Correction: IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients

Abstract

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Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder

“…It is described that patients harboring de novo IQSEC2 mutations disrupting of the C-terminus of the IQSEC2 protein relate a mild phenotype [ 17 ], and that missense variants cause a less severe phenotype than truncating variants [ 7 ]. Missense pathogenic variants have been described to affect the three IQSEC2 functional domains (IQ-like, Sec7 and PH domain) [ 3 , 18 ]. In general, males with missense variants present mild–severe intellectual disability with variable penetrance of seizures and ASD traits, and less frequently with speech deficits, whereas most females with missense variants in heterozygosity are asymptomatic, or mildly affected with intellectual disability or learning difficulties [ 6 ].…”

“…In general, males with missense variants present mild–severe intellectual disability with variable penetrance of seizures and ASD traits, and less frequently with speech deficits, whereas most females with missense variants in heterozygosity are asymptomatic, or mildly affected with intellectual disability or learning difficulties [ 6 ]. Truncating variants, which are associated with more severe neurodevelopmental phenotype due to the loss of IQSEC2 function [ 7 ], are generally better tolerated in females than in males [ 3 ]. Male patients with loss of function variants generally present severe intellectual disability, seizures and speech deficiency [ 3 , 19 , 20 ], while female patients with loss of function variants in heterozygosity present a variability in phenotype severity for intellectual disability, seizures and global developmental delay [ 3 , 21 ].…”

“…The IQ motif and SEC7 domain containing protein 2 is coded by an X-chromosome gene ( IQSEC2) , abundantly expressed in the brain which plays an important role in neuronal development, excitatory synapses and synaptic plasticity [ 1 ]. Mutations in IQSEC2 gene cause X-linked intellectual developmental disorder-1, XLID1, (MIM: #309530), preferentially characterized by moderate to profound intellectual disability [ 2 ], often accompanied by seizures and autism spectrum disorder (ASD) [ 1 , 3 , 4 ]. A number of different pathogenic variants were identified by the exome sequencing of nonsyndromic intellectual disability [ 5 ].…”

“…The genotype–phenotype correlation is not yet well-known, however, missense variants generally have a less severe phenotype than truncating variants [ 7 ]. Recent studies show that although IQSEC2 mutations affect both sexes, females are variably and generally less affected than males [ 3 , 8 ].…”

“…However, IQSEC2 is one of approximately 20% of X chromosomal genes that escape XCI and therefore it is expressed from both X alleles in females. This phenomenon is largely unknown and complex, causing variable phenotypes in females with X-linked neurodevelopmental disorders [ 3 , 9 ].…”