A number sign (#) is used with this entry because of evidence that O'Donnell-Luria-Rodan syndrome (ODLURO) is caused by heterozygous mutation in the KMT2E gene (608444) on chromosome 7q22.

O'Donnell-Luria-Rodan syndrome (ODLURO) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, variably delayed intellectual development, and subtle dysmorphic features. Some patients may have autism, seizures, hypotonia, and/or feeding difficulties (summary by O'Donnell-Luria et al., 2019).

O'Donnell-Luria et al. (2019) reported 30 individuals, most of whom were in the first decade of life, with a similar neurodevelopmental disorder associated with heterozygous protein-truncating variants in the KMT2E gene. A few of the patients had previously been reported in larger studies. Available history of all patients indicated global developmental delay from infancy, with the average age of walking and first word at 20 months (range 12 to 48 months). Many had hypotonia, but all could walk independently, and most were verbal, although several had speech difficulties. IQ data available for 7 patients showed a mean of 74 (range, 62-98). Seven patients were diagnosed with autism, and several others had attention-deficit/hyperactivity disorder (ADHD) or other behavioral concerns, such as stereotypies, skin-picking behavior, self-injurious behavior, aggression, and/or anxiety. About half had mild macrocephaly, although other growth parameters were normal. One patient had neonatal ischemic encephalopathy associated with seizures, but otherwise, only 4 patients had epilepsy, most of which was controlled. Brain imaging was normal or showed nonspecific findings, such as abnormal corpus callosum, signal abnormalities in the white matter, decreased volume, delayed myelination, small areas of heterotopia, or small localized cysts. Many patients had gastrointestinal symptoms, including reflux, vomiting, or bowel motility issues. Most patients had subtle dysmorphic features, including dolichocephaly, large forehead, deep-set eyes, downslanting palpebral fissures, periorbital fullness, prominent cheeks, and prominent nasolabial folds. Rare features included cardiac septal defects, neonatal jaundice, kyphosis, tapering fingers, and cryptorchidism. There were 4 additional patients with heterozygous missense mutations, which was associated with a more severe phenotype. All of these patients had epilepsy, including 3 with infantile epileptic encephalopathy, and all had more severe global developmental delay compared to patients with truncating mutations. All 4 were nonverbal, 2 had microcephaly, and only 2 could walk. Four additional patients with a similar phenotype had larger heterozygous deletions of chromosome 7q22 that encompassed the KMT2E gene. O'Donnell-Luria et al. (2019) noted that most (70%) of the patients were male, and expressivity was variable by sex: affected females tended to have epilepsy, whereas affected males tended to have autism.

Velmans et al. (2022) reported 18 new patients from 17 families with O'Donnell-Luria-Rodan syndrome and summarized the phenotypic findings in these patients along with those previously reported by O'Donnell-Luria et al. (2019), for a total of 52 patients. Most patients (73%) were male. Commonly observed findings included macrocephaly (55%), motor delay (69%), speech delay (83%), mildly to moderately impaired intellectual development (72%), autism spectrum disorder (31%), muscular hypotonia (51%), and epilepsy (15%). Findings on brain imaging included corpus callosum hypoplasia, ventriculomegaly, cerebral cysts, and delayed myelination. In the cohort of 18 patients, sleep disturbances were noted in 8 of 17 (47%).

O'Donnell-Luria et al. (2019) reported autosomal dominant inheritance of ODLURO. Most of the mutations occurred de novo.

In 34 individuals with ODLURO, O'Donnell-Luria et al. (2019) identified heterozygous mutations in the KMT2E gene (see, e.g., 608444.0001-608044.0006). The patients were ascertained through collaboration of several research centers, and the mutations were found by exome or genome sequencing. Most of the mutations resulted in a truncated protein, consistent with haploinsufficiency, although 4 patients carried missense mutations that affected highly conserved residues. The vast majority of the mutations occurred de novo, although there was 1 family with 3 affected sibs who may have inherited the variant from an affected father; DNA from the father was not available. Functional studies of the variants and studies of patient cells were not performed, but the authors postulated haploinsufficiency for KMT2E as the pathogenic mechanism for the protein-truncating mutations, and altered KMT2E binding properties for the missense mutations.

In 18 patients from 17 families with ODLURO, Velmans et al. (2022) identified heterozygous mutations in the KMT2E gene, including 4 nonsense mutations, 7 frameshift mutations, 2 single nucleotide substitutions involving the canonical splice site, 1 multinucleotide deletion spanning the canonical splice site, and 1 apparent synonymous mutation that was predicted to create a novel splice donor site (608444.0007). Two patients had microdeletions (a 711-kb deletion encompassing approximately 98% of the coding sequence, and a 61-kb deletion encompassing approximately 75% of the coding sequence). Of all 17 mutations, 13 were confirmed to be de novo, 2 were proven not to be inherited from the mother but the fathers were unable to be tested, and 2 were inherited from fathers. Only one of the variants (608444.0008) had previously been reported.