Further characterization of the BRSK2-associated neurodevelopmental disorder.

Heterozygous variants in BRSK2, encoding brain-specific kinase 2; partial loss of function for most kinase domain missense variants tested in Drosophila, with possible gain of function for three variants.

The authors assembled 52 cases with heterozygous BRSK2 variants and variable neurodevelopmental phenotypes, with frequent neuropsychiatric and behavioural symptoms. The spectrum included 15 different truncating variants, seven (potential) splice variants, three structural variants and 12 missense variants, seven of them in the kinase domain; variants were de novo in 19 cases and inherited in 18. In Drosophila, pan-neuronal knockdown of the orthologue sff impaired locomotor behaviour and caused seizure susceptibility, while overexpression of wild-type human BRSK2 was toxic (lethality or locomotor impairment). Six of seven kinase domain missense variants and one KA1 domain variant did not or only incompletely affected viability and locomotion, supporting an at least partial loss-of-function effect, whereas three other missense variants suggested possible gain of function.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Fifty-two cases and a systematic functional assay in Drosophila: this is the kind of paper that makes a recently described gene genuinely interpretable during exome analysis. The most useful element for a laboratory is the differentiated reading of kinase domain missense variants, with a gain-of-function signal for the most C-terminal ones — a functional argument usable in ACMG classification. One notable caveat: 18 inherited cases versus 19 de novo, suggesting incomplete penetrance or highly variable expressivity, which calls for caution in family counselling.

Analysis by Dr Thibaut Benquey