WDTC1 Haploinsufficiency as a Cause of Neurodevelopmental Phenotypes

WD and tetratricopeptide repeats protein 1 (WDTC1) encodes a component of the cullin-RING E3 ligase complexes that mediate polyubiquitination of specific target proteins for degradation and has been shown to regulate lipid storage in studies performed in Drosophila, mice, and humans. WDTC1 is expressed in a wide variety of tissues and organs including the brain and is predicted to be loss-of-function intolerant. To determine the phenotypes associated with WDTC1 haploinsufficiency, we identified seven individuals, six of whom have not been previously reported, who are heterozygous for loss-of-function or putatively damaging missense variants in WDTC1. None of these individuals were reported to be obese, but all had neurodevelopmental phenotypes that included developmental delay and intellectual disability. Seizures were also recurrently reported. One loss-of-function variant was inherited from an affected mother, and one missense variant was inherited from an unaffected father. Our findings suggest that WDTC1 haploinsufficiency causes a neurodevelopmental syndrome characterized by variable developmental delay, intellectual disability, and seizures. The identification of additional patients with loss-of-function variants will be needed to identify recurrent patterns of less common phenotypes, determine with greater certainty if obesity is or is not a feature associated with this disorder, and confirm that this disorder is incompletely penetrant.