A number sign (#) is used with this entry because of evidence that vertebral, cardiac, renal, and limb defects syndrome-1 (VCRL1) is caused by homozygous or compound heterozygous mutation in the HAAO gene (604521) on chromosome 2p21.

Vertebral, cardiac, renal, and limb defects syndrome-1 (VCRL1) is an autosomal recessive congenital malformation syndrome characterized by vertebral segmentation abnormalities, congenital cardiac defects, renal defects, and mild distal limb defects. Additional features are variable (summary by Shi et al., 2017).

Genetic Heterogeneity of Vertebral, Cardiac, Renal, and Limb Defects Syndrome

See also VCRL2 (617661), caused by mutation in the KYNU gene (605197) on chromosome 2q22, and VCRL3 (618845), caused by mutation in the NADSYN1 gene (608285) on chromosome 11q13.

Shi et al. (2017) reported 2 unrelated patients, each born of consanguineous parents of Iraqi (family A) and Lebanese (family B) descent, respectively, with VCRL1. Both patients had vertebral segmentation defects predominantly affecting the thoracolumbar spine and spinal lipoma; patient A had sacral agenesis and patient B had spinal dysraphism. Both had cardiac defects: atrial septal defect in patient A and hypoplastic left heart with mitral and aortic stenosis in patient B. Patient A had a cleft palate, bifid uvula, and laryngeal web with persistent tracheomalacia, and patient B had a left vocal cord palsy that was possibly iatrogenic with no other laryngeal defects. Additional features found in both patients included microcephaly, hypoplastic kidneys, and sensorineural hearing loss. Patient A had short stature, talipes, delayed development, moderate intellectual disability and behavioral issues at age 12 years, whereas patient B died at age 11 months from complications of hypoplastic left heart.

Szot et al. (2021) reported 3 unrelated patients with congenital heart defects, including tetralogy of Fallot, Shone syndrome with aortic coarctation, and hypoplastic left heart. Two of the patients had limb defects, including abnormal digits of the hands and feet and shortened limbs. Two patients had hemivertebrae, 1 patient had scoliosis, and 1 patient had 11 pairs of ribs. One patient (family 3) had an absent left kidney and multicystic right kidney and intrauterine growth retardation in addition to cardiac and skeletal abnormalities; due to the phenotypic severity observed in this patient, this pregnancy was terminated.

The transmission pattern of VCRL1 in the families reported by Shi et al. (2017) was consistent with autosomal recessive inheritance.

In 2 unrelated patients, each born of consanguineous parents, with VCRL1, Shi et al. (2017) identified homozygous truncating mutations in the HAAO gene (604521.0001 and 604521.0002). The mutations, which were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies showed that both mutations essentially abolished HAAO enzymatic activity. Analysis of patient plasma showed increased levels of the upstream metabolite 3HAA and decreased levels of the downstream metabolites NAD and NAH(H). Both patients belonged to a pair of dizygotic twins; their twins were unaffected and heterozygous for the mutation. 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.

In 3 unrelated patients with VCRL1, Szot et al. (2021) identified compound heterozygous or homozygous mutations in the HAAO gene (604521.0003-604521.0007). Yeast with a homozygous knockout for bna1, the ortholog of human HAAO, were transformed with plasmids containing HAAO with each mutation or with wildtype HAAO. Each mutant HAAO resulted in smaller yeast mass compared to wildtype when grown in niacin-free culture media. NAD levels were also reduced in yeast transformed with the mutant HAAO plasmids compared to wildtype. Szot et al. (2021) concluded that the compromised growth of the bna1 knockout yeast transfected with each mutant HAAO was a result of abnormal HAAO enzyme activity.

Shi et al. (2017) found that Haao-null mice were viable and normal. Plasma analysis showed increased 3HAA 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 levels of 3HAA but 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 Haao resulted in multiple defects, including defects in vertebral segmentation, heart defects, small kidney, cleft palate, talipes, syndactyly, and caudal agenesis. Supplementation of Haao-null mouse embryos with niacin during gestation restored NAD levels and prevented the disruption of embryogenesis.