Fig. 5

Flow-chart in patients with NDD and/or MCA and/or Dysmorphisms. The first step is the collection of appropriate family and clinical history and physical/dysmorphological evaluation. If the patient has a recognizable syndrome, we have to confirm it with specific genetic tests. Otherwise, except for other possible neurological or metabolic implications, we will proceed by considering aCGH (in case of male subjects with ID, it would be appropriate to consider the molecular survey for Fragile X syndrome). The blood draw should always be done on the trio in order to perform aCGH on parent’s sample if anomalous in the child. If aCGH detects CNVs, they will be carefully interpreted. Some CNVs can be classified as pathogenic because linked to known syndromes or to “new microdeletion/microduplication syndromes”. If CNVs are less known or poorly described they have an uncertain clinical significance (VOUS): we suggest some variables that might be useful in distinguishing likely pathogenic from likely benign CNVs (continuous box). Additionally, the presence of some phenotypic variables, as well as the analysis of non-coding regions, could be useful in classifying VOUS as likely pathogenic (dashed box) [* Phenotypic variables significant for pathogenic CNVs: developmental delay, ID, prematurity, IUGR, dysmorphisms, congenital heart disease, hypotonia, cerebral malformations; Phenotypic variables significant for likely pathogenic CNVs: abnormal EEG, hand and lower limb dysmorphisms; Independent predictive factors for pathogenic CNVs: prematurity, ventricular septal defect, dysmorphisms]. In the case of normal chromosomal pattern or likely benign CNVs, it will be necessary to re-evaluate the patient. If the clinical features are strongly suggestive of a genetic/syndromic condition further genetic investigations will be carried out. These may include targeted sequencing, exome sequencing and, in selected cases, genome sequencing. Otherwise clinical follow up should be implemented in the event that evocative elements could emerge over time recommending future genetic investigations