Review synthesizes IQSEC2 variant features in developmental encephalopathy and Rett-like syndrome cases

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Frontiers in Medicine Published May 14, 2026 Medically reviewed May 14, 2026 DOI ↗ By Dr. Sofia Müller, MD · Lifespan & Whole-Person Care

Key Takeaway

Consider routine IQSEC2 screening for unexplained developmental and epileptic encephalopathy or Rett-like syndrome.

This publication is a case report and literature review that examines IQSEC2-related developmental and epileptic encephalopathy and Rett-like syndrome. The scope includes two brothers with a novel IQSEC2 truncating variant, their heterozygous mother, and a synthesis of 38 published cases. The authors compare these findings against MECP2-related Rett syndrome as a comparator.

The review identifies several key features. Male predominance emerged as a key feature of the condition. Regression occurred inconsistently among the patients. All nine missense variants mapped to functionally critical domains of the IQSEC2 protein, whereas 82% of the truncating mutations clustered outside these regions. Patients with large duplications or deletions demonstrated more severe phenotypic variability.

The authors note that genotype-phenotype relationships in IQSEC2-associated Rett-like syndromes remain poorly characterized. This limitation underscores the need for further research to define the full spectrum of clinical presentations associated with these genetic variants.

The practice relevance is to support routine IQSEC2 screening in patients with unexplained developmental and epileptic encephalopathy and Rett-like syndrome. Clinicians should interpret these findings with caution given the incomplete characterization of genotype-phenotype correlations.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

Rett syndrome, related to methyl-CpG binding protein 2 (MECP2), primarily affects females, though recent studies have identified additional causative genes, such as IQ motif and SEC7 domain-containing protein 2 (IQSEC2), which mainly affect males and are characterized by prominent developmental encephalopathy. Variations in these genes produce clinical manifestations similar to Rett syndrome but do not fully align with it, posing diagnostic challenges. Currently, they are clinically categorized as Rett-like syndromes. The genotype–phenotype relationships in IQSEC2-associated Rett-like syndromes remain poorly characterized. Herein, we describe two brothers with a novel IQSEC2 truncating variant and Rett-like syndrome manifestations and, alongside a synthesis of 38 published cases, provide insights into the genotype–phenotype correlations of IQSEC2. Two brothers with a novel IQSEC2 variant presented with Rett-like syndrome, exhibiting developmental delay, microcephaly, refractory epilepsy, stereotypic hand movements, and absent speech. Their heterozygous mother displayed mild intellectual disability and late-onset epilepsy. Among the 38 published cases and combined with these siblings, male predominance emerged as a key feature. Regression—unlike in MECP2-related Rett syndrome—occurred inconsistently. We hypothesize that this may represent a phenotype of developmental arrest rather than true regression. All nine missense variants mapped to functionally critical domains of the IQSEC2 protein, whereas 82% of the truncating mutations clustered outside these regions. The patients with large duplications or deletions demonstrated more severe phenotypic variability. Thus, these genotype–phenotype correlations support routine IQSEC2 screening in patients with unexplained developmental and epileptic encephalopathy and Rett-like syndrome. Missense and truncated mutations associated with Rett-like syndrome demonstrate a clustered distribution within the IQSEC2 protein. The genotypes and variant locations help explain the phenotypic variation in patients with IQSEC2 variants.