Table 1.
Patients (n = 31) with positive genetic variants are shown arranged by phenotype categories.
| Subject | Clinical features | FH | Sex/age/ethnicity | Genetic testing | ACMG criteria | Genetic diagnosis | Impact of genetic diagnosis |
|---|---|---|---|---|---|---|---|
| Tubular transport | |||||||
| 15 | Hypokalemia, nephrocalcinosis | N | M/40/EUR | SLC12A3 p.Gly741Arg—homozygous | Pathogenic (PS1, PS3, PM2, PM3, PP3) | Gitelman syndrome | Altered clinical diagnosis |
| 24 | Nephrocalcinosis | Y | M/41/EUR | CLCN5 p.Arg704Ter | Pathogenic (PVS1, PS1, PM2, PP3) | X-linked Dent disease | Establish a diagnosis, cascade screening, recurrence risk |
| 33 | Resistant HTN childhood onset | Y | F/23/EUR | CYP11B1 p.Phe79Ile | Likely pathogenic (PS1, PM2, PP3) | Carrier for 11 β-hydroxylase deficiency | Exclude other monogenic forms of resistant hypertension |
| 55 | Hyperkalemia | Y | M/56/EUR | KLHL3 p.Arg496His; SLC3A1 p. Glu321Valfs*6 | Likely pathogenic (PS1, PM2, PP2, PP3, PP5) | Gordon syndrome | Establish a diagnosis, cascade screening, initiated thiazides |
| 57 | Hypokalemia | N | F/62/EUR | SLC12A3 p.Cys994Tyr | Likely pathogenic (PS1, PP2, PP3, PP5) | Carrier for Gitelman syndrome | Diagnosis not confirmed; treat as Gitelman |
| Glomerular | |||||||
| 3 | Microscopic hematuria | Y | M/31/EUR | COL4A5 p.Gly1415Asp | Likely pathogenic (PM1, PM2, PP2, PP3, PP5) | X-linked Alport nephropathy | Initiated ACEI, discuss prognosis |
| 25 | Proteinuria, ESRD, kidney transplant | Y | M/59/EUR | COL4A5 p.Gly1143Ser | Likely pathogenic (PM1, PM2, PM5, PP3, PP5) | X-linked Alport nephropathy | Cascade screening |
| 29–1 | Alport syndrome (biopsy) | Y | F/59/EUR | COL4A3 p.Gly934Arg | Likely pathogenic (PM1, PM2, PP1, PP3) | Autosomal dominant Alport nephropathy | Cascade screening |
| 38 | Deafness, retinal dystrophy, podocyte myeloid bodies | Y | M/54/EUR | PEX1 p.Gln1192Stop; PEX1 p.Ile989Thr; PEX1 p.Pro674Leu | Pathogenic (PVS1, PM2, PP3, PP5) VUS (PM2, PP3, PP5) VUS (PM2, PP3) | Zellweger spectrum disorder | Establish a diagnosis, treatment |
| 39–2 | Chronic kidney disease | Y | M/33/EUR | COL4A5 p.Cys1521Ser | Likely pathogenic (PM1, PM2, PP1, PP3, PP5) | X-linked Alport nephropathy | Establish a diagnosis, cascade screening, recurrence risk |
| 39–3 | Microhematuria, proteinuria | Y | M/28/EUR | COL4A5 p.Cys1521Ser | Likely pathogenic (PM1, PM2, PP1, PP3, PP5) | X-linked Alport nephropathy | Establish a diagnosis, initiate ARB, prognostic information |
| 42–1 | Microscopic hematuria | Y | M/4/EUR | COL4A4 p.Gly622Argfs*35 | Likely pathogenic (PVS1, PM2, PP1, PP3) | Autosomal dominant Alport nephropathy | Establish a diagnosis, cascade screening, prognosis |
| 42–2 | Microhematuria, proteinuria, and TBMD | Y | F/36/EUR | COL4A4 p.Gly622Argfs*35 | Likely pathogenic (PVS1, PM2, PP1, PP3) | Autosomal dominant Alport nephropathy | Prognostic information |
| 42–3 | ESRD, kidney transplant | Y | M/78/EUR | COL4A4 p.Gly622Argfs*35 | Likely pathogenic (PVS1, PM2, PP1, PP3) | Autosomal dominant Alport nephropathy | Establish a diagnosis |
| 53 | CKD 5, global glomerulosclerosis | Y | F/30/AFR | APOL1 G1/G2 | Risk alleles | APOL1 associated nephropathy | Siblings may be at risk |
| 59 | Microhematuria, ESRD | Y | M/34/EUR | COL4A5 p.Gln1234Ter | Pathogenic (PVS1, PS1, PM2, PM4, PP3) | X-linked Alport nephropathy | Establish a diagnosis, family planning, cascade screening |
| 65 | Focal segmental glomerulosclerosis | N | F/26/EUR | TRPC6 p. Asn125Ser | Likely pathogenic (PS1, PP3, PP5) | Autosomal dominant FSGS | Establish a diagnosis, avoid steroids |
