RESUMEN
Intellectual disability (ID), a genetically and clinically heterogeneous disorder, affects 1%-3% of the general population and is a major health problem, especially in developing countries and in populations with a high frequency of consanguineous marriage. Using whole exome sequencing, a homozygous missense variation (c.3264G>C, p.W1088C) in a plausible disease causing gene, GPR126, was identified in two patients presenting with profound ID, severe speech impairment, microcephaly, seizures during infancy, and spasticity accompanied by cerebellar hypoplasia. The role of GPR126 in radial sorting and myelination in Schwann cells suggests a mechanism of pathogenesis for ID. Involvement of GPR126 in lethal congenital contracture syndrome 9 has been identified previously, but this is the first report of a plausible candidate gene, GPR126, in ID.
Asunto(s)
Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Receptores Acoplados a Proteínas G/genética , Adolescente , Cerebelo/anomalías , Cerebelo/fisiopatología , Consanguinidad , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Genes Recesivos/genética , Humanos , Lactante , Discapacidad Intelectual/fisiopatología , Masculino , Microcefalia/genética , Microcefalia/fisiopatología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/fisiopatología , Linaje , Células de Schwann/patología , Convulsiones/genética , Convulsiones/fisiopatología , Trastornos del Habla/genética , Trastornos del Habla/fisiopatología , Secuenciación del ExomaRESUMEN
During the past years, significant advances have been made in our understanding of the development of the human brain, and much of this knowledge comes from genetic studies of disorders associated with abnormal brain development. We employed array-comparative genomic hybridization (CGH) to investigate copy number variants (CNVs) in a cohort of 169 patients with various structural brain malformations including lissencephaly, polymicrogyria, focal cortical dysplasia, and corpus callosum agenesis. The majority of the patients had intellectual disabilities (ID) and suffered from symptomatic epilepsy. We detected at least one rare CNV in 38 patients (22.5%). All genes located within the rare CNVs were subjected to enrichment analysis for specific Gene Ontology Terms or Kyoto Encyclopedia of Genes and Genomes pathways and to protein-protein network analysis. Based on these analyses, we propose that genes involved in "axonal transport," "cation transmembrane transporter activity," and the "c-Jun N-terminal kinase (JNK) cascade" play a significant role in the etiology of brain malformations. This is to the best of our knowledge the first systematic study of CNVs in patients with structural brain malformations and our data show that CNVs play an important role in the etiology of these malformations, either as direct causes or as genetic risk factors.