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...

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Bibliographic Details
Published in:Neuromolecular medicine 2012-12, Vol.14 (4), p.281-284
Main Authors: Zatz, Mayana, Pavanello, Rita de Cassia M., Lourenço, Naila Cristina V., Cerqueira, Antonia, Lazar, Monize, Vainzof, Mariz
Format: Article
Language:English
Subjects:
Adult
Anxiety
Asymptomatic Diseases
Biological Specimen Banks
Biomedical and Life Sciences
Biomedicine
Biopsy
Causality
Child
Child Behavior Disorders - genetics
Chromosomes, Human, X - genetics
Cognition Disorders - genetics
Coloboma - genetics
Comparative Genomic Hybridization
DNA
DNA - genetics
DNA sequencing
Dystrophin
Dystrophin - genetics
Dystrophin - physiology
Exons
Exons - genetics
Facies
Female
Gene deletion
Genetic Variation - genetics
Genomes
Guanylate cyclase
Hearing loss
Hearing Loss, Bilateral - genetics
Hearing Loss, Sensorineural - genetics
Humans
Incidental Findings
Internal Medicine
Male
Middle Aged
Muscle, Skeletal - pathology
Muscles
Muscular dystrophy
Mutation
Neurology
Neurosciences
Nucleotide sequence
Original Paper
Pathogenicity
Pedigree
Prognosis
Sequence Deletion
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Summary: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.
ISSN:1535-1084
1559-1174
DOI:10.1007/s12017-012-8186-x