RESUMO
We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in â¼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.
Assuntos
Fácies , Marcha/genética , Haploinsuficiência/genética , Deficiência Intelectual/genética , Proteínas/genética , Convulsões/genética , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Sequência de Bases , Pré-Escolar , Deleção Cromossômica , Feminino , Crescimento e Desenvolvimento/genética , Humanos , Deficiência Intelectual/complicações , Masculino , Mutação/genética , Proteínas/química , Estabilidade de RNA/genética , Convulsões/complicações , SíndromeAssuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/metabolismo , Leucemia Promielocítica Aguda/metabolismo , RNA Neoplásico/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo , Transportadores de Cassetes de Ligação de ATP/sangue , Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Idoso , Antineoplásicos/farmacologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Medula Óssea/metabolismo , Linhagem Celular Tumoral , Criança , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Mutação , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , RNA Neoplásico/sangue , Espécies Reativas de Oxigênio/metabolismo , Sequências de Repetição em Tandem , Tirosina Quinase 3 Semelhante a fms/sangue , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Achieving a major molecular response (MMR) is an important predictor of progression-free survival in chronic myeloid leukemia patients treated with imatinib. This requires accurate measurement of BCR-ABL1 transcripts normalized to a control gene, as well as defining a level (BCR-ABL1/control gene ratio) that will correlate with sustained clinical response. To make these measurements comparable between laboratories, an international scale (IS) is necessary. A BCR-ABL1/control gene ratio of 0.10% represents MMR in the IS. In collaboration with an international reference laboratory in Adelaide, S.A., Australia, we have established and validated a lab-specific conversion factor for expressing BCR-ABL1 transcript levels in the IS. In this report, we explain the process and steps involved in obtaining a valid lab-specific conversion factor for expressing BCR-ABL1 transcript levels in the IS.
