Alternative titles; symbols
ORPHA: 521438;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q13.4 | Vertebral, cardiac, renal, and limb defects syndrome 3 | 618845 | Autosomal recessive | 3 | NADSYN1 | 608285 |
A number sign (#) is used with this entry because of evidence that vertebral, cardiac, renal, and limb defects syndrome-3 (VCRL3) is caused by homozygous or compound heterozygous mutation in the NADSYN1 gene (608285) on chromosome 11q13.
Vertebral, cardiac, renal, and limb defects syndrome-3 (VCRL3) is an autosomal recessive disorder characterized by severe cardiac and renal anomalies that are lethal in infancy, including hypoplastic or absent left ventricle, transposition of the great arteries, absent pulmonary trunk, and hypoplastic or absent kidneys. Patients also exhibit vertebral segmentation defects and shortening of the proximal long bones or micromelia (Szot et al., 2020).
For a discussion of genetic heterogeneity of VCRL, see VCRL1 (617660).
Szot et al. (2020) studied 5 patients from 4 unrelated families with multiple overlapping congenital anomalies and biallelic mutations in the NADSYN1 gene. All 5 individuals exhibited renal abnormalities, ranging from a mild hyperechoic renal cortex to the complete absence of both kidneys. Limb involvement, including short proximal long bones or micromelia, was observed in 4 patients. Cardiac and vertebral abnormalities were present in 3 patients. Vertebral defects included scoliosis with multiple malformed vertebrae and ribs, and segmentation defects of the thoracic, lumbar, and sacral spine. The heart was either hypoplastic due to underdevelopment of the left ventricle or compromised by malformation of the aorta and pulmonary artery. Various other abnormalities were also noted, including sacral dimples in 2 patients, and dysmorphic facial features, pulmonary hypoplasia, echogenic bowel, and polysplenia in 1 patient. Of the 5 pregnancies, 2 were terminated at 16 weeks of gestation and 1 at 23 weeks due to the severity of their phenotypes, and the other 2 patients died within 3 months of birth.
The transmission pattern of VCRL3 in the families studied by Szot et al. (2020) was consistent with autosomal recessive inheritance.
In 2 sibs (family 1) with vertebral, cardiac, renal, and limb abnormalities, Szot et al. (2020) performed whole-exome sequencing and identified homozygosity for a missense mutation in the NADSYN1 gene (A573T; 608285.0001), for which their unaffected parents were heterozygous. Using GeneMatcher, 3 more similarly affected probands were identified with mutations in NADSYN1 (see, e.g., 608285.0002-608285.0004).
Szot, J. O., Campagnolo, C., Cao, Y., Iyer, K. B., Cuny, H., Drysdale, T., Flores-Daboub, J. A., Bi, W., Westerfield, L., Liu, P., Leung, T. N., Choy, K. W., Chapman, G., Xiao, R., Siu, V. M., Dunwoodie, S. L. Bi-allelic mutations in NADSYN1 cause multiple organ defects and expand the genotypic spectrum of congenital NAD deficiency disorders. Am. J. Hum. Genet. 106: 129-136, 2020. [PubMed: 31883644] [Full Text: https://doi.org/10.1016/j.ajhg.2019.12.006]