Table 1.

Clinical characteristics and type IV collagen gene mutations in patients with bilateral kidney cysts without PKD1 or PKD2 mutations

Patient no.	Cohort	Agea (yr)/sex (ethnicity)	eGFRb/CKD stage/severity classc	Family history	Type IV collagen gene mutation and predicted protein change	Genetic diagnosis	Type IV collagen variant details
							Variant type	MAFd	Prior report
COL4A4 variants
1	NMD-ADPKD	25/M (Caucasian)	eGFR:125 (85)/CKD stage 1(2)/class IC	Not available	COL4A4: exon28: c. G2383A: p. G795R	COL4A4-related renal disease	Splice site; exon 28 skipping by minigene assay	1 × 10–6	None
2	TBM	28/M (Caucasian)	CKD stage 3	ESRD in father	COL4A4:exon46:c.4503dupA:p.A1502Sfs*17	COL4A4-related renal disease	Frameshift and premature truncation	Novel	None
3	TBM	42/M (Caucasian)	CKD stage 3	Microhematuria in father; sibling	COL4A4: exon24: c.1697–1G>C	COL4A4-related renal disease	Canonical splice site variant	Not listed	One kindred with familial hematuriaS17
4	TBM	52/F (Caucasian)	CKD stage 4	Microhematuria in father; sibling	COL4A4: exon 39: c.3704delC: p. P1235Qfs*53	COL4A4-related renal disease	Frameshift and premature truncation	Novel	None
COL4A5 variant
5	TBM	49/F (Caucasian)	CKD stage 2	Not available	COL4A5: exon16:c.C899T: p. P300L	COL4A5 carrier	Missense, likely pathogenic	1 × 10–5	Nonee
COL4A1 variant
6	NMD-ADPKDf	41/M (Caucasian)	eGFR:77 (78)/ CKD stage 2 (2)/ class IB	Not available	COL4A1: exon31:c.C2351T: p. P784L	HANAC-like syndrome	Missense, likely pathogenic	1 × 10–5	Noneg

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; F, female; HANAC, hereditary angiopathy, nephropathy, aneurysms, muscle cramps; M, male; MAF, minor allele frequency; NMD-ADPKD, no PKD mutation detected–autosomal dominant polycystic kidney disease; TBM, thin glomerular basement membrane.

^aAge (yr) at clinical/imaging or histopathological diagnosis of ADPKD or TBM disease.

^bModification of Diet in Renal Disease eGFR in ml/min per 1.73 m² or CKD stage recorded at the time of inclusion (and at 4-yr follow-up into ADPKD cohort) or at diagnosis of TBM.

^cSeverity class–based age and height-adjusted total kidney volumeS3 at inclusion into CRISP study.S1

^dPopulation minor allele frequency as listed in the genome aggregation database (http://gnomad.broadinstitute.org).

^eThis particular variant has not been reported in the Alport syndrome database (http://www.arup.utah.edu). Proline substitutions at this third position of tripeptide repeating unit (G-X-Y) in the collagen triple-helical domain undergo post-translational modification and there are 5 proline substitutions listed as pathogenic in the Alport database.

^fTwo additional patients from this 17-patient NMD-ADPKD cohort have been previously reported as individual de-identified cases with HANAC syndrome; variant (COL4A1: exon25:c.C1612T: p. R538W)³; variant (COL4A1: exon13:c.C739T: p. Q247X).⁴

^gProline-to-lysine substitution at another residue 352 in COL4A1 is previously reported as pathogenic and tested in a cell culture–based secretion assay.S18