IQSEC2 disorder: A new disease entity or a Rett spectrum continuum?

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Human Molecular Genetics

Background:

• IQSEC2 mutations cause IQSEC2-related intellectual disability (ID), with a complex genotype-phenotype relationship.
• Phenotypic diversity in IQSEC2-related ID includes symptoms overlapping with Rett syndrome (RTT).
• Increasing case reports are refining the understanding of IQSEC2's phenotypic spectrum.

Purpose of the Study:

• To establish a genotype-phenotype correlation for IQSEC2 mutations.
• To investigate the relationship between IQSEC2 variants and clinical presentation, including RTT-like features.
• To assess the role of variant type, position, and gender in IQSEC2-associated phenotypes.

Main Methods:

• Collected data from 16 patients with IQSEC2 point mutations (15 new) and 5 patients with copy number variations (CNVs) encompassing IQSEC2.
• Analyzed clinical data to correlate genetic findings with observed phenotypes.
• Compared clinical courses of IQSEC2 patients with RTT phenotypes.

Main Results:

• Most patients presented with a moderate-to-mild phenotype.
• Clinical similarities were observed between mild IQSEC2 cases and milder forms of atypical RTT.
• Data confirm that variant position, type, and gender are crucial for delineating the IQSEC2-associated phenotype.

Conclusions:

• IQSEC2 mutations should be considered in the differential diagnosis of RTT, given the overlapping clinical spectrum.
• The study reinforces the hypothesis that IQSEC2-mutated patients may fall within the broad clinical spectrum of RTT.
• Understanding genotype-phenotype correlations is essential for accurate diagnosis and management of IQSEC2-related ID.