[en] Intellectual disability (ID), megalencephaly, frontal predominant pachygyria, and seizures, previously called "thin" lissencephaly, are reported to be caused by recessive variants in CRADD. Among five families of different ethnicities identified, one homozygous missense variant, c.509G>A p.(Arg170His), was of Finnish ancestry. Here we report on the phenotypic variability associated for this potential CRADD founder variant in 22 Finnish individuals. Exome sequencing was used to identify candidate genes in Finnish patients presenting with ID. Targeted Sanger sequencing and restriction enzyme analysis were applied to screen for the c.509G>A CRADD variant in cohorts from Finland. Detailed phenotyping and genealogical studies were performed. Twenty two patients were identified with the c.509G>A p.(Arg170His) homozygous variant in CRADD. The majority of the ancestors originated from Northeastern Finland indicating a founder effect. The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening. All patients show ID of variable severity. Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients. This study provides detailed data about the phenotypic spectrum of patients with lissencephaly due to a CRADD variant that affects function. High inter- and intrafamilial phenotypic heterogeneity was identified in patients with pachygyria caused by the homozygous CRADD founder variant. The phenotype variability suggests that additional genetic and/or environmental factors play a role in the clinical presentation. Since frontotemporal pachygyria is the hallmark of the disease, brain imaging studies are essential to support the molecular diagnosis for individuals with ID and a CRADD variant.
Disciplines :
Genetics & genetic processes
Author, co-author :
Polla, Daniel L ; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands ; CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil
Rahikkala, Elisa; Department of Clinical Genetics, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
Bode, Michaela K; Department of Diagnostic Radiology, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland
Määttä, Tuomo; Disability Services, Joint Authority for Kainuu, Kainuu, Finland
Varilo, Teppo; Department of Medical Genetics, University of Helsinki, Helsinki, Finland
Loman, Thyrza; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
Philips, Anju K; Department of Medical Genetics, University of Helsinki, Helsinki, Finland
Kurki, Mitja; Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA ; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA ; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Palotie, Aarno; Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA ; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA ; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA ; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
Körkkö, Jarmo; Northern Ostrobothnia Hospital District, Center for Intellectual Disability Care, 90220, Oulu, Finland
Vieira, Päivi; Clinic for Children and Adolescents, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
Avela, Kristiina; Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland
JACQUEMIN, VALERIE ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique ; Medical Genetics, IRIBHM, Université Libre de Bruxelles, Brussels, Belgium
Pirson, Isabelle; Medical Genetics, IRIBHM, Université Libre de Bruxelles, Brussels, Belgium
Abramowicz, Marc; Medical Genetics, IRIBHM, Université Libre de Bruxelles, Brussels, Belgium
de Brouwer, Arjan P M; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
Kuismin, Outi; Department of Clinical Genetics, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland ; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
van Bokhoven, Hans; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
Järvelä, Irma; Department of Medical Genetics, University of Helsinki, Helsinki, Finland. irma.jarvela@helsinki.fi
CAPES - Coordenação de Aperfeicoamento de Pessoal de Nível Superior EC - European Commission
Funding text :
Acknowledgements We are grateful to the families for participating in the study. We thank Shaffaq Raza, Minna Varhala, and Eija H\u00E4m\u00E4-l\u00E4inen for excellent technical help. We thank all the clinicians who have recruited patients to this study. This work was supported by the European Union\u2019s Seventh Framework Program (Gencodys; grant 241995 to HvB). DLP is recipient of a CAPES Fellowship (99999.013311/2013\u201301).
van Bokhoven H. Genetic and epigenetic networks in intellectual disabilities. Annu Rev Genet. 2011;45:81–104.
Willemsen MH, Kleefstra T. Making headway with genetic diagnostics of intellectual disabilities. Clin Genet. 2014;85:101–10.
Riazuddin S, Hussain M, Razzaq A, Iqbal Z, Shahzad M, Polla DL, et al. Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Mol Psychiatry. 2017;22:1604–14.
Institute of Medicine (U.S.). Committee to evaluate the supplemental security income disability program for children with mental disorders. In: Boat TF, Wu JT, editors. National Academies of Sciences Engineering and Medicine: mental disorders and disabilities among low-income children. Washington, D.C.: National Academies Press, 2015.
Ropers HH. Genetics of early onset cognitive impairment. Annu Rev Genom Hum Genet. 2010;11:161–87.
Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD, Dobyns WB. A developmental and genetic classification for malformations of cortical development: update 2012. Brain. 2012;135:1348–69.
Guerrini R, Dobyns WB. Malformations of cortical development: clinical features and genetic causes. Lancet Neurol. 2014;13:710–26.
Guerrini R, Marini C. Genetic malformations of cortical development. Exp Brain Res. 2006;173:322–33.
