature. 2014;508:199–206.
pubmed: 24695229
pmcid: 4105188
doi: 10.1038/nature13185
Zhu Y, Sousa AMM, Gao T, Skarica M, Li M, Santpere G, et al. Spatiotemporal transcriptomic divergence across human and macaque brain development. Science. 2018;362:eaat8077.
pubmed: 30545855
pmcid: 6900982
doi: 10.1126/science.aat8077
Bergeron L, Perez GI, Macdonald G, Shi L, Sun Y, Jurisicova A, et al. Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev. 1998;12:1304–14.
pubmed: 9573047
pmcid: 316779
doi: 10.1101/gad.12.9.1304
Le Hir H, Sauliere J, Wang Z. The exon junction complex as a node of post-transcriptional networks. Nat Rev Mol Cell Biol. 2016;17:41–54.
pubmed: 26670016
doi: 10.1038/nrm.2015.7
Popp MW, Maquat LE. Leveraging rules of nonsense-mediated mRNA decay for genome engineering and personalized medicine. Cell. 2016;165:1319–22.
pubmed: 27259145
pmcid: 4924582
doi: 10.1016/j.cell.2016.05.053
Doll J, Kolb S, Schnapp L, Rad A, Ruschendorf F, Khan I, et al. Novel loss-of-function variants in CDC14A are associated with recessive sensorineural hearing loss in Iranian and Pakistani patients. Int J Mol Sci. 2020;21:311.
pubmed: 31906439
pmcid: 6982189
doi: 10.3390/ijms21010311