Psychiatric features and variable neurodevelopment outcome in four females with IQSEC2 spectrum disorder
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Ó Indian Academy of Sciences (0123456789().,-volV) (0123456789().,-volV)
RESEARCH NOTE
Psychiatric features and variable neurodevelopment outcome in four females with IQSEC2 spectrum disorder ANDREA ACCOGLI1,2, G. ERIC JARVIS3, ALESSANDRA SCHIAVETTO4, LAURENCE LAI4, EVANGELIA L. AMIRALI5, DANIEL ALEXANDER JIMENEZ CRUZ6, JEAN-BAPTISTE RIVIE`RE6,7 and YANNIS TRAKADIS1,7* 1Department
of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada - Universita` di Genova, 16126 Genoa, Italy 3First Episode Psychosis Program, Jewish General Hospital and McGill University, Montreal, QC H3T 1E2, Canada 4Neuropsychology Service, Department of Psychology and Psychiatry, CIUSS Centre West-Jewish General Hospital and McGill University, Montreal, QC H3T 1E2, Canada 5De´partement de Psychiatrie CHU Ste-Justine, Universite´ de Montre´al, Montreal, QC H3T 1C5, Canada 6Bioinformatics Platform, Research Institute of the McGill University Health Centre, Montre´al, QC H4A 3J1, Canada 7Faculty of Medicine, Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada 2DINOGMI
*For correspondence. E-mail: [email protected]. Received 9 October 2019; revised 3 March 2020; accepted 9 March 2020 Abstract. IQSEC2 is an X-linked gene highly expressed at the excitatory synapses where it plays a crucial role in a-amino-3-hydroxy-5methyl-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. Keywords.
IQSEC2 gene; psychiatric disorders; intellectual disability; postsynaptic density; small GTPases.
Introduction Neurodevelopmental disorders are clinically and genetically heterogeneous group of diseases with o
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