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.
Reiner O, Carrozzo R, Shen Y, Wehnert M, Faustinella F, Dobyns WB, et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature. 1993;364:717–21.
Parrini E, Conti V, Dobyns WB, Guerrini R. Genetic basis of brain malformations. Mol Syndromol. 2016;7:220–33.
Fry AE, Cushion TD, Pilz DT. The genetics of lissencephaly. Am J Med Genet C Semin Med Genet. 2014;166C:198–210.
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.
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.
Puffenberger EG, Jinks RN, Sougnez C, Cibulskis K, Willert RA, Achilly NP, et al. Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS ONE. 2012;7:e28936.
Kurki MI, Saarentaus E, Pietilainen O, Gormley P, Lal D, Kerminen S et al. Contribution of rare and common variants to intellectual disability in a high-risk population sub-isolate of Northern Finland. bioRxiv. 2019;10:410.
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.
Sorva R, Tolppanen EM, Lankinen S, Perheentupa J. [Evaluation of childhood growth]. Duodecim. 1985;101:465–76.
Karvonen M, Hannila ML, Saari A, Dunkel L. New Finnish reference for head circumference from birth to 7 years. Ann Med. 2012;44:369–74.
Saari A, Sankilampi U, Hannila ML, Kiviniemi V, Kesseli K, Dunkel L. New Finnish growth references for children and adolescents aged 0 to 20 years: Length/height-for-age, weight-for-length/height, and body mass index-for-age. Ann Med. 2011;43:235–48.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.
Sequencing Initiative Suomi project (SISu), Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland. http://sisuproject.fi. [SISu v4.1, 03/2018].
Martin AR, Karczewski KJ, Kerminen S, Kurki MI, Sarin AP, Artomov M, et al. Haplotype sharing provides insights into fine-scale population history and disease in Finland. Am J Hum Genet. 2018;102:760–75.
Varilo T, Nikali K, Suomalainen A, Lonnqvist T, Peltonen L. Tracing an ancestral mutation: genealogical and haplotype analysis of the infantile onset spinocerebellar ataxia locus. Genome Res. 1996;6:870–5.
Duan H, Dixit VM. RAIDD is a new ‘death’ adaptor molecule. Nature. 1997;385:86–89.
Lin Y, Ma W, Benchimol S. Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nat Genet. 2000;26:122–7.
Berube C, Boucher LM, Ma W, Wakeham A, Salmena L, Hakem R, et al. Apoptosis caused by p53-induced protein with death domain (PIDD) depends on the death adapter protein RAIDD. Proc Natl Acad Sci USA. 2005;102:14314–20.
Ribe EM, Jean YY, Goldstein RL, Manzl C, Stefanis L, Villunger A, et al. Neuronal caspase 2 activity and function requires RAIDD, but not PIDD. Biochem J. 2012;444:591–9.
Shalini S, Dorstyn L, Wilson C, Puccini J, Ho L, Kumar S. Impaired antioxidant defence and accumulation of oxidative stress in caspase-2-deficient mice. Cell Death Differ. 2012;19:1370–80.
Zhang Y, Padalecki SS, Chaudhuri AR, De Waal E, Goins BA, Grubbs B, et al. Caspase-2 deficiency enhances aging-related traits in mice. Mech Ageing Dev. 2007;128:213–21.
Ranta S, Zhang Y, Ross B, Lonka L, Takkunen E, Messer A, et al. The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nat Genet. 1999;23:233–6.
Aula P, Autio S, Raivio KO, Rapola J, Thoden CJ, Koskela SL, et al. “Salla disease”: a new lysosomal storage disorder. Arch Neurol. 1979;36:88–94.
Renlund M, Aula P, Raivio KO, Autio S, Sainio K, Rapola J, et al. Salla disease: a new lysosomal storage disorder with disturbed sialic acid metabolism. Neurology. 1983;33:57–66.
Kure S, Takayanagi M, Narisawa K, Tada K, Leisti J. Identification of a common mutation in Finnish patients with nonketotic hyperglycinemia. J Clin Invest. 1992;90:160–4.
Peltonen L, Palotie A, Lange K. Use of population isolates for mapping complex traits. Nat Rev Genet. 2000;1:182–90.
Polvi A, Linturi H, Varilo T, Anttonen AK, Byrne M, Fokkema IF, et al. The Finnish disease heritage database (FinDis) update-a database for the genes mutated in the Finnish disease heritage brought to the next-generation sequencing era. Hum Mutat. 2013;34:1458–66.
Romero DM, Bahi-Buisson N, Francis F. Genetics and mechanisms leading to human cortical malformations. Semin. Cell Dev. Biol. 2017;76:33–75.
