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Neurol Genet. 2016 May 24;2(3):e76. doi: 10.1212/NXG.0000000000000076. eCollection 2016 Jun.

Mutation of TBCK causes a rare recessive developmental disorder.

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Department of Molecular Neuroscience (R.J.G., J.B.), Institute of Neurology; MRC Laboratory for Molecular Cell Biology (R.B., S.E.M.), University College London; Manchester Centre for Genomic Medicine (D.D.), University of Manchester and Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust; Royal Preston Hospital (C.d.G.), Genetics and Genomics Medicine Programme (S.E.M.), UCL Institute of Child Health and Department of Genetics, Evolution and Environment, University College London, UK.



To characterize the underlying genetic defect in a family with 3 siblings affected by a severe, yet viable, congenital disorder.


Extensive genetic and metabolic investigations were performed, and the affected children were imaged at different ages. Whole-genome genotyping and whole-exome sequencing were undertaken. A single large region (>8 Mb) of homozygosity in chromosome 4 (chr4:100,268,553-108,609,628) was identified that was shared only in affected siblings. Inspection of genetic variability within this region led to the identification of a novel mutation. Sanger sequencing confirmed segregation of the mutation with disease.


All affected siblings share homozygosity for a novel 4-bp deletion in the gene TBCK (NM_033115:c.614_617del:p.205_206del).


This finding provides the genetic cause of a severe inherited disease in a family and extends the number of mutations and phenotypes associated with this recently identified disease gene.

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