Wednesday, December 28, 2022

IQSEC2 mutation

Inspired by a patient

Baladron B, Mielu LM, López-Martín E, Barrero MJ, Lopez L, Alvarado JI, Monzón S, Varona S, Cuesta I, Cazorla R, Lara J, Iglesias G, Román E, Ros P, Gomez-Mariano G, Cubillo I, Miguel EH, Rivera D, Alonso J, Bermejo-Sánchez E, Posada M, Martínez-Delgado B. Differences in Expression of IQSEC2 Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder. Int J Mol Sci. 2022 Aug 22;23(16):9480. doi: 10.3390/ijms23169480. PMID: 36012761; PMCID: PMC9409358.


Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males. Two novel unrelated cases, one male and one female, with de novo IQSEC2 variants were detected by trio-based whole exome sequencing. The female case had a previously undescribed frameshift mutation (NM_001111125:c.3300dup; p.Met1101Tyrfs*5), and the male showed an intronic variant in intron 6, with a previously unknown effect (NM_001111125:c.2459+21C>T). IQSEC2 gene expression study revealed that this intronic variant created an alternative donor splicing site and an aberrant product, with the inclusion of 19bp, confirming the pathogenic effect of the intron variant. Moreover, a strong reduction in the expression of the long, but also the short IQSEC2 isoforms, was detected in the male correlating with a more severe phenotype, while the female case showed no decreased expression of the short isoform, and milder effects of the disease. This suggests that the abnormal expression levels of the different IQSEC2 transcripts could be implicated in the severity of disease manifestations.

Brant B, Stern T, Shekhidem HA, Mizrahi L, Rosh I, Stern Y, Ofer P, Asleh A, Umanah GKE, Jada R, Levy NS, Levy AP, Stern S. IQSEC2 mutation associated with epilepsy, intellectual disability, and autism results in hyperexcitability of patient-derived neurons and deficient synaptic transmission. Mol Psychiatry. 2021 Dec;26(12):7498-7508. doi: 10.1038/s41380-021-01281-0. Epub 2021 Sep 17. PMID: 34535765; PMCID: PMC8873005.


Mutations in the IQSEC2 gene are associated with drug-resistant, multifocal infantile and childhood epilepsy; autism; and severe intellectual disability (ID). We used induced pluripotent stem cell (iPSC) technology to obtain hippocampal neurons to investigate the neuropathology of IQSEC2-mediated disease. The neurons were characterized at three-time points during differentiation to assess developmental progression. We showed that immature IQSEC2 mutant dentate gyrus (DG) granule neurons were extremely hyperexcitable, exhibiting increased sodium and potassium currents compared to those of CRISPR-Cas9-corrected isogenic controls, and displayed dysregulation of genes involved in differentiation and development. Immature IQSEC2 mutant cultured neurons exhibited a marked reduction in the number of inhibitory neurons, which contributed further to hyperexcitability. As the mutant neurons aged, they became hypoexcitable, exhibiting reduced sodium and potassium currents and a reduction in the rate of synaptic and network activity, and showed dysregulation of genes involved in synaptic transmission and neuronal differentiation. Mature IQSEC2 mutant neurons were less viable than wild-type mature neurons and had reduced expression of surface AMPA receptors. Our studies provide mechanistic insights into severe infantile epilepsy and neurodevelopmental delay associated with this mutation and present a human model for studying IQSEC2 mutations in vitro.

Levy AP, Levy NS, Heyman E, Schertz M, Genizi J. Reduction in seizure burden in a child with a A350V IQSEC2 mutation using heat therapy with a Jacuzzi. Clin Case Rep. 2021 Aug 30;9(9):e04734. doi: 10.1002/ccr3.4734. PMID: 34484768; PMCID: PMC8405536.


A child with a A350V IQSEC2 missense mutation resulting in drug-resistant epilepsy stops having seizures when he has a fever. We demonstrate that raising the body temperature of the child using a commercial Jacuzzi dramatically reduces his seizures and appears to improve his social behavioral interactions.

Liu X, Zhang S, Wan L, Zhang X, Wang H, Zhang H, Zhu G, Liang Y, Yan H, Zhang B, Yang G. IQSEC2-related encephalopathy in male children: Novel mutations and phenotypes. Front Mol Neurosci. 2022 Oct 3;15:984776. doi: 10.3389/fnmol.2022.984776. PMID: 36267700; PMCID: PMC9577604.


