Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features

Abstract

The ornithine decarboxylase 1 (ODC1) gene plays an important role in physiological and cell developmental processes including embryogenesis, organogenesis, and neoplastic cell growth. Here, we report an 32‐month‐old Caucasian female with a heterozygous de novo nonsense mutation in the ODC1 gene that leads to a premature abrogation of 14‐aa residues at the ODC protein c‐terminus. This is the first human case confirming similar symptoms observed in a transgenic ODC1 mouse model first described over 20 years ago. Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss. We here describe for the first time a new pediatric disorder that is directly linked to a de novo pathogenic variant in the ODC1 gene. The ODC1 gene mutation (c.1342 A>T) was identified by whole‐exome sequencing and confirmed by Sanger sequencing. Red blood cells obtained from our patient showed elevated ODC protein and polyamine levels compared to healthy controls. Our autosomal dominant patient who carries this gain‐of‐function ODC1 mutation may benefit from treatment with α‐difluoromethylornithine, a well‐tolerated, U.S. Food and Drug Administration (FDA). FDA‐approved drug.

The human phenotype of ornithine decarboxylase superactivity: A new syndrome

“…The first rate‐limiting step in the de novo synthesis of polyamines involves the conversion of ornithine to putrescine via ornithine decarboxylase (ODC), encoded by ODC1 (see Figure ). In the December 2019 issue of the American Journal of Medical Genetics part A, Bupp, Schultz, Uhl, Rajasekaran, and Bachmann () report the first patient with ODC superactivity. Subsequently, Rodan et al () described four additional patients with…”

“…Bupp et al () described elevation of putrescine in red blood cells, while Rodan et al () reported elevation of N‐acetylputrescine in plasma from one patient. The latter is reminiscent of what has been reported in Snyder‐Robinson syndrome, where the accumulated substrate undergoes N‐acetylation, and the elevated N‐acetylated product (N8‐acetylspermidine) can be identified via plasma metabolomics (Abela et al, ).…”

Gain‐of‐function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities

“…All of the patients in our series have very closely located truncating variants in the final exon of the ODC1 gene, proximal to the C‐terminal 37‐amino acid destabilization region of the protein. As such, these variants are predicted to lead to a mutant protein that both escapes nonsense‐mediated decay (NMD) and has reduced degradation compared to wild‐type, resulting in a net gain‐of‐function of ODC1 enzyme activity, as has been recently demonstrated (Bupp et al, ). In addition, the very close proximity of the reported variants suggests that this region may be a hotspot for DNA rearrangement.…”

“…For its degradation, the ODC1 monomer noncovalently binds with an ODC antizyme protein, inactivating it and directing it for ubiquitin‐independent degradation by the proteasome. The ODC antizyme binds to a C‐terminal 37‐amino acid destabilization region of the protein (Bupp et al, ; Moinard et al, ; Nowotarski, Woster, & Casero, ).…”

“…Ornithine decarboxylase 1 (ODC1) is the rate‐limiting enzyme in endogenous polyamine synthesis and converts the amino acid l ‐ornithine to putrescine (Moinard et al, ). A single case of an individual with a de novo variant in the ODC1 gene causing a gain‐of‐function was recently described in the American Journal of Medical Genetics A (Bupp, Schultz, Uhl, Rajasekaran, & Bachmann, ). Here we report an additional four patients with de novo variants in the ODC1 gene that further delineate the clinical and biochemical phenotype of an ODC1 gene‐related disorder associated with neurodevelopmental abnormalities, macrocephaly, facial dysmorphisms, ectodermal abnormalities, and neuroimaging findings.…”