Delineating the Cognitive Profile of ODLURO Syndrome: Emergent Clues on the Endophenotype Across KMT2 Disorders

O'Donnell-Luria-Rodan syndrome (ODLURO) is a very rare disorder caused by heterozygous pathogenic variants in KMT2E. While intellectual disability is associated with this syndrome based on retrospective chart review, the neurocognitive phenotype remains unexplored. This case series provides insight into the cognitive profile of ODLURO and discusses these trends in the context of other better-characterized disorders in the KMT2 families. This study involved a retrospective chart review of psychological or neuropsychological assessment reports from 10 patients with a likely pathogenic or pathogenic variant in KMT2E. The majority of participants scored within normal limits in verbal abstract reasoning and expressive vocabulary. In contrast, most participants performed below average to very low ranges in non-verbal abstract reasoning, working memory, sight word reading, and math computation skills. Wilcoxon paired tests showed verbal reasoning was stronger than non-verbal reasoning skills (p = 0.04). Over half of respondents rated their children in the at-risk to clinically significant range for attention problems and hyperactivity. Our cohort of patients with ODLURO presented with greater difficulties in non-verbal reasoning, attention, working memory, sight word reasoning, and math computation skills, juxtaposed with relative strengths in verbal skills. Our resulting trends show some similarities to cognitive profiles of Wiedemann-Steiner syndrome and Kabuki syndrome type 1, disorders caused by variants in KMT2A and KMT2D, respectively. Emergent findings suggest possible endophenotypes related to haploinsufficiency of the histone methyltransferases in the KMT2 group.