RESUMO
The spinal muscular atrophies (SMAs) are among the most common autosomal recessive disorders. The mapping of the gene responsible for SMA to chromosome 5 has allowed the assessment of genetic heterogeneity in kindreds with a putative diagnosis of SMA. We report linkage analysis of 71 Canadian SMA families (types 1, 2, and 3) using polymorphisms that both flank and are linked to SMA. Data demonstrating nonlinkage to 5q markers were initially obtained in five kindreds; reexamination of the clinical status of these families showed that one fulfilled all the SMA diagnostic criteria, two showed patterns for which a diagnosis of SMA was possible but not conclusive, and two showed patterns for which the diagnosis of SMA appeared unlikely. This results in a degree of genetic heterogeneity between 1.5% and 4.5%. The three kindreds for which SMA appeared either possible or likely were simplex (ie, contained only one affected individual), and therefore the possibility that they represented new mutations could not be discounted. Thus, the significant majority of classic SMA cases are caused by a mutation in the 5q13.1 locus. Low genetic heterogeneity has implications for both genetic counseling and the applicability of conventional and genetic therapies following cloning of the SMA gene.
Assuntos
Ligação Genética , Atrofia Muscular Espinal/genética , Adulto , Mapeamento Cromossômico , Feminino , Humanos , Masculino , LinhagemRESUMO
Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked gigantism syndrome characterized primarily by a coarse facies and somatic overgrowth which we have observed to be associated with an increased risk for embryonal tumors. Genetic linkage analysis for two SGBS kindreds in which X linked dominant inheritance was observed has been conducted for the X chromosome. The closest linkage to SGBS was observed for the Xq26 locus HPRT (Z max = 7.45, theta max = 0.00). SGBS-Xq marker recombinations map the disease locus to the DXS425-DXS1123 interval on Xq25-q27. This maps the disease locus to a region known to contain a previously characterized chromosomal translocation breakpoint found in a young girl with somatic overgrowth. This observation may have implications for the cloning of the SGBS gene.
Assuntos
Gigantismo/genética , Cromossomo X , Sequência de Bases , Southern Blotting , Mapeamento Cromossômico , DNA/sangue , DNA/genética , Primers do DNA , Feminino , Triagem de Portadores Genéticos , Ligação Genética , Marcadores Genéticos , Genótipo , Humanos , Hipoxantina Fosforribosiltransferase/genética , Masculino , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Recombinação Genética , Síndrome , Translocação GenéticaAssuntos
Diagnóstico Pré-Natal/métodos , Atrofias Musculares Espinais da Infância/diagnóstico , Amniocentese , Amostra da Vilosidade Coriônica , DNA/genética , Feminino , Amplificação de Genes , Marcadores Genéticos , Humanos , Lactente , Masculino , Linhagem , Gravidez , Atrofias Musculares Espinais da Infância/genéticaRESUMO
The spinal muscular atrophies (SMA) are among the most common autosomal recessive disorders. We have performed linkage analysis using both standard restriction fragment length polymorphisms (RFLPs) as well as microsatellite polymorphisms [Ca(n)] on 49 Canadian SMA families (types 1, 2, and 3) that both flank and are linked to SMA. The closest SMA linkage was observed with the MAP1B locus (zmax = 8.04, theta max = 0.0). Multipoint linkage analysis gave a high probability of SMA mapping between D5S6 and D5S39. Only one family (type 3) that fulfilled our diagnostic criteria for SMA showed nonlinkage with 5q13 markers. This study shows the feasibility of accurate molecular diagnosis of SMA utilizing 5q13 satellite polymorphisms.