| 69 | ESRD, delayed female puberty | N | F/15/EUR | WT1 c.745+5G>A | Likely pathogenic (PS1, PM2, PP3, PP5) | Frasier syndrome | Establish a diagnosis, prophylactic gonadectomy |
| Ciliopathy | |||||||
| 4–2 | Bilateral renal cysts | Y | M/33/EUR | PKD1 p.Tyr2622Ter | Likely pathogenic (PVS1, PM2) | Autosomal dominant polycystic kidney disease | Family planning, prognostic information, tolvaptan |
| 19–1 | Bilateral renal cysts, liver cysts | Y | F/38/EUR | PKD2 p.Tyr311Leufs*2 | Pathogenic (PVS1, PM2, PP1, PP3, PP5) | Autosomal dominant polycystic kidney disease | Prognostic information, cascade screening |
| 19–2 | Bilateral renal cysts, liver cysts | Y | F/20/EUR | PKD2 p.Tyr311Leufs*2 | Pathogenic (PVS1, PM2, PP1, PP3, PP5) | Autosomal dominant polycystic kidney disease | Prognosis, cascade screening, family planning |
| 21 | Cystic kidney disease | N | F/21/EUR | PKD1 p.Thr2250Met | VUS (PM1, PP3) | Not established | Family screening and segregation analysis |
| 35–1 | Bilateral renal cysts, enlarged kidneys | N | F/12/EUR | PKHD1 c.390+1G>T; PKD1 p.Leu1106Val | Pathogenic (PVS1, PM2, PP3); likely benign (BP4, BP6) | Carrier for ARPKD | Likely ARPKD based on cascade screening |
| 40–1 | Asymptomatic | Y | F/28/EUR | PKD1 p.Tyr2004Thrfs*112 | Pathogenic (PVS1, PM2, PP3) | Autosomal dominant polycystic kidney disease | Establish a diagnosis, family planning, treatment |
| 48 | CKD 3, congenital hepatic fibrosis | Y | F/27/EUR | PKHD1 p.Arg375Trp; PKHD1 p.Ile222Leu | Likely pathogenic (PS1, PM1, PM2, PP3); likely pathogenic: PM1, PM2, PM5, PP2, PP3 | Autosomal recessive polycystic kidney disease | Establish a diagnosis |
| 58 | Renal and liver cysts, ESRD, HTN | Adopted | M/50/EUR | PKD1 p.Ala2332Trpfs*7 | Pathogenic (PVS1, PS1, PM2, PP3) | Autosomal dominant polycystic kidney disease | Recurrence risk, cascade screening, prognosis, treatment |
| 60 | Bilateral renal cysts | Y | F/41/EUR | PKD1 p.Val1105Gly | VUS (PM1, PM2, PP3) | Not established | Family screening and segregation analysis |
| 68 | Bilateral renal cysts | N | M/23/EUR | PKD1 p.Val1144Alafs*68 | Pathogenic (PVS1, PM2, PP3) | Autosomal dominant polycystic kidney disease | Establish a diagnosis, cascade screening, prognosis, tolvaptan |
| 70 | Bilateral renal cysts, liver cysts | N | F/43/EUR | PKD2 p.Leu409Argfs*42 | Pathogenic (PVS1, PM2, PP3) | Autosomal dominant polycystic kidney disease | Establish a diagnosis, prognosis, cascade screening |
| CAKUT | |||||||
| 12 | Unilateral atrophy versus hypoplasia | Y | F/48/EUR | PAX2 p.Arg140Leu | Likely pathogenic (PM1, PM2, PP1, PP2, PP3) | PAX2-mediated CAKUT | Establish a diagnosis, evaluate for eye disease, recurrence risk |
| 52 | Multicystic dysplastic kidney | Y | F/7/EUR | PAX2 p.His62Tyr | Likely pathogenic (PM1, PM2, PP2, PP3) | PAX2-mediated CAKUT | Cascade screening, recurrence risk |
ACEI angiotensin-converting enzyme inhibitor, ACMG American College of Medical Genetics and Genomics, AFR African/African American, AJ Ashkenazi Jewish, ARB Angiotensin 2 receptor blocker, ARPKD autosomal recessive polycystic kidney disorder, CAKUT congenital anomaly of the kidney or urinary tract, CKD chronic kidney disease, EA East Asian, ESRD end-stage renal disease, EUR Caucasian, FH family history, FSGS focal segmental glomerulosclerosis, HTN hypertension, LAT Hispanic or Latino, NA American Indian or Alaska Native, TBMD thin basement membrane disease, VUS variant of unknown significance.