Asunto(s)
Agenesia del Cuerpo Calloso/etiología , Trastornos del Crecimiento/etiología , Discapacidad Intelectual/genética , Síndrome de Deleción Distal 11q de Jacobsen/etiología , Síndrome de Pierre Robin/etiología , Trombocitopenia/congénito , Trombocitopenia/genética , Agenesia del Cuerpo Calloso/genética , Proteínas de Unión al ADN/genética , Facies , Trastornos del Crecimiento/genética , Humanos , Síndrome de Deleción Distal 11q de Jacobsen/genética , Antígenos de Histocompatibilidad Menor/genética , Mutación , Síndrome de Pierre Robin/genética , Trombocitopenia/etiologíaRESUMEN
Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2-25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro-rearrangements (n=188), the patient had an increased volume of the sub-cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2-25 deletion on brain anatomy.
Asunto(s)
Trastorno del Espectro Autista/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 11 , Moléculas de Adhesión de Célula Nerviosa/genética , Adulto , Encéfalo/anomalías , Encéfalo/fisiopatología , Estudios de Casos y Controles , Variaciones en el Número de Copia de ADN , Femenino , Proteínas Ligadas a GPI/genética , Predisposición Genética a la Enfermedad , Humanos , Síndrome de Deleción Distal 11q de Jacobsen/etiología , Síndrome de Deleción Distal 11q de Jacobsen/genética , Imagen por Resonancia Magnética , Masculino , Megalencefalia/genética , Mutación , Polimorfismo de Nucleótido Simple , EmbarazoRESUMEN
In 1973, the Danish geneticist Petrea Jacobsen described a three-generation family in which the proband carried a presumed terminal deletion at the end of the long arm of chromosome 11 (11q). This patient had dysmorphic features, congenital heart disease, and intellectual disability. Since Dr. Jacobsen's initial report, over 200 patients with Jacobsen syndrome have been reported, suggesting that Jacobsen syndrome is a contiguous gene disorder. With the advent of high resolution deletion mapping and the completion of the human genome sequencing project, a comprehensive genotype/phenotype analysis for Jacobsen syndrome became possible. In this article, we review research describing individual causal genes in distal 11q that contribute to the overall Jacobsen syndrome clinical phenotype. Through a combination of human genetics and the use of genetically engineered animal models, causal genes have been identified for the clinical problems in JS that historically have caused the greatest morbidity and mortality: congenital heart disease, the Paris-Trousseau bleeding disorder, intellectual disability, autism, and immunodeficiency. Insights gained from these studies are being applied for future drug development and clinical trials, as well as for a potential strategy for the prevention of certain forms of congenital heart disease. The results of these studies will likely not only improve the prognostic and therapeutic approaches for patients with Jacobsen syndrome, but also for the general population afflicted with these problems.
