Identification of C12orf4 as a gene for autosomal recessive intellectual disability
Philips, A. K.; Pinelli, M.; de Bie, C. I.; Mustonen, A.; Määttä, T.; Arts, H. H.; Wu, K.; Roepman, R.; Moilanen, J. S.; Raza, S.; Varilo, T.; Scala, G.; Cocozza, S.; Gilissen, C.; van Gassen, K. L I; Järvelä, I.
(2017) Clinical Genetics, volume 91, issue 1, pp. 100 - 105
(Article)
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
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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.
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Keywords: C12orf4, Founder effect, Frameshift variant, Intellectual disability, Missense variant, Whole exome sequencing, Genetics(clinical), Genetics, Journal Article, Case Reports
ISSN: 0009-9163
Publisher: Wiley-Blackwell
Note: Funding Information: We are grateful to the families for participating in the study. This work was supported by the Finnish Medical Society and the Biomedicum Helsinki Foundation. H. H. A. and R. R. were funded by the Netherlands Organization for Scientific Research grants (Vici-016.130.664 to R. R. and Veni-91613008 to H. H. A.) and the European Community's Seventh Framework Program FP7/2009 (grant agreement 241955 SYSCILIA to R. R.). We thank the High-Throughput Genomics Group at the Welcome Trust Centre for Human Genetics (funded by Welcome Trust grant reference 090532/Z/09/Z and MRC Hub grant G0900747 91070) for the generation of the sequencing data. Publisher Copyright: © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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