Hemizygous SMARCA1 variants cause X-linked intellectual disability

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Pathogenic variants in SNF2 related chromatin remodeling ATPase 1 (SMARCA1) are linked to X-linked intellectual disability (XLID).
• XLID associated with SMARCA1 variants often presents with macrocephaly and diverse neurological symptoms.

Purpose of the Study:

• To identify novel genetic variants in SMARCA1 associated with XLID in two unrelated male patients.
• To investigate the functional impact of identified SMARCA1 variants on protein structure and DNA interaction.

Main Methods:

• Whole exome sequencing was employed to detect SMARCA1 variants in patients with XLID.
• Structural modeling was utilized to predict the effect of a missense variant on SMARCA1 protein function.

Main Results:

• Two unrelated male patients with XLID were found to have distinct, novel hemizygous SMARCA1 variants.
• Patient 1 presented with macrocephaly, behavioral issues, and learning disability due to a nonsense variant (p.[Gln599*]).
• Patient 2 exhibited ataxia and speech delay, associated with a missense variant (p.[Arg448Leu]) predicted to destabilize DNA binding.

Conclusions:

• Hemizygous SMARCA1 variants impairing its function can lead to XLID in males.
• XLID caused by SMARCA1 variants can manifest with variable features including macrocephaly and ataxia.
• The identified variants, inherited from unaffected mothers, expand the known spectrum of SMARCA1-related neurodevelopmental disorders.