The isoleucine-glutamine (IQ) motif and Sec7 domain-containing protein 2 (IQSEC2) gene, located at Xp11. 2, are associated with nervous system diseases, such as epilepsy, autism, and intellectual disabilities. Gender-related differences in the severity of phenotype severity have been described previously. Here, we report the details of seven male children with IQSEC2 mutations from different families. During this investigation, we explored the relationship between the genotype and phenotype of IQSEC2 mutations; to do so, we recruited seven children with pathogenic/likely pathogenic IQSEC2 mutations who were diagnosed with global developmental delay and/or epilepsy. Their clinical features were assessed, and Trio-based whole-exome sequencing (trio WES) was conducted in seven pedigrees. A variety of algorithms and computational tools were used to calculate the pathogenicity, protein stability, conservation, side chain properties, and protein-protein interactions of mutated proteins. The seven patients ranged in age from 18 months to 5 years. Among them, six children were found to have both developmental delay and epilepsy, and one child only exhibited developmental delay. Four novel mutations (c.316C > T, c.443_4 44dup, c.3235T > C, and c.1417G > T) were newly reported. Two patients did not have truncated aberrant proteins caused by missense mutations. Still, they did have severe phenotypes, such as early-onset epilepsy in infancy, because the mutations were located in domains like the pleckstrin homology and IQ calmodulin-binding motif domains. The bioinformatics analysis also proved that missense mutations may be located in the functional region, which affects protein stability and is harmful. In summary, severe phenotypes, such as early-onset epilepsy in infancy, occur in male patients with a missense mutation in specific domains (e.g., pleckstrin homology and IQ calmodulin-binding motif domains). Some female individuals with IQSEC2 mutations may be asymptomatic because of the skewed inactivation of the X chromosome.


  1. From the Levi et al article above:

    Over 20 different seizure medications and a ketogenic diet have failed to reduce seizures in the male child E.H. hemizygous for the A350V IQSEC2 mutation. The failure of conventional medical treatment to suppress the child's seizures has prompted our group to investigate alternative approaches. A remarkable finding in this child repeatedly observed by his parents beginning at 1 year of age until the present (age 8) is that when he has a fever of greater than 38°C lasting more than 1 day his seizures abruptly stop and then he has a seizure‐free window of up to 3 weeks after the fever has resolved. In this case report, we set out to determine whether the purposeful induction of a rise in body core temperature could have the same benefit as fever on reducing seizures.
    We have previously reported on the developmental progression of EH thru age 5 including the onset of seizures at age 8 months and the refractory nature of these seizures to all treatments.5 Seizure activity has been repeatedly documented using video EEG with the most recent EEG prior to this study (12/2019) showing nearly continuous severe epileptiform activity which was well correlated with frequent short head drops as well as generalized tonic‐clonic (GTC) seizures and drop attacks. Prior to beginning this current investigation, the frequency of different seizure types was very variable from day to day, but it was not uncommon for the child to have over 20 seizures a day and due to post‐ictal effects to be lethargic and non‐interactive a substantial portion of the day.

    We considered several possibilities to try to raise the child's body core temperature to see if we could recapitulate the apparent protective effect of fever on seizures as described above. Previous studies have established that 15‐ to 20‐min exposures to water baths at 40°C can safely raise the body core temperature to up to 39°C without risk of hyperthermia.7, 8, 9 We chose for this purpose a temperature‐controlled water bath (Coleman 13804‐BW SaluSpa), which is sold commercially as a Jacuzzi and operated the Jacuzzi at a setting of 40°C. The child was encouraged to sit in the Jacuzzi for treatments of up to 20 min and was monitored closely by an adult caregiver. More often the child would jump around and play during these treatments.(continued)

  2. (continued) Beginning in October 2020, 2 months prior to initiating the Jacuzzi treatments the child's seizures were carefully documented for 2–3 h a day by a single caretaker and recorded as being either small (head drops) or large (tonic‐clonic followed by post‐ictal drowsiness lasting at least 15 min). Once daily outdoor Jacuzzi treatments without any control of the air temperature of the region surrounding the Jacuzzi (temperature outside the Jacuzzi ranging from 10 to 15°C) were initiated in December 2020 with no apparent benefit on the number of head drops or GTC seizures. Beginning in February 2021, twice daily Jacuzzi treatments were initiated in conjunction with the housing of the Jacuzzi inside a tent and the installation of a heating system in the tent allowing the air temperature in the tent to be controlled at 30°C during the Jacuzzi treatments. Figure 1 demonstrates the percentage of days per 30‐day interval that the child was observed to have at least two observed head drops or one GTC seizure over the four consecutive 30‐day intervals prior to beginning the twice daily Jacuzzi treatments and during the 30‐day period when he received twice daily treatments (average of 7–11 days per 30‐day interval prior to twice daily treatments compared to 1 day during the 30‐day interval of twice daily treatments, p = 0.003 calculated by the chi‐square test comparing the frequency of days with seizures for the 4 months before and the 30‐day interval on twice daily Jacuzzi treatments).

    During the 30‐day interval, in which the child received twice daily Jacuzzi treatments, the child was more alert and interactive with his caregivers and teachers. His sleep was also markedly improved. Although the child is averbal, during this period the child demonstrated increased vocalizations.

    After 30 days of twice daily Jacuzzi treatments, an EEG was performed (March 2021) and demonstrated a marked improvement in the amount of epileptiform activity. Representative EEGs from the period before and after the twice daily Jacuzzi treatments are shown in Figure 2. Interictal discharges were manually counted over a representative 20‐min interval of the pre‐treatment and on‐treatment EEGs. Compared to his most recent EEG done prior to the Jacuzzi treatments (Dec 2019) there was a marked reduction in interictal discharges (A1 prior and A2 after treatment; mean of six interictal discharges per minute compared to one interictal discharge per minute). Moreover, background brain wave activity of the EEG after treatment was markedly improved (B1 prior and B2 after treatment) with normal sleep patterns after twice daily Jacuzzi treatments and a reduction in delta wave activity seen prior to treatment.