RESUMEN
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.
Asunto(s)
Facies , Marcha/genética , Haploinsuficiencia/genética , Discapacidad Intelectual/genética , Proteínas/genética , Convulsiones/genética , Proteínas Adaptadoras Transductoras de Señales , Secuencia de Aminoácidos , Secuencia de Bases , Preescolar , Deleción Cromosómica , Femenino , Crecimiento y Desarrollo/genética , Humanos , Discapacidad Intelectual/complicaciones , Masculino , Mutación/genética , Proteínas/química , Estabilidad del ARN/genética , Convulsiones/complicaciones , SíndromeAsunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica , Leucemia Mieloide Aguda/metabolismo , Leucemia Promielocítica Aguda/metabolismo , ARN Neoplásico/metabolismo , Tirosina Quinasa 3 Similar a fms/metabolismo , Transportadoras de Casetes de Unión a ATP/sangre , Transportadoras de Casetes de Unión a ATP/genética , Adolescente , Adulto , Anciano , Antineoplásicos/farmacología , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Médula Ósea/metabolismo , Línea Celular Tumoral , Niño , Resistencia a Antineoplásicos , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/sangre , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Mutación , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , ARN Neoplásico/sangre , Especies Reactivas de Oxígeno/metabolismo , Secuencias Repetidas en Tándem , Tirosina Quinasa 3 Similar a fms/sangre , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
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.