Righetti Sarah, Allcock Richard J N, Yaplito-Lee Joy, Adams Louisa, Ellaway Carolyn, Jones Kristi J, Selvanathan Arthavan, Fletcher Janice, Pitt James, van Kuilenburg André B P, Delatycki Martin B, Laing Nigel G, Kirk Edwin P
University of New South Wales, Sydney, NSW, Australia.
PathWest Laboratory Medicine, Perth, WA, Australia.
Mol Genet Metab. 2022 Sep-Oct;137(1-2):62-67. doi: 10.1016/j.ymgme.2022.07.011. Epub 2022 Jul 25.
Beta-ureidopropionase deficiency, caused by variants in UPB1, has been reported in association with various neurodevelopmental phenotypes including intellectual disability, seizures and autism.
We aimed to reassess the relationship between variants in UPB1 and a clinical phenotype.
Literature review, calculation of carrier frequencies from population databases, long-term follow-up of a previously published case and reporting of additional cases.
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.
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.
The relationship between beta-ureidopropionase deficiency due to UPB1 variants and clinical phenotypes is uncertain.
由UPB1基因变异引起的β-脲基丙酸酶缺乏症已被报道与多种神经发育表型相关，包括智力残疾、癫痫和自闭症。
我们旨在重新评估UPB1基因变异与临床表型之间的关系。
文献综述、从人群数据库计算携带者频率、对先前发表的病例进行长期随访以及报告其他病例。
共识别出53例已发表的病例，本文还报告了另外2例。其中，14例无症状，4例有短暂的神经学特征；其余病例的临床特征各不相同，包括非神经学表现。一些先前被报道为致病的变异在人群数据库中的频率高于罕见病的预期频率。特别是，最常被报道为致病的变异p.Arg326Gln在东亚人群中非常常见，在gnomAD v2.1.1中，该变异的携带者频率为1/19，纯合子频率为1/907。
在获得进一步证据之前，应将UPB1视为“临床意义不确定的基因”。对于神经发育表型患者，在将β-脲基丙酸酶缺乏症的生化特征和/或UPB1基因变异赋予临床意义时应谨慎。目前，UPB1不适合纳入生殖遗传携带者筛查的基因检测板。
由UPB1基因变异引起的β-脲基丙酸酶缺乏症与临床表型之间的关系尚不确定。
