A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL Syndrome

Abstract

Vertebral, Cardiac, Renal and Limb Defect Syndrome (VCRL), is a very rare congenital malformation syndrome. Pathogenic variants in HAAO (3-Hydroxyanthranilate 3,4-dioxygenase), NADSYN1 (NAD+ Synthetase-1) and KYNU (Kynureninase) have been identified in a handful of affected individuals. All three genes encode for enzymes essential for the NAD+ de novo synthesis pathway. Using Trio-Exome analysis and CGH array analysis in combination with long range PCR, we have identified a novel homozygous copy number variant (CNV) encompassing exon 5 of KYNU in an individual presenting with overlapping features of VCRL and Catel–Manzke Syndrome. Interestingly, only the mother, not the father carried the small deletion in a heterozygous state. High-resolution SNP array analysis subsequently delineated a maternal isodisomy of chromosome 2 (UPD2). Increased xanthurenic acid excretion in the urine confirmed the genetic diagnosis. Our findings confirm the clinical, genetic and metabolic phenotype of VCRL1, adding a novel functionally tested disease allele. We also describe the first patient with NAD+ deficiency disorder resulting from a UPD. Furthermore, we provide a comprehensive review of the current literature covering the genetic basis and pathomechanisms for VCRL and Catel–Manzke Syndrome, including possible phenotype/genotype correlations as well as genetic causes of hypoplastic left heart syndrome.

NAD+ deficiency in human congenital malformations and miscarriage: A new model of pleiotropy

“…In 2017, the first four patients with confirmed biallelic variants in the NAD+ de novo synthesis pathway were reported (Shi et al, 2017). Since that time, an additional 18 reported or known individuals with biallelic variants in HAAO , KYNU , or NADSYN1 have been described (Szot et al, 2020; Ehmke et al, 2020; L. Bird, personal communication, September 14, 2021; Schüle et al, 2021; Szot et al, 2021). Initially these patients were labeled as having Vertebral, Cardiac, Renal and Limb Defects (VCRL) syndrome, because of the phenotypic frequency of these four malformations (OMIM 617660, 617661).…”

“…Since that time, an additional 18 reported or known individuals with biallelic variants in HAAO, KYNU, or NADSYN1 have been described (Szot et al, 2020;Ehmke et al, 2020;L. Bird, personal communication, September 14, 2021;Schüle et al, 2021;Szot et al, 2021). Initially these patients were (Szot et al, 2020).…”

“… Note : Adapted from Shi et al (2017), Szot et al (2020), Ehmke et al (2020), Schüle et al (2021), Szot et al (2021), and L. Bird, personal communication, September 14, (2021). …”

Viewing teratogens through the lens of nicotinamide adenine dinucleotide (NAD+)

“…To date, there have been 24 patients described with biallelic variants in NAD+ Synthesis pathway genes, specifically HAAO, KYNU, and NADSYN1 (Shi et al, 2017;Szot et al, 2020;Ehmke et al, 2020;Schüle et al, 2021;Szot et al, 2021;L. Bird, personal communication, September 14, 2021, Kortbawi et al, 2022.…”

“…T A B L E 1Note: (Not all organ systems were evaluated for potential anomalies), and anomalies seen in affected patients with known biallelic variants in HAAO, KYNU, and NADSYN1 b a Adapted fromCuny et al, 2020. b Adapted fromShi et al, 2017, Szot et al, 2020, Ehmke et al, 2020, Schüle et al, 2021, Szot et al, 2021, L. Bird, personal communication, September 14, 2021 …”