RESUMO
OBJECTIVE: To characterize the underlying genetic defect in a family with 3 siblings affected by a severe, yet viable, congenital disorder. METHODS: 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. RESULTS: All affected siblings share homozygosity for a novel 4-bp deletion in the gene TBCK (NM_033115:c.614_617del:p.205_206del). CONCLUSIONS: 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.
