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

Abstract

This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

IQSEC2mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy

“…Most females with missense variants in the heterozygous state belong to families with affected males and are generally either asymptomatic carriers, or mildly affected with learning difficulties or borderline intellectual disability (ID; Table ). There are at least three cases in which females with missense variants in IQSEC2 were ascertained due to their seizure phenotype (de Kovel et al., ; Helbig, et al ., , Mignot et al., ) (Table ). The only non‐synonymous missense change found outside of any known functional domain was identified in an affected male with a phenotype of ASD, but no intellectual disability or seizures (Piton et al., ), representing the mildest reported phenotype within the IQSEC2 related disorders.…”

“…An alternative transcript for the longer IQSEC2 isoform, resulting in a 1,478‐residue protein, has also been proposed. A third isoform has been reported [GenBank:NM_001243197.1] that does not share any exons with the longest isoform, encodes a distinct, short 73‐residue protein (NP_001230126.1), and as such is likely to have a distinct function and localization (Mignot et al., ). IQSEC2, also known as BRAG1 and IQ‐ArfGEF, is a neuronally expressed ARFGEF for the small GTPase ARF6 (Murphy, Jensen, & Walikonis, ; Sakagami et al., ; Shoubridge et al., ) and is located at excitatory glutamatergic synapses in the forebrain.…”

“…Clinical features within these non‐syndromic XLID families were moderate to severe intellectual disability in all affected males, with variable seizures, autistic traits and psychiatric problems (Shoubridge et al., ). Since this time, a total of 85 cases/families have been reported, including 37 novel variants in a recent report by Mignot and colleagues (Mignot et al., ). Overall, there are 70 different pathogenic variants arising from nine distinct variant types (Table ), encompassing missense, nonsense, splice‐site, deletions, indels, duplications, and several structural variations (SV).…”

“…Of these 15 missense variants, there are nine familial cases and seven cases arising de novo in patients (Table ) and all disease‐causing missense changes occur within specific functional domains of IQSEC2 (with only one exception). Pathogenic variants are located within the IQ‐like domain (Shoubridge et al., ; Zerem et al., ; Zhang et al., ), Sec7 domain (de Kovel et al., ; Gandomi et al., ; Helbig, et al ., ; Helm et al., ; Kalscheuer et al., ; Mignot et al., ; Shoubridge et al., ), or PH domain (Helm et al., ; Mignot et al., ). The IQ‐like and Sec7 functional domains are both involved in catalytic activity of guanine nucleotide exchange and activation of the substrate ARF6, while the PH domain may be involved in IQSEC2‐accessory protein interactions, increasing the association of substrates (ARFGDP) with the catalytic Sec7 domain or recruiting IQSEC2 and associated signaling pathways to different subcellular compartments via interactions with phosphoinositides (Roy, Yohe, Randazzo, & Gruschus, ).…”

Non‐syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies

“…Pathogenic variants found in females are mainly truncating, whereas males also have missense and truncating variants. Truncating mutations in males and females are associated with severe neurodevelopmental disorder, females being globally less severely affected . Missense variants altering functional domains IQ and Sec7 are better tolerated in females and therefore can be inherited over several generations …”