RESUMO
Haploinsufficiency of AUTS2 has been associated with neurodevelopmental disorders and dysmorphic features (MIM # 615834). More than 50 patients have been described, mostly carrying de novo deletions of one or more exons, including eight patients with exon 6 deletions. We report on two siblings, a girl and a boy aged 11 and 13 years, in whom the same pathogenic 85 kb deletion on 7q11.22 encompassing exon 6 of AUTS2 by SNP array analysis was identified. Both children had typical symptoms of AUTS2 syndrome such as intellectual impairment and behavioral problems, but with markedly different expression. SNP array analysis excluded the deletion in blood samples of both parents and a healthy brother. Conventional karyotyping of both parents and additional FISH analyses, marking the flanking regions of the deletion, did not show any structural rearrangements involving 7q11.22. A germ cell mosaicism was suggested as the most probable explanation for occurrence of the same deletion in these two siblings. To our knowledge this is the first report of germ cell mosaicism for AUTS2 syndrome. It additionally provides further evidence of intrafamilial phenotypic variability in AUTS2 syndrome and adds clinical information to the phenotypic spectrum of patients with AUTS2 exon 6 deletions.
Assuntos
Anormalidades Múltiplas/genética , Proteínas do Citoesqueleto/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Criança , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/patologia , Éxons/genética , Feminino , Células Germinativas/metabolismo , Células Germinativas/patologia , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Mosaicismo , Deleção de Sequência/genéticaRESUMO
In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent â¼4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping â¼5 Mb duplication of Xp11.23-p11.3. Patient 4 showed a duplication of â¼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a â¼8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic.
