O'donnell-Luria-Rodan Syndrome

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.

Description

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).

Clinical Features

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 other 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.

Molecular Genetics

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.