Objective:

To characterize two brothers with a novel IQSEC2 truncating variant and manifestations resembling Rett syndrome, and to provide insights into the genotype–phenotype correlations of IQSEC2.

Key Findings:

• Both brothers exhibited developmental delay, microcephaly, refractory epilepsy, and stereotypic hand movements.
• The mother displayed mild intellectual disability and late-onset epilepsy.
• Male predominance was observed among the cases reviewed.
• Regression was inconsistent, suggesting a phenotype of developmental arrest rather than true regression.
• Missense variants clustered in functionally critical domains, while truncating mutations were mostly outside these regions.

Interpretation:

The findings suggest that IQSEC2 variants can lead to Rett-like syndromes with distinct clinical features, warranting routine IQSEC2 screening in unexplained developmental and epileptic encephalopathy cases to improve diagnosis and management.

Limitations:

• The study is based on a small sample size of two cases and a literature review, which may not fully represent the variability of IQSEC2-related disorders, potentially limiting the generalizability of the findings.
• The retrospective nature of the literature review may introduce bias in the interpretation of genotype–phenotype correlations.

Conclusion:

The study highlights the importance of recognizing IQSEC2 variants in patients with developmental and epileptic encephalopathy, as they may present with Rett-like features but differ significantly from classic Rett syndrome.