Molecular and Clinical Insights into KMT2E-Related O'Donnell-Luria-Rodan Syndrome in a Novel Patient Cohort

• Published in: European journal of medical genetics 2024-12, p.104990
• Main Authors: Vecchio, Davide, Panfili, Filippo M, Macchiaiolo, Marina, Dentici, Maria Lisa, Trivisano, Marina, Benitez Medina, Carolina, Capolino, Rossella, Salzano, Emanuela, Cortellessa, Fabiana, Busè, Martina, Pantaleo, Antonio, Cocciadiferro, Dario, Gonfiantini, Michaela V, Niceta, Marcello, De Dominicis, Angela, Specchio, Nicola, Piccione, Maria, Digilio, Maria Cristina, Tartaglia, Marco, Novelli, Antonio, Bartuli, Andrea
• Format: Article
• Language: English
• ISSN: 1878-0849; 1878-0849
• DOI: 10.1016/j.ejmg.2024.104990

O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant neurodevelopmental disorder mainly characterized by global development delay/intellectual disability, white matter abnormalities, and behavioral manifestations. It is caused by pathogenic variants in the KMT2E gene. Here we report seven new patients with loss-of-function KMT2E variants, six harboring frameshift/nonsense changes, and one with a 7q22.3 microdeletion encompassing the entire gene-locus. We further characterize both the clinical phenotype as well as its associated pathogenic variants' spectrum providing new information on sex-related phenotype distribution, according to the variant groups. We also highlight different epilepsy phenotype-genotype correlation with preferential association of generalized epilepsy and/or developmental and epileptic encephalopathy with missense pathogenic variants and focal epilepsy, childhood absence epilepsy and/or febrile seizures with pathogenic truncating variants and structural rearrangements. By a systematic review of the previously reported series, we also discuss previously unappreciated findings, including progressive macrocephaly, apraxia, and higher risk of bone fractures.O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant neurodevelopmental disorder mainly characterized by global development delay/intellectual disability, white matter abnormalities, and behavioral manifestations. It is caused by pathogenic variants in the KMT2E gene. Here we report seven new patients with loss-of-function KMT2E variants, six harboring frameshift/nonsense changes, and one with a 7q22.3 microdeletion encompassing the entire gene-locus. We further characterize both the clinical phenotype as well as its associated pathogenic variants' spectrum providing new information on sex-related phenotype distribution, according to the variant groups. We also highlight different epilepsy phenotype-genotype correlation with preferential association of generalized epilepsy and/or developmental and epileptic encephalopathy with missense pathogenic variants and focal epilepsy, childhood absence epilepsy and/or febrile seizures with pathogenic truncating variants and structural rearrangements. By a systematic review of the previously reported series, we also discuss previously unappreciated findings, including progressive macrocephaly, apraxia, and higher risk of bone fractures.