RESUMO
We isolated NSD1 from the 5q35 breakpoint in an individual with Sotos syndrome harboring a chromosomal translocation. We identified 1 nonsense, 3 frameshift and 20 submicroscopic deletion mutations of NSD1 among 42 individuals with sporadic cases of Sotos syndrome. The results indicate that haploinsufficiency of NSD1 is the major cause of Sotos syndrome.
Assuntos
Acromegalia/genética , Proteínas de Transporte/genética , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Nucleares/genética , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 5 , Clonagem Molecular , Códon sem Sentido , Cosmídeos , DNA Complementar/metabolismo , Éxons , Ossos Faciais/anormalidades , Mutação da Fase de Leitura , Deleção de Genes , Gigantismo/genética , Transtornos do Crescimento/genética , Heterozigoto , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Humanos , Hibridização in Situ Fluorescente , Modelos Genéticos , Dados de Sequência Molecular , Homologia de Sequência do Ácido Nucleico , Síndrome , Translocação GenéticaRESUMO
The 1p36 deletion syndrome is a newly delineated multiple congenital anomalies/mental retardation syndrome characterized by mental retardation, growth delay, epilepsy, congenital heart defects, characteristic facial appearance, and precocious puberty. We analyzed 11 patients by fluorescence in situ hybridization (FISH) using commercially available bacterial artificial chromosome and P1-derived artificial chromosome genomic clones to define the chromosomal deletion responsible for the 1p36 deletion syndrome. Cytogenetic investigation revealed two cases with a terminal deletion of 1p36. Nine patients had an apparently normal karyotype with standard G-bands by trypsin using Giemsa (GTG), but FISH screening with the highly polymorphic genetic marker D1Z2, which is mapped to 1p36.3 and contains an unusual reiterated 40-bp variable number tandem repeat, revealed a submicroscopic deletion. All patients had severe to profound mental retardation. Based on the University of California Santa Cruz Genome Browser, we constructed a deletion map and analyzed the relationship between neurological findings and chromosomal deletions for the 11 cases. Six cases had intractable epilepsy and three had no seizures. The common deletion interval was about 1 million base pairs (Mbp) located between RP11-82D16 and RP4-785P20 (Rho guanine exchange factor (GEF) 16). The severity of clinical symptoms correlates with the size of the deletion. This is demonstrated by the 3 patients with at least 8Mbp deletions that display profound mental retardation and congenital heart defects. Although haploinsufficiency of the potassium channel beta-subunit (KCNAB2) is thought to be responsible for intractable seizures in the 1p36 deletion syndrome, this was not the case for 3 of the 11 patients in this study. Further investigation of the 1p36 region is necessary to allow identification of genes responsible for the 1p36 deletion syndrome.
Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Cromossomos Humanos Par 1/genética , Adolescente , Criança , Pré-Escolar , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , MasculinoRESUMO
We describe a de novo balanced reciprocal translocation between the long arms of chromosomes 5 and 8 [46,XX,t(5;8)(q35;q24.1)] in a 15-month-old girl with a typical Sotos syndrome phenotype. Involvement of the 5q35 region was previously reported (Maroun et al. [1994: Am J Med Genet 50:291-293]) as one of translocation breakpoints in the present patient. We suggest that the gene responsible for Sotos syndrome is located to a distal long-arm region of chromosome 5.
Assuntos
Cromossomos Humanos Par 5 , Cromossomos Humanos Par 8 , Anormalidades Craniofaciais/genética , Translocação Genética , Feminino , Humanos , Lactente , SíndromeRESUMO
We present a boy and two girls with paternal uniparental disomy of chromosome 14q (patUPD14). One girl had a Robertsonian translocation, whereas two a normal karyotype. Based on the manifestations of these patients and four previously reported patients who all had translocated chromosome 14, The patUPD14 was thought to constitute a distinctive syndrome. The hallmarks included abdominal muscular defects, skeletal anomalies, and characteristic facies. The phenotype of patUPD14 was consistent with that of a previously reported mouse model, i.e., mouse embryos with paternal uniparental disomy of chromosome 12 that has a region orthologous to that of human chromosome 14. Dose effects of newly recognized imprinted genes on human chromosome 14q32, DLK1 and GTL2, could play an important role in the pathogenic mechanism of the distinctive malformation complex.