KYNU was first reported in relation to autosomal recessive vertebral, cardiac, renal, and limb defects syndrome 2 in 2017 (Shi H, et al., 2017, PMID: 28792876) but was previously identified with hydroxykynureninuria in 2007 (Christensen M, et al., 2007, PMID: 17334708). Congenital defects found in VCRL2 include segmentation defects, cardiac defects such as hypoplastic heart, hypoplastic kidneys, missing kidneys, clinodactyly, radial deviation, and polydactyly. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 14 unique variants (e.g. missense, nonsense, frameshift, splicing, and large deletion) have been reported in 11 probands from 5 publications (PMIDs: 28792876, 33942433, 31923704, 17334708, 34200361). Variants in this gene segregated with disease in 1 additional family member. The gene KYNU encodes Kynureninase, one of the enzymes responsible for the biosynthesis of NAD from Trpytophan. This gene-disease association is further supported by its biochemical function in the kynurenine pathway (PMID: 8706755) and a knockout mouse model (PMID: 28792876) which recapitulates the phenotype on a NAD-restricted diet. In summary, KYNU is definitively associated with autosomal recessive vertebral, cardiac, renal, and limb defects syndrome 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This gene-disease pair was originally evaluated by the Aminoacidopathy GCEP on 07/10/2020. It was reevaluated on 08/01/2022. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of 5 new cases (PMIDs: 33942433 and 34200361).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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