RESUMO
It has been proposed that copy number variations (CNVs) are associated with increased risk of autism spectrum disorder (ASD) and, in conjunction with other genetic changes, contribute to the heterogeneity of ASD phenotypes. Array comparative genomic hybridization (aCGH) and exome sequencing, together with systems genetics and network analyses, are being used as tools for the study of complex disorders of unknown etiology, especially those characterized by significant genetic and phenotypic heterogeneity. Therefore, to characterize the complex genotype-phenotype relationship, we performed aCGH and sequenced the exomes of two affected siblings with ASD symptoms, dysmorphic features, and intellectual disability, searching for de novo CNVs, as well as for de novo and rare inherited point variations-single nucleotide variants (SNVs) or small insertions and deletions (indels)-with probable functional impacts. With aCGH, we identified, in both siblings, a duplication in the 4p16.3 region and a deletion at 8p23.3, inherited by a paternal balanced translocation, t(4, 8) (p16; p23). Exome variant analysis found a total of 316 variants, of which 102 were shared by both siblings, 128 were in the male sibling exome data, and 86 were in the female exome data. Our integrative network analysis showed that the siblings' shared translocation could explain their similar syndromic phenotype, including overgrowth, macrocephaly, and intellectual disability. However, exome data aggregate genes to those already connected from their translocation, which are important to the robustness of the network and contribute to the understanding of the broader spectrum of psychiatric symptoms. This study shows the importance of using an integrative approach to explore genotype-phenotype variability.
Assuntos
Transtorno do Espectro Autista/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 8/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Exoma/genética , Estudos de Associação Genética , Translocação Genética , Criança , Cromossomos Humanos Par 4/ultraestrutura , Cromossomos Humanos Par 8/ultraestrutura , Feminino , Duplicação Gênica , Redes Reguladoras de Genes , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/genética , Deficiências da Aprendizagem/genética , Masculino , Megalencefalia/genética , Proteínas do Tecido Nervoso/genética , Técnicas de Amplificação de Ácido Nucleico , Deleção de Sequência , Irmãos , SíndromeRESUMO
Prader-Willi syndrome (PWS) is a neurobehavioral disorder caused by deletions in the 15q11-q13 region, by maternal uniparental disomy of chromosome 15 or by imprinting defects. Structural rearrangements of chromosome 15 have been described in about 5% of the patients with typical or atypical PWS phenotype. An 8-year-old boy with a clinical diagnosis of PWS, severe neurodevelopmental delay, absence of speech and mental retardation was studied by cytogenetic and molecular techniques, and an unbalanced de novo karyotype 45,XY,der(4)t(4;15)(q35;q14),-15 was detected after GTG-banding. The patient was diagnosed by SNURF-SNRPN exon 1 methylation assay, and the extent of the deletions on chromosomes 4 and 15 was investigated by microsatellite analysis of markers located in 4qter and 15q13-q14 regions. The deletion of chromosome 4q was distal to D4S1652, and that of chromosome 15 was located between D15S1043 and D15S1010. Our patient's severely affected phenotype could be due to the extent of the deletion, larger than usually seen in PWS patients, although the unbalance of the derivative chromosome 4 cannot be ruled out as another possible cause. The breakpoint was located in the subtelomeric region, very close to the telomere, a region that has been described as having the lowest gene concentrations in the human genome.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 4/ultraestrutura , Síndrome de Prader-Willi/genética , Translocação Genética , Criança , Quebra Cromossômica , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 4/genética , Metilação de DNA , Humanos , Masculino , Repetições de Microssatélites , Fenótipo , Telômero/genética , Translocação Genética/genéticaRESUMO
An inversion, inv(4)(p14q27), was found as the sole karyotypic anomaly at diagnosis in the bone marrow cells from a 65-year-old male patient with an M4 acute nonlymphocytic leukemia (ANLL). To our knowledge, the breakpoints observed in this case appear to be different from other inversions of chromosome 4 previously described in ANLL. The patient we described had a poor response to chemotherapy and had a short survival.
Assuntos
Inversão Cromossômica , Cromossomos Humanos Par 4/ultraestrutura , Leucemia Mielomonocítica Aguda/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Cromossomos Humanos Par 4/genética , Citarabina/administração & dosagem , Evolução Fatal , Humanos , Idarubicina/administração & dosagem , Cariotipagem , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Masculino , Mitoxantrona/administração & dosagemRESUMO
Introducción. El síndrome de Wolf-Hirschhorn (SWH) es una cromosopatía poco frecuente, debido a la delección en la banda del brazo 4p16.3 que se manifiesta con una amplia variedad clínica, incluyendo malformaciones craneofaciales importantes. Caso clínico. Paciente de 3 mmeses de edad que acudió por presentar paladar hendido y que inició su manejo en el servicio de cirugía maxilofacial. Con el antecedente materno de haber presentado cuadro exantemático diagnósticado como rubéola durante el primer trimestre del embarazo. Se detectaron múltiples malformaciones congénitas agregadas (cardiovasculares, oftalmológicas y ortopédicas). Conclusiones. De acuerdo a los hallazgos fenotípicos se realizó el diagnóstico de SWH asociado a síndrome de rubéola congénita. Es éste el primer reporte en que se documenta la asociación de ambos síndromes