Bi-allelic variants in WDR47 cause a complex neurodevelopmental syndrome

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• The corpus callosum is crucial for interhemispheric communication, formed by projection neuron axons.
• Defects in corpus callosum formation result in syndromic corpus callosum dysgenesis (CCD).

Purpose of the Study:

• To identify the genetic cause of a novel neurodevelopmental syndrome characterized by CCD.
• To elucidate the function of the identified gene in brain development.

Main Methods:

• Analysis of five unrelated families with bi-allelic WDR47 variants.
• In vitro and in vivo mouse models to study WDR47 function.
• Complementation assays to confirm WDR47's role.

Main Results:

• WDR47 variants are associated with CCD, microcephaly, and enlarged ventricles.
• WDR47 is essential for callosal neuron survival.
• WDR47 maintains mitochondrial and microtubule homeostasis.

Conclusions:

• WDR47 is a causative gene for a new neurodevelopmental syndrome with corpus callosum abnormalities.
• The severity of CCD correlates with the degree of WDR47 loss-of-function.