ABSTRACT
IQSEC2 is an X-linked gene highly expressed at the excitatory synapses where it plays a crucial role in a-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid receptor trafficking and synaptic plasticity. To date, several males and females with severe to profound intellectual disability have been reported harbouring frameshift and nonsense variants in this gene, whereas a milder phenotype has been recognized in females carrying missense pathogenic variants. Here, we report two novel IQSEC2 variants in four females with psychiatric features and otherwise variable cognitive impairment. A female (case 1) with severe verbal language learning disorder and a psychotic episode (precipitated by exposure to anti-contraceptive pill) harboured a de novo pathogenic frameshift variant (c.1170dupG,p.Gln391Alafs*5), whereas the female proband of family 2, displaying severe psychomotor regression and complex psychiatric features carried a missense variant of uncertain significance (c.770G[A,p.Ser257Asn) that was maternally inherited. Skewed X-inactivation was noted in the carrier mother. The maternal aunt, affected by schizophrenia, was found to bear the same IQSEC2 variant. We discuss the variable clinical presentation of IQSEC2 spectrum disorders and the challenging genotype–phenotype correlation, including the possible role of environmental factors as triggers for decompensation. Our report highlights how psychiatric features may be the main clinical presentation in subtle IQSEC2 phenotype, suggesting that the prevalence of IQSEC2 mutations in patients with psychiatric disorders may be underestimated.