Assessing Pathogenicity for Novel Mutation/Sequence Variants: The Value of Healthy Older Individuals

Improvement in DNA technology is increasingly revealing unexpected/unknown mutations in healthy persons and generating anxiety due to their still unknown health consequences. We report a 44-year-old healthy father of a 10-year-old daughter with bilateral coloboma and hearing loss, but without muscle weakness, in whom a whole-genome CGH revealed a deletion of exons 38-44 in the dystrophin gene. This mutation was inherited from her asymptomatic father, who was further clinically and molecularly evaluated for prognosis and genetic counseling (GC). This deletion was never identified by us in 982 Duchenne/Becker patients. To assess whether the present case represents a rare case of non-penetrance, and aiming to obtain more information for prognosis and GC, we suggested that healthy older relatives submit their DNA for analysis, to which several complied. Mutation analysis revealed that his mother, brother, and 56-year-old maternal uncle also carry the 38-44 deletion, suggesting it an unlikely cause of muscle weakness. Genome sequencing will disclose mutations and variants whose health impact are still unknown, raising important problems in interpreting results, defining prognosis, and discussing GC. We suggest that, in addition to family history, keeping the DNA of older relatives could be very informative, in particular for those interested in having their genome sequenced.

CEPIDFAPESP (Centro de Pesquisa, Inovacao e DifusaoFundacao de Amparo a Pesquisa do Estado de Sao Paulo)

CEPID-FAPESP (Centro de Pesquisa, Inovacao e Difusao-Fundacao de Amparo a Pesquisa do Estado de Sao Paulo)

CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico)

Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)

Instituto Nacional de Ciencia e Tecnologia (INCT)

INCT (Instituto Nacional de Ciencia e Tecnologia)

FINEP

FINEP

ABDIM

ABDIM