The relationship between beta-ureidopropionase deficiency due to UPB1 variants and human phenotypes is uncertain.

Background: Beta-ureidopropionase deficiency, caused by variants in UPB1, has been reported in association with various neurodevelopmental phenotypes including intellectual disability, seizures and autism.

Aim: We aimed to reassess the relationship between variants in UPB1 and a clinical phenotype.

Methods: Literature review, calculation of carrier frequencies from population databases, long-term follow-up of a previously published case and reporting of additional cases.

Results: Fifty-three published cases were identified, and two additional cases are reported here. Of these, 14 were asymptomatic and four had transient neurological features; clinical features in the remainder were variable and included non-neurological presentations. Several of the variants previously reported as pathogenic are present in population databases at frequencies higher than expected for a rare condition. In particular, the variant most frequently reported as pathogenic, p.Arg326Gln, is very common among East Asians, with a carrier frequency of 1 in 19 and 1 in 907 being homozygous for the variant in gnomAD v2.1.1.

Conclusion: Pending the availability of further evidence, UPB1 should be considered a 'gene of uncertain clinical significance'. Caution should be used in ascribing clinical significance to biochemical features of beta-ureidopropionase deficiency and/or UPB1 variants in patients with neurodevelopmental phenotypes. UPB1 is not currently suitable for inclusion in gene panels for reproductive genetic carrier screening.

Synopsis: The relationship between beta-ureidopropionase deficiency due to UPB1 variants and clinical phenotypes is uncertain.