RESUMO
Apparently balanced chromosomal inversions may lead to disruption of developmentally important genes at the breakpoints of the inversion, causing congenital malformations. Characterization of such inversions may therefore lead to new insights in human development. Here, we report on a de novo inversion of chromosome 7 (p15.2q36.3) in a patient with postaxial polysyndactyly. The breakpoints do not disrupt likely candidate genes for the limb phenotype observed in the patient. However, on the p-arm the breakpoint separates the HOXA cluster from a gene desert containing several conserved noncoding elements, suggesting that a disruption of a cis-regulatory circuit of the HOXA cluster could be the underlying cause of the phenotype in this patient.
Assuntos
Cromossomos Humanos Par 7/genética , Cromossomos Humanos Y/genética , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Proteínas de Homeodomínio/genética , Polidactilia/genética , Sequência de Bases , Southern Blotting , Quebra Cromossômica , Inversão Cromossômica , Deformidades Congênitas do Pé/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Deformidades Congênitas da Mão/patologia , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Polidactilia/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Using SNP array and FISH analysis, a patient with moderate intellectual disability and obesity was found to harbour an atypical 1.6 Mb inverted duplication on 8p23.1, directly flanked by a distally located interstitial deletion of 2.3 Mb and a terminal segmental uniparental disomy. The duplicated and deleted regions lie exactly between the two segmental duplication regions. These segmental duplications on chromosome 8p23.1 are known to be involved in chromosomal rearrangements because of mutual homology and homology to other genomic regions. Genomic instability mediated by these segmental duplications is generally caused by non-allelic homologous recombination, resulting in deletions, reciprocal duplications, inversions and translocations. Additional analysis of the parental origin of the fragments of this atypical inverted duplication/interstitial deletion shows paternal contribution in the maternal derivate chromosome 8. Combined with the finding that the normal chromosome 8 carries an inversion in 8p23.1 we hypothesize that a double strand break in 8p23.1 of the maternal chromosome was postzygotically repaired with the paternal inverted copy resulting in a duplication, deletion and segmental uniparental disomy, with no particular mediation of the 8p23.1 segmental duplication regions in recombination.
Assuntos
Transtornos Cromossômicos/genética , Deficiência Intelectual/genética , Obesidade/genética , Criança , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Duplicação Cromossômica , Cromossomos Humanos Par 8/genética , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Obesidade/diagnóstico , Síndrome , Telômero/genéticaRESUMO
In 1980, a case report on a boy with cleft palate, club feet, dysmorphic features, and developmental delay was published by Bijlsma as a possible distinct syndrome. This case is listed in the London Medical Databases version 1.0. We have reevaluated this patient at adult age. Using high resolution karyotyping and Affymetrix 250k SNP array analysis we identified an unbalanced three-way translocation with breakpoints at 17q22, 18q22.1, and 20p12.2 leading to deletion 18q and duplication 20p. Also, a 715 kb duplication in 1p34.2 and a 245 kb deletion at 1p21.1 were found. Mental retardation, cleft palate, and club feet have repeatedly been reported in deletion 18q patients and therefore we conclude that most of the patient's features can be explained by an 18q deletion.