PBX1 – Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay

PBX1 encodes a three–amino acid loop extension (TALE) homeodomain transcription factor essential for organogenesis. Heterozygous loss-of-function variants in PBX1 cause an autosomal dominant syndrome characterized by congenital anomalies of the kidney and urinary tract with or without hearing loss, abnormal ears, or developmental delay (MONDO:0060549).

Genetic evidence includes three unrelated probands with de novo or mosaic truncating PBX1 variants. A de novo single-nucleotide insertion, c.400dupG (p.Ala134GlyfsTer65), was identified in an infant with pelvic kidney, hypotonia, patent ductus arteriosus, abnormal pinnae, and developmental delay (PMID:34797033). A heterozygous nonsense variant, c.862C>T (p.Arg288Ter), was reported in a Chinese CAKUTHED patient presenting with renal hypoplasia and hearing impairment (PMID:36318887). Additionally, paternal post-zygotic mosaicism for p.Arg107Trp was found in a family with recurrent perinatal death and CAKUT features (PMID:32141698).

All reported pathogenic variants are predicted to result in loss of function through frameshift or premature truncation, consistent with haploinsufficiency. No recurrent or founder alleles have been described to date.

Functional studies support haploinsufficiency as the disease mechanism. A CRISPR–Cas9 mouse model of the de novo missense variant c.551G>C (p.Arg184Pro) demonstrated multi-organ malformations including renal hypoplasia, confirming the dominant effect of PBX1 variants on kidney development (PMID:31625560). A recent review of PBX1 germline variants highlights that truncating alleles yield milder renal-predominant phenotypes while missense substitutions produce more severe multi-system defects (PMID:35451537).

No conflicting reports dispute the PBX1-CAKUTHED association. The concordance between de novo/truncating variant occurrence, animal modeling, and phenotypic spectra across studies meets strong ClinGen criteria for gene–disease validity.

Key Take-home: Heterozygous loss-of-function PBX1 variants cause an autosomal dominant CAKUTHED syndrome; PBX1 sequencing should be considered in patients with congenital urinary tract anomalies, hearing loss, abnormal ears, or developmental delay.

References

• American journal of medical genetics. Part A • 2022 • De novo PBX1 variant in a patient with glaucoma, kidney anomalies, and developmental delay: An expansion of the CAKUTHED phenotype. PMID:34797033
• Nephron • 2023 • A Pathogenic Variant of PBX1 Identified by Whole Exome Sequencing in a Chinese CAKUTHED Case. PMID:36318887
• American journal of medical genetics. Part A • 2020 • Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1-related syndrome. PMID:32141698
• Human molecular genetics • 2020 • Functional characterization of a novel PBX1 de novo missense variant identified in a patient with syndromic congenital heart disease. PMID:31625560
• Human mutation • 2022 • The TALE never ends: A comprehensive overview of the role of PBX1, a TALE transcription factor, in human developmental defects. PMID:35451537

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