The whole truth and nothing but the truth, but what is the truth?

The moral aspects of genetic counselling are explored in situations where the outcome of a DNA test does not lead to certain knowledge. The most frequent type of interaction between counsellor and counsellee is when factual information is given, but sometimes "factual" information is difficult to obtain. How do counsellors deal with "uncertain" knowledge in genetics? Arguments and assumptions are presented and the finding of a 27 CAG repeat in the Huntington gene is used as an example. However, the questions "how far does the duty to inform reach?" and "to what extent is the doctor responsible?" are important in the whole field of genetics, and will be even more important in the future. The aims of science and clinical practice are discussed; we conclude that counsellors run the risk of taking on an infinite responsibility

Identification of regions critical for the integrity of the TSC1-TSC2-TBC1D7 complex

The TSC1-TSC2-TBC1D7 complex is an important negative regulator of the mechanistic target of rapamycin complex 1 that controls cell growth in response to environmental cues. Inactivating TSC1 and TSC2 mutations cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterised by the occurrence of benign tumours in various organs and tissues, notably the brain, skin and kidneys. TBC1D7 mutations have not been reported in TSC patients but homozygous inactivation of TBC1D7 causes megaencephaly and intellectual disability. Here, using an exon-specific deletion strategy, we demonstrate that some regions of TSC1 are not necessary for the core function of the TSC1-TSC2 complex. Furthermore, we show that the TBC1D7 binding site is encoded by TSC1 exon 22 and identify amino acid residues involved in the TSC1-TBC1D7 interaction

A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]

Hereditary spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders for which >/=14 different genetic loci have been identified. In some SCA types, expanded tri- or pentanucleotide repeats have been identified, and the length of these expansions correlates with the age at onset and with the severity of the clinical phenotype. In several other SCA types, no genetic defect has yet been identified. We describe a large, three-generation family with early-onset tremor, dyskinesia, and slowly progressive cerebellar ataxia, not associated with any of the known SCA loci, and a mutation in the fibroblast growth factor 14 (FGF14) gene on chromosome 13q34. Our observations are in accordance with the occurrence of ataxia and paroxysmal dyskinesia in Fgf14-knockout mice. As indicated by protein modeling, the amino acid change from phenylalanine to serine at position 145 is predicted to reduce the stability of the protein. The present FGF14 mutation represents a novel gene defect involved in the neurodegeneration of cerebellum and basal ganglia

Targeted Next Generation Sequencing reveals previously unidentified and mutations

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in and . Conventional DNA diagnostic screens identify a or mutation in 75 - 90% of individuals categorised with definite TSC. The remaining individuals either have a mutation that is undetectable using conventional methods, or possibly a mutation in another as yet unidentified gene. Methods: Here we apply a targeted Next Generation Sequencing (NGS) approach to screen the complete and genomic loci in 7 individuals fulfilling the clinical diagnostic criteria for definite TSC in whom no or mutations were identified using conventional screening methods. Results: We identified and confirmed pathogenic mutations in 3 individuals. In the remaining individuals we identified variants of uncertain clinical significance. The identified variants included mosaic changes, changes located deep in intronic sequences and changes affecting promoter regions that would not have been identified using exon-only based analyses. Conclusions: Targeted NGS of the and loci is a suitable method to increas