RESUMO
New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.
Assuntos
Variações do Número de Cópias de DNA/genética , Gametogênese/genética , Doenças Genéticas Inatas/genética , Células Germinativas/citologia , Mutação em Linhagem Germinativa/genética , Mosaicismo , Divisão Celular , Feminino , Genômica , Humanos , Masculino , Modelos Genéticos , Mutação , Linhagem , Estudos Prospectivos , Recidiva , Risco , Caracteres Sexuais , Síndrome de Smith-Magenis/genéticaRESUMO
Genetic counseling can best be performed if a systematic approach is taken. The geneticist or genetic counselor has the difficult task of conveying complex information to patients in an understandable form. At the same time, this must be done in a nondirective manner, affording the patient the right to make his or her own decisions. Obtaining accurate family and medical history information is crucial to the genetic counseling process. Given the nature of genetic information, multiple sessions may be necessary to ensure that the patient understands the risks involved in his or her particular situation.