O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum

Abstract

Background: O'Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O'Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility.

Methods: Affected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible.

Results: We report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances.

Conclusion: Our study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.

Keywords: behavioural; genetic counselling; genetics; human genetics; mutation.

Figure 1

(A) Localisation of KMT2E variants reported in this study at the protein level. Exon regions are depicted with alternating grey shading, the first coding exon in NM_182931.2 is exon 3. Frameshifting variants are written in red, nonsense variants in blue and (putative) splice variants in green. The c.65del (p.(Gly22Valfs*7)) variant represents the earliest truncating variant in KMT2E published to date. PHD, PHD zinc finger domain; SET, SET domain; †, variants predicted to escape nonsense-mediated decay. (B) Genomic locations of the CNVs reported in individuals 17 and 18.

Figure 2

Facial photographs of two patients reported in this study: (A) patient 17 frontal; (B) patient 17 profile; (C) patient 8 frontal.