TFE3-associated neurodevelopmental disorder: A distinct recognizable syndrome

Area of Science:

• Genetics
• Developmental Biology
• Human Pathology

Background:

• The TFE3 gene regulates embryonic stem cell differentiation and is implicated in certain cancers.
• TFE3 inactivation promotes differentiation; mutations can lead to developmental disorders.
• Previous studies identified TFE3 missense mutations causing a mosaic developmental disorder with intellectual disability and distinctive features.

Purpose of the Study:

• To expand the understanding of the phenotypic and mutational spectrum of TFE3-associated developmental disorders.
• To report new cases with de novo TFE3 variants and a consistent phenotype.

Main Methods:

• Whole exome sequencing was used to identify genetic variants.
• Clinical phenotyping and diagnostic evaluations were performed.

Main Results:

• Two unrelated females with de novo heterozygous TFE3 variants were identified.
• Both patients presented with severe intellectual disability, coarse facial features, and Blaschkoid pigmentary mosaicism.
• One patient had a nonsynonymous missense variant, and the other had a canonical splice site variant, expanding the known mutation types.

Conclusions:

• De novo TFE3 variants are associated with a recognizable human developmental disorder.
• The phenotypic spectrum includes intellectual disability, coarse facial features, pigmentary mosaicism, and normal brain MRI.
• Splice site variants, in addition to missense variants, can cause this TFE3-related disorder.