IQSEC2 and X-linked syndromal intellectual disability

Despite the recent acceleration in the discovery of genetic risk factors for intellectual disability (ID), the genetic etiology of ID is unknown in approximately half of cases and remains a major frontier of genetics in medicine and psychiatry. The distinction between syndromal and nonsyndromal forms of ID is of great clinical importance, but the boundary between these clinical entities is difficult to ascertain for many genes of interest. ID is more common in men than in women, but the genetic explanation of this sex asymmetry is incompletely understood. This Review systematically examines the reported cases of X-linked ID caused by de novo loss-of-function mutations in the gene IQSEC2. This gene is largely known as a cause of X-linked nonsyndromal ID in male patients. However, depending on the severity of the mutation, the phenotypic spectrum of IQSEC2-related ID can range from the classic X-linked nonsyndromal form of the disease to a severe syndrome that has been reported in the context of de novo mutations only, in both male and female patients. Bioinformatics analysis suggests that truncation of the longer of the two protein isoforms of the gene can be sufficient to lead to the syndrome, which may be caused by the disruption of cell signaling and signal transduction pathways. The clinical features of the syndrome converge on a pattern of global developmental delay, deficits in social communication, stereotypical hand movements, and hypotonia. In addition, many if not all of these patients have seizures, microcephaly, and language regression in addition to delay. We argue that it is clinically appropriate to test for IQSEC2 mutations in male and female patients with this symptom profile but without a known genetic mutation.