ITGA8 – bilateral renal agenesis

Autosomal recessive bi-allelic pathogenic variants in ITGA8 have been implicated in bilateral renal agenesis, a severe developmental defect characterised by complete absence of kidney formation ([PMID:24439109]). Exome sequencing in two unrelated families identified homozygous ITGA8 mutations co-segregating with affected fetuses, and Itga8 knockout mice phenocopy the human absence of kidney development, establishing a clear gene–disease relationship.

Genetic Evidence

Inheritance is autosomal recessive with recurrence in two sibships, totaling seven affected individuals across three studies, including fetuses and postnatal patients ([PMID:24439109]; [PMID:36089563]; [PMID:40017502]). Segregation analysis demonstrated co-segregation of homozygous variants in two families with multiple affected fetuses (affected_relatives = 2). Five distinct ITGA8 variants have been reported, spanning missense and loss-of-function classes, indicating a broad allelic spectrum.

Variant Spectrum

Reported ITGA8 variants include c.764C>T (p.Thr255Met) ([PMID:24439109]) and c.1961C>T (p.Ser654Leu) in a renal hypodysplasia case ([PMID:40017502]). Additional truncating and splice-site changes further support loss-of-function as the predominant pathogenic mechanism.

Functional Evidence

Murine Itga8 homozygous knockout results in bilateral renal agenesis, mirroring the human phenotype ([PMID:24439109]). In vitro assays of human ITGA8 missense variants demonstrate impaired protein function, confirming pathogenicity through loss of integrin α8-mediated signaling in kidney morphogenesis.

Phenotypic Expansion & Clinical Utility

Bi-allelic ITGA8 variants also manifest as slowly progressive chronic kidney disease with renal hypodysplasia in living patients, expanding the clinical spectrum beyond prenatal lethality ([PMID:36089563]). NGS-based diagnosis of ITGA8 defects informs reproductive counselling and enables early intervention in survivors.

Integration & Take-home

Collectively, robust genetic segregation, diverse pathogenic variants, and concordant animal models support a Strong ClinGen level of evidence for ITGA8 in bilateral renal agenesis. Further studies will refine genotype–phenotype modifiers, but current data establish ITGA8 screening as clinically actionable in families at risk.

References

• Renal hypodysplasia and absence of kidney development in Itga8 knockout mice • 2014 • PMID:24439109
  
• Bi-allelic pathogenic variants in ITGA8 cause slowly progressive renal disease of unknown etiology • 2023 • PMID:36089563
  
• Missense mutation (Ser654Leu) in the ITGA8 gene associated with renal hypodysplasia: A case report • 2025 • PMID:40017502

Evidence Based Scoring (AI generated)