Recurrent missense variants in can cause syndromic intellectual disability.

PURPOSE

Binding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A missense variant in was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm as a neurodevelopmental disease gene, and elucidate the -associated neurodevelopmental phenotype in a patient cohort.

METHODS

We discovered a variant in the index case via exome sequencing and sought individuals with variants via international data-sharing initiatives. modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.

RESULTS

We identified 12 unrelated individuals with five missense variants in , four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.

CONCLUSION

Missense variants in cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.