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

Isabel Schüle,Sarah C Grünert,Miriam Schmidts,Martin Pohl,Uta Matysiak,Brigitte Stiller,Urs Berger,Ute Spiekerkoetter,Ekkehart Lausch,Gunda Ruzaike

doi:10.3390/genes12060879

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.

Highlights

Vertebral, Cardiac, Renal and Limb Defect Syndrome (VCRL) is a rare autosomalrecessively inherited condition associated with cardiac malformations, including hypoplastic left heart syndrome, short stature, dysmorphic facial features such as microcephaly, low set ears and a flat nasal bridge, skeletal malformations as vertebral segmentation defects, rhizomelic shortening of the limbs, finger hyperphalangism and kidney malformations
The authors described pathogenic variants in the KYNU and HAAO gene to be causative for this malformation syndrome (VCRL1, OMIM # 617660 and VCRL2, OMIM # 617661)
All three enzymes play a role in the biosynthesis of nicotinamide adenine dinucleotide (NAD+) cofactors from tryptophan and pathogenic mutations in HAAO as well as KYNU were found to cause reduced NAD+ levels in affected individuals, potentially resulting in the distinct malformations observed in VCRL [1], the precise underlying pathomechanism has remained elusive

Summary

Introduction

Cardiac, Renal and Limb Defect Syndrome (VCRL) is a rare autosomalrecessively inherited condition associated with cardiac malformations, including hypoplastic left heart syndrome, short stature, dysmorphic facial features such as microcephaly, low set ears and a flat nasal bridge, skeletal malformations as vertebral segmentation defects, rhizomelic shortening of the limbs, finger hyperphalangism and kidney malformations. The authors described pathogenic variants in the KYNU and HAAO gene to be causative for this malformation syndrome (VCRL1, OMIM # 617660 and VCRL2, OMIM # 617661). All three enzymes play a role in the biosynthesis of nicotinamide adenine dinucleotide (NAD+) cofactors from tryptophan and pathogenic mutations in HAAO as well as KYNU were found to cause reduced NAD+ levels in affected individuals, potentially resulting in the distinct malformations observed in VCRL [1], the precise underlying pathomechanism has remained elusive. All but two cases were found to suffer from congenital heart defects (two cases could not be assessed due to termination of pregnancy), including 5 individuals with hypoplastic left heart syndrome (HLHS) [1,2,3]

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