Abstract

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.

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Acknowledgements

We are grateful to the families for participating in the study. We thank Shaffaq Raza, Minna Varhala, and Eija Hämäläinen for excellent technical help. We thank all the clinicians who have recruited patients to this study. This work was supported by the European Union’s Seventh Framework Program (Gencodys; grant 241995 to HvB). DLP is recipient of a CAPES Fellowship (99999.013311/2013–01).

Author information

Author notes

  1. These authors contributed equally: Daniel L. Polla, Elisa Rahikkala, Michaela K. Bode

  2. These authors jointly supervised this work: Hans van Bokhoven, Irma Järvelä

Affiliations

  1. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

    • Daniel L. Polla
    • , Thyrza Loman
    • , Arjan P. M. de Brouwer
    •  & Hans van Bokhoven
  2. CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil

    • Daniel L. Polla
  3. Department of Clinical Genetics, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland

    • Elisa Rahikkala
    •  & Outi Kuismin
  4. Department of Diagnostic Radiology, Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland

    • Michaela K. Bode
  5. Disability Services, Joint Authority for Kainuu, Kainuu, Finland

    • Tuomo Määttä
  6. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    • Teppo Varilo
    • , Anju K. Philips
    •  & Irma Järvelä
  7. Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    • Mitja Kurki
    •  & Aarno Palotie
  8. The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Mitja Kurki
    •  & Aarno Palotie
  9. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    • Mitja Kurki
    • , Aarno Palotie
    •  & Outi Kuismin
  10. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    • Aarno Palotie
  11. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    • Aarno Palotie
  12. Northern Ostrobothnia Hospital District, Center for Intellectual Disability Care, 90220, Oulu, Finland

    • Jarmo Körkkö
  13. Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland

    • Kristiina Avela
  14. Medical Genetics, IRIBHM, Université Libre de Bruxelles, Brussels, Belgium

    • Valérie Jacquemin
    • , Isabelle Pirson
    •  & Marc Abramowicz

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Correspondence to Irma Järvelä.

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DOI

https://doi.org/10.1038/s41431-019-0383-8