RESUMO
We have analyzed the survival motor neuron gene (SMN1) dosage in 100 parents of children with homozygous SMN1 deletions. Of these parents, 96 (96%) demonstrated the expected one-copy SMN1 carrier genotype. However, four parents (4%) were observed to have a normal two-copy SMN1 dosage. The presence of two intact SMN1 genes in the parent of an affected child indicates either the occurrence of a de novo mutation event or a situation in which one chromosome has two copies of SMN1, whereas the other is null. We have separated individual chromosomes from two of these parents with two-copy SMN1 dosage by somatic cell hybridization and have employed a modified quantitative dosage assay to provide direct evidence that one parent is a two-copy/ zero-copy SMN1 carrier, whereas the other parent had an affected child as the result of a de novo mutation. These findings are important for assessing the recurrence risk of parents of children with spinal muscular atrophy and for providing accurate family counseling.
Assuntos
Cromossomos Humanos Par 5 , Triagem de Portadores Genéticos , Atrofia Muscular Espinal/genética , Proteínas do Tecido Nervoso/genética , Autorradiografia , Sequência de Bases , Mapeamento Cromossômico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Primers do DNA , Haplótipos , Humanos , Hibridização in Situ Fluorescente , Mutação , Proteínas de Ligação a RNA , Proteínas do Complexo SMN , Proteína 1 de Sobrevivência do Neurônio MotorRESUMO
Pfeiffer syndrome (PS) is an autosomal dominant disorder characterized by craniosynostosis, midfacial hypoplasia, and broad thumbs and great toes. We examined 129 individuals from 11 families with PS and performed linkage studies using microsatellite markers spanning the entire genome. Strongest support for linkage was with DNA markers (D8S255, GATA8G08) from chromosome 8. Obligate crossovers exclude close linkage to this region in six families, and there was significant evidence for genetic heterogeneity. A multipoint lod score of 7.15 was obtained in five families. The 11 cM interval between D8S278 and D8S285 contains one gene for PS and also spans the centromere of chromosome 8.
Assuntos
Acrocefalossindactilia/genética , Centrômero/genética , Cromossomos Humanos Par 8/genética , Heterogeneidade Genética , Ligação Genética , Troca Genética/genética , Feminino , Genes Dominantes/genética , Humanos , Masculino , LinhagemRESUMO
A statistical analysis of parental age and the incidence of new mutation has been performed. Some new data on Apert, Crouzon, and Pfeiffer syndromes is presented and combined with all available data from the literature on parental age and new mutation. Significant heterogeneity among syndromes for the rate of increase in incidence with parental age was found. A parsimonious conclusion is that mutations fall into two groups, one with a high rate of increase with age and the other with a low rate of increase with age. For the high-rate-of-increase group, a linear model relating incidence to age is rejected, while an exponential model is not. In addition, for this group, increased paternal age cannot account for the observed increase in maternal age--that is, increased maternal age also contributes to the incidence of new mutations. For the low-rate-of-increase group, increased paternal age alone can account for the observed increase in maternal ages; also, either a linear or exponential model is acceptable. In addition, there is no evidence for a mixture of parental age-independent cases with parental age-dependent cases for any of the syndromes examined. The curves reflecting incidence of new mutation and paternal age for two syndromes, Apert and neurofibromatosis, have an anomalous shape. In both cases the curve increases up to age 37 and drops at age 42 before increasing again at age 47. The usual explanation for the effect of parental age on new mutations is the mechanism of "copy-error" at mitotic division in male sperone that specifies an increased probability of mutation with time spent by a spermatozoon or ovum in a haploid state, a period of time that may also increase with age of the parent. A firm answer to the question of parental age and new mutation awaits identification of the molecular defect underlying some of these syndromes; we will then be in a position to determine in which parent the mutation occurred and at what age it did so.
Assuntos
Genes Dominantes , Idade Materna , Modelos Genéticos , Mutação , Idade Paterna , Acrocefalossindactilia/genética , Adulto , Disostose Craniofacial/genética , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Estatística como AssuntoRESUMO
Three patients are reported, two of whom had mothers who revealed ingestion of abortifacient drugs during pregnancy. All patients resemble one another and those described earlier with malformations that were probably either aminopterin- or methotrexate-induced. It is likely that Patients I and II have abnormalities associated with the teratogenic action of these folic-acid antagonists. The etiology of Patient III's defects remains uncertain.
