Renal ciliopathies

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 glomerulosclerosis in the mice. Hence, this gene can be promoted to Green on Renal ciliopathies at the next update.

Created: 10 Apr 2026, 12:24 p.m. | Last Modified: 10 Apr 2026, 12:47 p.m.

Panel Version: 4.18

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.

Created: 10 Apr 2026, 12:14 p.m. | Last Modified: 10 Apr 2026, 12:45 p.m.

Panel Version: 4.18

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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

Publications

• 34487921
• 35856135
• 39044457
• 40974269

Added this gene to this panel on advice from Genomics England clinical team. Rating amber as 1 case plus functional data.

Created: 11 Jan 2022, 11:20 a.m. | Last Modified: 11 Jan 2022, 11:20 a.m.

Panel Version: 1.46

Comment on list classification: Promoted from grey to amber. 1 case plus functional data.

Created: 16 Dec 2021, 3:46 p.m. | Last Modified: 16 Dec 2021, 3:46 p.m.

Panel Version: 1.15

Not associated with a phenotype in OMIM. In Gene2Phenotype it is associated with PDIA6-associated syndromic neonatal diabetes and asphyxiating thoracic dystrophy with Limited confidence.

As Zornitza Stark reports PMID: 33495992 (Al-Fadhli et al 2021) describes one 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.

The X-ray findings at 6 months were consistent with typical radiological features of ATD syndrome. Other features include intrauterine growth retardation, multiple cysts in both kidneys associated with renal oligohydramnios (in first antenatal ultrasound) and hyperglycemia on the second day of life.

Created: 16 Dec 2021, 3:01 p.m. | Last Modified: 16 Dec 2021, 3:23 p.m.

Panel Version: 1.14

I don't know

1 case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage‐dependent manner, supporting a loss‐of‐function effect of this variant. Phenotypic correlation with the previously reported mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. The phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans.

Rated Amber in view of the high impact variant combined with functional data including a mouse model.
Sources: Literature

Created: 19 Apr 2021, 9:57 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Asphyxiating thoracic dystrophy (ATD) syndrome and infantile‐onset diabetes

Publications

• 33495992