TBX6 – Congenital Anomaly of Kidney and Urinary Tract

Heterozygous dosage insufficiency of TBX6 has been implicated in the etiology of congenital anomaly of kidney and urinary tract (CAKUT). A genome-wide assessment of rare exonic copy number variants (CNVs) in 2,824 CAKUT cases versus 21,498 controls revealed a significant enrichment of 16p11.2 deletions, accounting for 65% of GD–CNVs in CAKUT, and pinpointed TBX6 as the driver gene for renal subphenotypes within this locus (n=2,824 cases) ([PMID:30578417]).

Targeted sequencing and CNV analysis of TBX6 in 269 Chinese CAKUT subjects identified two novel heterozygous noncoding variants: c.769-7delT in intron 5 from a patient with duplex renal and collecting system, and a 3′-UTR variant c.1392C>T in a case of unilateral renal hypoplasia. A mini-gene splicing assay demonstrated that c.769-7delT markedly reduced splicing efficiency of TBX6 intron 5 compared with wild-type ([PMID:30604070]).

In a multi-center cohort of 102 carriers of the 16p11.2 deletion, CAKUT prevalence was 25% in Chinese and 16% in Caucasian/Hispanic individuals versus ~0.1% in general populations at autopsy. Seven additional patients harboring heterozygous loss-of-function variants in TBX6 were identified; four exhibited CAKUT phenotypes. In mouse models, Tbx6 heterozygous null mutants (Tbx6+/–) developed solitary kidneys in 13% of cases, and compound heterozygotes combining a null allele with a mild hypomorphic allele (Tbx6mh/–) showed a 29% incidence of solitary kidneys and frequent renal hypoplasia ([PMID:32450157]).

Overall, the inheritance pattern is consistent with autosomal dominant haploinsufficiency. While no multi-generational segregation has been reported, convergent evidence from CNV enrichment, noncoding splicing defects, and LoF variants in unrelated probands (n=11 variant carriers; 6 with CAKUT) supports a moderate level of genetic evidence under ClinGen guidelines.

Functional studies corroborate a haploinsufficiency mechanism: intronic splicing assays confirm defective transcript processing, and murine Tbx6 dosage reduction faithfully recapitulates human renal malformations, fulfilling a moderate level of experimental evidence.

Together, these findings establish a moderate clinical validity for the TBX6–CAKUT association. Additional human segregation data and extended functional analyses may further solidify this link. Key take-home: TBX6 haploinsufficiency is a clinically actionable cause of CAKUT and should be considered in genetic diagnostics for renal anomalies.

References

• Nature genetics • 2019 • The copy number variation landscape of congenital anomalies of the kidney and urinary tract. PMID:30578417
• Molecular genetics and genomics : MGG • 2019 • Noncoding rare variants of TBX6 in congenital anomalies of the kidney and urinary tract. PMID:30604070
• Kidney international • 2020 • Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome. PMID:32450157

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