2. Academic Validation
  3. Identification of C12orf4 as a gene for autosomal recessive intellectual disability

Identification of C12orf4 as a gene for autosomal recessive intellectual disability

  • Clin Genet. 2017 Jan;91(1):100-105. doi: 10.1111/cge.12821.
A K Philips 1,  M Pinelli 2 3,  C I de Bie 4,  A Mustonen 5,  T Määttä 6,  H H Arts 7 8,  K Wu 7,  R Roepman 7,  J S Moilanen 5,  S Raza 1,  T Varilo 1,  G Scala 9,  S Cocozza 9,  C Gilissen 2,  K L I van Gassen 4,  I Järvelä 1
Affiliations

Affiliations

  • 1 Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
  • 2 Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Centre, Nijmegen, the Netherlands.
  • 3 The Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
  • 4 Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 5 Department of Clinical Genetics, PEDEGO Research Unit and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
  • 6 Disability Services, Joint Authority for Kainuu, Kainuu, Finland.
  • 7 Department of Human Genetics, Radboud University of Molecular Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands.
  • 8 Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
  • 9 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi di Napoli "Federico II", Naples, Italy.
PMID: 27311568 DOI: 10.1111/cge.12821
Abstract

Intellectual disability (ID) is a major health problem in our society. Genetic causes of ID remain unknown because of its vast heterogeneity. Here we report two Finnish families and one Dutch family with affected individuals presenting with mild to moderate ID, neuropsychiatric symptoms and delayed speech development. By utilizing whole exome Sequencing (WES), we identified a founder missense variant c.983T>C (p.Leu328Pro) in seven affected individuals from two Finnish consanguineous families and a deletion c.799_1034-429delinsTTATGA (p.Gln267fs) in one affected individual from a consanguineous Dutch family in the C12orf4 gene on chromosome 12. Both the variants co-segregated in the respective families as an autosomal recessive trait. Screening of the p.Leu328Pro variant showed enrichment in the North Eastern sub-isolate of Finland among anonymous local blood donors with a carrier frequency of 1:53, similar to Other disease mutations with a founder effect in that region. To date, only one Arab family with a three affected individuals with a frameshift insertion variant in C12orf4 has been reported. In summary, we expand and establish the clinical and mutational spectrum of C12orf4 variants. Our findings implicate C12orf4 as a causative gene for autosomal recessive ID.

Keywords

C12orf4; founder effect; frameshift variant; intellectual disability; missense variant; whole exome sequencing.

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