Vertebral, Cardiac, Renal, And Limb Defects Syndrome 2

A number sign (#) is used with this entry because of evidence that vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2) is caused by homozygous or compound heterozygous mutation in the KYNU gene (605197) on chromosome 2q22.

Description

VCRL2 is an autosomal recessive congenital malformation syndrome characterized by vertebral segmentation abnormalities, congenital cardiac defects, renal, and distal mild limb defects. Additional features are variable (summary by Shi et al., 2017).

For a discussion of genetic heterogeneity of VCRL, see VCRL1 (617660).

Clinical Features

Shi et al. (2017) reported 2 unrelated female patients, one born of consanguineous parents of Lebanese descent (family C) and the other born of unrelated parents from the United States (family D), with VCRL2. Both patients had segmentation defects predominantly affecting the thoracolumbar spine. Both had cardiac defects: patent ductus arteriosus in one patient and hypoplastic left heart in the other. Patient C had microcephaly, low-set ears, hypoplastic kidneys, rhizomelia, talipes, syndactyly, and anterior anus. She died at age 4 months of restrictive respiratory disease due to spondylocostal defects. Patient D had a narrow chest, solitary left kidney with chronic renal disease, short statue, and speech delay. Family history revealed that patient C was 1 of 13 pregnancies, 8 of which were lost in the first trimester. The birth of patient D was preceded by 2 first-trimester losses.

Inheritance

The transmission pattern of VCRL2 in the families reported by Shi et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated patients with VCRL2, Shi et al. (2017) identified homozygous truncating mutations in the KYNU gene (605197.0003-605197.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies showed that the mutations essentially abolished KYNU enzymatic activity. Analysis of plasma from patient D showed increased levels of the upstream metabolite 3HK and decreased levels of the downstream metabolites NAD and NAH(H). Studies in mice, which have different niacin levels compared to humans, indicated that the congenital malformations found in humans resulted from deficient NAD levels rather than increased 3HAA. Shi et al. (2017) noted that NAD is a cofactor with broad cellular effects, including ATP production, macromolecular biosynthesis, redox reactions, energy metabolism, DNA repair, and modulation of transcription factors, all of which play an important role in embryogenesis. Shi et al. (2017) theorized that niacin supplementation could be of benefit in such patients.

Animal Model

Shi et al. (2017) found that Kynu-null mice were viable and normal. Plasma analysis showed increased 3HK levels, but normal NAD levels. The authors noted that mice have increased niacin levels compared to humans and that mouse embryos may receive niacin from their mothers, resulting in a buffering effect on genetic-based NAD deficiency. These findings suggested that the congenital malformations found in humans with increased 3HK levels and decreased levels of NAD resulted from the deficient NAD levels. Indeed, further studies in mutant mice born to mothers on a niacin-free diet showed that NAD deficiency due to lack of Kynu resulted in multiple defects, including defects in vertebral segmentation, heart defects, small kidney, cleft palate, talipes, syndactyly, and caudal agenesis. Supplementation of Kynu-null mouse embryos with niacin during gestation restored NAD levels and prevented the disruption of embryogenesis.