The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk.Ībnormal formation of the cerebral cortex in utero leads to neurodevelopmental disorders known as malformations of cortical development (MCDs). Although individually rare, as a group MCDs represent a major cause of intellectual disability, autism, epilepsy and cerebral palsy 1, 2. The last update of the developmental and genetic classification for MCDs, which was published in 2012, includes 200 clinical entities and classifies them into three major groups: malformations secondary to abnormal neuronal and glial cell proliferation and apoptosis, including microcephaly and macrocephaly neuronal migration disorders, represented by heterotopia, lissencephaly and cobblestone malformation (COB) and malformations of postmigrational cortical organization and connectivity, represented by conditions such as polymicrogyria, schizencephaly and focal cortical dysplasia (FCD) 3. Many MCDs are caused by an underlying genetic defect. Rapid advances in molecular genetics and neuroimaging techniques in recent years have substantially increased the number of recognized MCD forms and their associated genes, and have highlighted the considerable genetic heterogeneity associated with these disorders 1.
Next-generation sequencing (NGS) of a selection of genes related to a phenotype (gene panel), the coding exons of the human genes (exome sequencing) or the genome of an individual (genome sequencing) has enabled rapid sequencing of large numbers of genes.Įven following intensive diagnostic assessments, many individuals with an MCD remain without a molecular diagnosis 4, 5, 6. The complex nature and high degree of clinical and genetic heterogeneity of MCDs demand highly specialized and multidisciplinary expertise. However, MCD experts usually work individually or in small multidisciplinary teams.
Currently, comprehensive guidelines for diagnosis and management are lacking, adding to the variability in the diagnostic approach between different centres.
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