WDTC1 Haploinsufficiency as a Cause of Neurodevelopmental Phenotypes

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• WDTC1 (WD and tetratricopeptide repeats protein 1) is a component of E3 ligase complexes involved in protein degradation.
• Previous studies in model organisms and humans suggest WDTC1 regulates lipid storage.
• WDTC1 is expressed in various tissues, including the brain, and is intolerant to loss-of-function variants.

Purpose of the Study:

• To investigate the clinical phenotypes associated with WDTC1 haploinsufficiency.
• To characterize individuals with heterozygous loss-of-function or damaging missense variants in WDTC1.

Main Methods:

• Clinical evaluation of seven individuals with WDTC1 variants.
• Genetic analysis to identify loss-of-function or missense variants.
• Phenotypic correlation including neurodevelopmental assessments and seizure history.

Main Results:

• Seven individuals were identified with heterozygous WDTC1 variants (six new cases).
• All individuals presented with neurodevelopmental phenotypes, including developmental delay and intellectual disability.
• Seizures were a recurrent feature; obesity was not observed in this cohort.

Conclusions:

• WDTC1 haploinsufficiency leads to a neurodevelopmental syndrome with variable developmental delay, intellectual disability, and seizures.
• Further studies with more patients are needed to confirm incomplete penetrance and the absence of obesity as a consistent feature.