Cystic kidney disease

Gene: PDIA6

Green List (high evidence)

Comment on list classification: There are two plausible reports of unrelated individuals with biallelic PDIA6 variants and polycystic kidney disease. Functional evidence from mouse models shows that pdia6 downregulation leads to cilia removal, resulting in abnormal kidney morphology and glomerulosclerosis in the mice. Hence, this gene can be promoted to Green on Cystic kidney disease at the next update.

Created: 10 Apr 2026, 12:48 p.m. | Last Modified: 10 Apr 2026, 12:48 p.m.

Panel Version: 8.12

PMID: 33495992 Al-Fadhli et al 2021
Case of a child with asphyxiating thoracic dystrophy (ATD) syndrome and infantile-onset diabetes who had a homozygous frameshift variant in the PDIA6 gene (NM_001282704.1:c.703del (p.Val235fs)) which is in exon 8 (of 15). The parents and unaffected sibling were heterozygous for this variant. The authors state that PDIA6 is not known yet to be involved in the formation or function of the primary cilia but suggest that it could be directly or indirectly interacting or required for proper protein folding of known or unknown ciliopathy protein.

PMID: 35856135 De Franco et al., 2022
Report of a biallelic loss-of-function PDIA6 NM_005742:p.Tyr316* variant in a male proband with polycystic kidney disease, infancy-onset diabetes, microcephaly, developmental delay, bilateral sensorineural hearing loss, hypotonia, visual impairment, and steatorrhea. Consanguineous, Middle Eastern parents with history of pregnancy loss.

PMID: 40974269 Al-Hadidi et al., 2026
Report of a full-term male neonate born to consanguineous Syrian parents, who presented with polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Homozygous for PDIA6 NM_005742.4 :c.1958delC, p.Pro653fs* variant - cannot find it anywhere, the NM_005742.4 transcript only has 440 amino acids..?

Functional evidence:
PMID: 34487921 Chhabra et al., 2023
Mouse model carrying a missense mutation (Phe175Ser) in PDIA6. Homozygous mice were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage, due to loss of pancreatic β-cell function and identity.
PMID: 39044457 Kim et al., 2024
Study involved Pdia6 knockout mice with in a 58 bp deletion in exon 3, and a frameshift mutation in exon 4 Downregulating PDIA6 leads to cilia removal, makes cells more sensitive to ferroptotic death caused by endoplasmic reticulum (ER) stress. The reduction of PDIA6 intensifies the ER stress response, while also impairing the regulation of primary cilia in various cell types. Pdia6+/− mice displayed glomerular abnormalities that are suggestive of glomerulosclerosis

Additional info: https://www.congresslife.com/e-poster/ESPN2023/def/[email protected]/poster.pdf - Abdullah et al
This conference poster reports 3 cases with PDIA6 variants and polycystic kidney disease with neonatal diabetes. Case 3 homozygous for PDIA6 c.702delT, p.Arg235Glufs*87, other genotypes not stated.
Sources: Literature

Created: 10 Apr 2026, 12:45 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Polycystic kidney dysplasia, HP:0000113; Diabetes mellitus, HP:0000819; Microcephaly, HP:0000252

Publications

• 33495992
• 34487921
• 35856135
• 39044457
• 40974269