RESUMO
The human induced pluripotent stem cell (iPSC) lines, iCS-MAF1-1 and iCS-MAF1-11, were generated from fibroblasts. The donor has a heterozygous mutation in the VPS13B gene, which manifests in her child as Cohen syndrome. It is a Golgi pathology, characterized by postnatal microcephaly and delayed growth and mental development. However, the process underlying pathological changes leading to the onset of the disease is still unknown. The use of iPSC will allow describing the early stages of neurogenesis, which is undoubtedly relevant for identifying key stages of development, at which phenotypic manifestations of mutations in the VPS13B gene are found.
RESUMO
Despite the acceptance of NextGen sequencing as a diagnostic modality suitable for probands and carriers of Mendelian diseases, its efficiency in identifying causal mutations is limited by both technical aspects of variant call algorithms and by imperfect, consensus-based criteria for assessing the pathogenicity of the findings. Here we describe the medical history of the family with a child born with Fanconi anemia. In this case, typical diagnostic routines were complicated by unusual combination of mutations. PALB2 variant NM_024675.3:c.172_175delTTGT (p.Gln60Argfs) in maternal sample, previously classified as a definitely pathogenic frameshift mutation, was in compound heterozygous state with PALB2 NM_024675.3:c.3114-16_3114-11del (p.Asn1039Glyfs*7), which led to validated PALB2 exon 11 skipping event in paternal locus. Findings enabled the development of the PGТ and successful selection of two mutation-free embryos. We show that even in absence of definitive exome findings, clinician-guided research inquiries into the structure and function of the suspected loci allow definitive diagnosis. Described case provides an example of a crucial input of an investigational workflow in genetic prognosis and successful PGT.
Assuntos
Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Mutação da Fase de Leitura , Íntrons/genética , Adulto , Pré-Escolar , Éxons , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/prevenção & controle , Evolução Fatal , Feminino , Fertilização in vitro/métodos , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pais , Diagnóstico Pré-Implantação/métodos , RNA Mensageiro/análise , RNA Mensageiro/genética , Sequenciamento do Exoma/métodosRESUMO
The paper presents the results of investigating the mechanisms of placental insufficiency and transplacental infection of infants born to HIV-infected mothers who have received specific antiretroviral therapy mothers and who have not.
