Case Report: Whole-exome sequencing revealing a novel PBX1 gene variant in a Chinese family with renal hypoplasia

Background and Aims Congenital Anomalies of the Kidney and Urinary Tract with or without Hearing Loss, Abnormal Ears, or Developmental Delay (CAKUTHED) is an autosomal dominant syndromic form of congenital anomalies of the kidney and urinary tract associated with heterozygous pathogenic variants in PBX1 . The disorder is characterized by marked phenotypic variability. Identification of the underlying genetic variant can facilitate accurate prenatal diagnosis and genetic counselling of affected families. Materials and Methods We recruited a Chinese family affected by CAKUTHED and performed chromosomal microarray analysis, whole-exome sequencing, and Sanger validation in available family members. Exploratory conservation, structural, and transcriptomic analyses were subsequently performed to investigate potential consequences associated with the identified variant. Results A novel heterozygous PBX1 variant, c.780C > A(p.Y260X), was identified by whole-exome sequencing and co-segregated with the renal phenotype among the available tested family members. The variant introduces a premature termination codon within the PBX1 homeodomain and is consistent with a predicted loss-of-function effect. Exploratory structural and transcriptomic analyses yielded hypothesis-generating observations but did not establish the molecular mechanism of the variant. Conclusion We identified a novel heterozygous PBX1 variant, NM_002585.4: c.780C > A(p.Y260X), in a Chinese family with familial renal hypoplasia. The variant co-segregated with the renal phenotype among the available tested family members and is consistent with the established loss-of-function spectrum of PBX1-related CAKUTHED. The available evidence is most consistent with a haploinsufficiency mechanism; however, NMD of the mutant allele was not directly demonstrated, and a potential dominant-negative contribution from an NMD-escaped truncated protein cannot be formally excluded. The transcriptomic and molecular dynamics findings should be regarded as exploratory and hypothesis-generating observations. Further allele-specific RNA analyses, NMD-inhibition experiments, direct protein detection, replicated simulations, and functional assays are required to distinguish between these potential mechanisms.