The pathogenic variant of WBP11 has been known as one of the various genetic causes of VACTERL syndrome. VACTERL syndrome is usually diagnosed with at least three clinical features of vertebral, heart, tracheal, esophageal, kidney, and limb anomalies. So far, only four WBP11 pathogenic variants have been documented from 13 patients, first and latest described in 2020. In this clinical report, we present a patient with an isolated vertebral anomaly and Sprengel's deformity, carrying a pathogenic variant of WBP11, representing a distinctive case of patient that has never been described before. An eight-month-old boy with a 5°-10° head tilt to the right was referred to our institution and the cervical X-ray imaging showed the vertebral anomaly. Three-dimensional (3D) volume-rendered computed tomography (CT) of the cervical spine revealed the fusion state of the right C2 and C3 facet joints. And the right shoulder appeared to be raised and right scapula elevation was identified in the 3D chest CT. In addition, whole genome sequencing presented a de novo novel WBP11 heterozygous pathogenic variant, with frameshift resulting in a loss of function. WBP11 is a cell cycle-related pleiotropic gene that encodes a pre-messenger RNA splicing factor involved in centriole duplication. Pathogenic variants in WBP11 are genetically implicated in the development of multiple congenital anomalies. Clinically, WBP11 has been previously associated with VACTERL syndrome. In this report, we document clinical manifestations, including vertebral anomalies and Sprengel's deformity. The findings presented in this report indicate that haploinsufficiency of WBP11, resulting from a heterozygous pathogenic variant, may give rise to a more diverse array of clinical phenotypes than previously documented.

The mechanism underlying anorectal malformations (ARMs)-related VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, and renal and limb abnormalities) remains unclear. Copy number variation (CNV) contributed to VACTERL pathogenicity. Here, we report a novel CNV in 8p23 and 12q23.1 identified in a case of ARMs-related VACTERL association. This 12-year-old girl presented a cloaca (urethra, vagina, and rectum opening together and sharing a single tube length), an isolated kidney, and a perpetuation of the left superior vena cava at birth. Her intelligence, growth, and development were slightly lower than those of normal children of the same age. Array comparative genomic hybridization revealed a 9.6-Mb deletion in 8p23.1-23.3 and a 0.52-Mb duplication in 12q23.1 in her genome. Furthermore, we reviewed the cases involving CNVs in patients with VACTERL, 8p23 deletion, and 12q23.1 duplication, and our case was the first displaying ARMs-related VACTERL association with CNV in 8p23 and 12q23.1. These findings enriched our understanding between VACTERL association and the mutations of 8p23 deletion and 12q23.1 duplication. IMPACT: This is a novel case of a Chinese girl with anorectal malformations (ARMs)-related VACTERL with an 8p23.1-23.3 deletion and 12q23.1 duplication. Cloaca malformation is presented with novel copy number variation in 8p23.1-23.3 deletion and 12q23.1 duplication.

While mitotic errors commonly cause aneuploid clones soon after conception, the embryos often normalize as clones are rapidly eliminated. Although generally considered benign, evidence suggests clone elimination as the primary cause of the vertebral, ano-rectal, cardiac, tracheo-esophageal, renal, and limb (VACTERL) association of anomalies, and possibly other adverse outcomes as well. Here, clone elimination-related development disruption at specific locations is used as the basis of a comprehensive theoretical VACTERL association model that also elucidates mitotic mosaic aneuploidy effects. For the association, the model explains random temporal and spatial origins during a limited time frame and overlapping clusters of component anomalies. It supports early developmental effects involving the stage of determination, where the position in a specific morphogen field controls what a cell will become and where it will be located. Developmental properties related to determination also create specific vulnerabilities to the midline and distal defects, the latter explaining exclusively radial and tibial defects with duplications and deficiencies. The model also supports isolated anomalies as part of the association and, for mosaic mitotic aneuploidy, indicates that clone elimination nears completion at the time of lower limb determination. Although mosaic clone elimination may cause other defects, occurrences in different developmental fields separate them from VACTERL anomalies. Clone elimination may also be related to risks for a single umbilical artery and for non-structural adverse pregnancy outcomes such as losses, prematurity, and growth delays, while a paucity of clone lethality in non-humans explains the rarity of the association and of single umbilical arteries in animals.