Table 5.

Monogenic Kidney Diseases in the Differential Diagnosis of ADTKD-REN

Gene(s)DisorderMOIRenal PhenotypeDistinguishing Features of Disorder
CEP290
INVS
IQCB1
NPHP1
NPHP3
NPHP4
TMEM67
(19 genes 1)		Isolated nephronophthisis (NPH)ARTubulointerstitial kidney disease; often seen in childhood & can be assoc w/anemia & mild hypotension
  • Absence of affected family members in multiple generations
  • Anemia usually correlates w/level of kidney function (i.e., may not be present in childhood).
  • Severity of kidney failure is usually much greater (usually requiring dialysis in teens & early 20s).
  • Hyperkalemia & acidemia are not as pronounced.
COL4A3
COL4A4
COL4A5 		Alport syndrome (& other types of hereditary glomerulonephritis)XL
AR
AD		Microscopic hematuria (microhematuria), proteinuria, progression to ESKD
  • Frequent cochlear & ocular manifestations
  • Hematuria is present.
  • Much more severe in males than in females
DNAJB11
GANAB
PKD1
PKD2 		Autosomal dominant polycystic kidney disease (ADPKD)ADBland urinary sediment 2; large # of cysts > age 25 yrsNumerous cysts seen on kidney ultrasound
GLA Fabry disease, classic formXLProteinuria (usually ↑ than in ADTKD-UMOD); gradual deterioration of renal function to ESKD in ~3rd-5th decade 3Classic form (males w/<1% α-Gal A activity) usually has onset in childhood or adolescence w/periodic crises of severe pain in extremities (acroparesthesias); vascular cutaneous lesions (angiokeratomas), hypohidrosis, & characteristic corneal & lenticular opacities.
MUC1

ADTKD-MUC1

ADMinimal proteinuria; slowly progressive CKDOnly clinical findings are chronic kidney disease & its sequelae. 4
UMOD ADTKD-UMOD ADProteinuria is rare; slowly progressive CKD
  • Not assoc w/anemia in childhood or acidemia & hyperkalemia often seen in ADTKD-REN 4
  • Phenotype is indistinguishable from adult-onset ADTKD-REN.
DNAJB11 4Atypical ADPKD-ADTKDADSlowly progressive CKD, multiple renal cystsNumerous kidney cysts are common.
HNF1B ADTKD-HNF1BADVariable other manifestations incl maturity-onset diabetes of the young, hyperuricemia & gout, CKD, CAKUT, & unexplained liver function abnormalitiesIncomplete penetrance for characteristic renal involvement & absence of other variable manifestations
mtDNAm.547A>T 5MatChronic tubulointerstitial kidney diseaseAbsence of childhood anemia, hyperkalemia, & acidemia
PAX2 PAX2-related disorder ADGlomerular proteinuria, hematuria, CKD, & ocular colobomaAbsence of hematuria, proteinuria, & coloboma
SEC61A1 ADTKD-SEC61A1ADSlowly progressive CKD, leukopenia, abscess formation, & intrauterine & postnatal growth restrictionAbsence of leukopenia, abnormal growth

α-Gal A = alpha-galactosidase A; AD = autosomal dominant; AR = autosomal recessive; CAKUT = congenital anomalies of the kidneys and urinary tract; CKD = chronic kidney disease; ESKD = end-stage kidney disease; Mat = maternal; MOI = mode of inheritance; XL = X-linked

1.

Listed genes represent the most common genetic causes of isolated nephronophthisis. Other genes known to be associated with nephronophthisis are ANKS6, CEP164, CEP83, DCDC2, GLIS2, IFT172, NEK8, RPGRIP1L, SDCCAG8, TTC21B, WDR19, and ZNF423.

2.

"Bland" refers to urinary sediment with little blood or protein.

3.

Males with >1% alpha-galactosidase A activity have a cardiac or renal variant phenotype. Rarely, heterozygous carrier females may have symptoms as severe as those observed in males with the classic phenotype.

4.
5.

From: Autosomal Dominant Tubulointerstitial Kidney Disease – REN

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