Identifying the Potential Role of Missense KIRREL3 Variants in Neurodevelopmental Phenotypes: A Case Series.

Rare missense variants in KIRREL3, a gene expressed in the developing human basal ganglia and amygdala, predicted damaging on the basis of REVEL score.

KIRREL3, expressed in the developing human basal ganglia and amygdala, has previously been associated with neurodevelopmental disorders. Through GeneMatcher and the Simons Foundation Powering Autism Research (SPARK) project, the authors assembled 26 individuals carrying different rare missense KIRREL3 variants predicted damaging based on their REVEL score. All probands had a neurodevelopmental diagnosis: autism spectrum disorder, global developmental delay, intellectual disability, or a learning disability. A full review of previous publications additionally identified 10 rare missense KIRREL3 variants in 13 individuals with at least one diagnosis of autism spectrum disorder or intellectual disability. The authors conclude that missense KIRREL3 variants may play a role in neurodevelopmental disorders, warranting further study.

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

Genotype-driven matchmaking recruitment is a limitation to keep in mind when writing a report: assembling 26 carriers who are all affected does not establish association, since the recruitment route only surfaces phenotyped cases. Without comparison to a control population, family segregation or functional evidence, a KIRREL3 missense variant predicted damaging by REVEL remains a variant of uncertain significance, and an in silico score alone cannot shift ACMG classification. The practical value of this series is to provide a phenotype-matching resource for isolated cases, not to settle the diagnostic discussion.

Analysis by Dr Thibaut Benquey