| Subtype | Causal gene(s) | Inheritance | Key mechanistic theme | Hallmark renal features | Notable extrarenal features | Key supporting citation |
|---|---|---|---|---|---|---|
| FRTS1 | **GATM** | Autosomal dominant | Mutant glycine amidinotransferase forms intracellular aggregates, increasing ROS, inflammatory signaling, cell death, and renal fibrosis; proximal-tubule mitochondrial pathology is emphasized in later mechanistic reviews (pqac-00000026, pqac-00000000) | Generalized proximal tubular dysfunction/Fanconi syndrome; progressive CKD reported for FRTS1 kindreds (pqac-00000013, pqac-00000026) | No consistent syndromic extrarenal phenotype established in the gathered evidence | Shen 2023, Front Pediatr, https://doi.org/10.3389/fped.2023.1097062 (pqac-00000026) |
| FRTS2 | **SLC34A1** | Autosomal recessive (debated/very rare in classic FRTS2) | Loss of NaPi-IIa–mediated phosphate reabsorption causes phosphate wasting; proposed intracellular phosphate depletion leads to insufficient ATP generation in proximal tubule cells (pqac-00000001, pqac-00000026) | Phosphaturia-dominant Fanconi phenotype, hypophosphatemia/rickets, hyperphosphaturia; reported in only two siblings in classic recessive FRTS2 literature summarized by Klootwijk et al. (pqac-00000001, pqac-00000028) | Rickets/osteopenia predominate; broader SLC34A1 spectrum can include nephrolithiasis/nephrocalcinosis and infantile hypercalcemia phenotypes (pqac-00000001) | Klootwijk 2015, NDT, https://doi.org/10.1093/ndt/gfu377 (pqac-00000001) |
| FRTS3 | **EHHADH** | Autosomal dominant | p.E3K creates a de novo mitochondrial targeting motif in the peroxisomal enzyme EHHADH, causing mistargeting to mitochondria, impaired oxidative phosphorylation, and dominant-negative disruption of proximal-tubule energy metabolism (pqac-00000005, pqac-00000006) | Isolated Fanconi syndrome with lifelong proximal tubular solute loss; normal/age-appropriate GFR and “no kidney failure” emphasized in the family originally studied (pqac-00000024, pqac-00000028) | No major consistent extrarenal syndrome despite broader tissue expression of EHHADH (pqac-00000024, pqac-00000005) | Klootwijk 2014, N Engl J Med, https://doi.org/10.1056/NEJMoa1307581 (pqac-00000005) |
| FRTS4 | **HNF4A** | Autosomal dominant | Specific heterozygous HNF4A variants (especially p.Arg85Trp / historical p.R76W or p.R63W annotation differences) alter transcriptional control of proximal-tubule programs, reduce expression of proximal tubule-specific genes, and are linked to mitochondrial/lipid metabolic abnormalities (pqac-00000012, pqac-00000022, pqac-00000026) | Fanconi renal tubulopathy with hypophosphatemia, phosphaturia, glycosuria, aminoaciduria; can include hypercalciuria, nephrocalcinosis, CKD, and sometimes absence of overt RTA/hypouricemia in atypical cases (pqac-00000002, pqac-00000023) | Neonatal hyperinsulinemic hypoglycemia, macrosomia, later MODY-1/diabetes; hypophosphatemic rickets/osteomalacia; liver involvement and occasional additional anomalies reported (pqac-00000023, pqac-00000015) | Hudson 2024, J Nephrol, https://doi.org/10.1007/s40620-023-01666-0 (pqac-00000023) |
| FRTS5 | **NDUFAF6** | Not clearly specified in gathered evidence; reported as the Acadian variant | Aberrant splicing/loss of the mitochondria-localized NDUFAF6 isoform causes mitochondrial respiratory chain complex I deficiency (pqac-00000031, pqac-00000032) | Proximal renotubular dysfunction from birth with progressive kidney disease (pqac-00000031) | Pulmonary interstitial fibrosis; reported in Acadians (pqac-00000031) | Shen 2023 citing Hartmannová 2016, Front Pediatr, https://doi.org/10.3389/fped.2023.1097062; underlying Acadian variant reference DOI https://doi.org/10.1093/hmg/ddw245 (pqac-00000031, pqac-00000032) |


*Table: This table summarizes Fanconi renotubular syndrome subtypes 1-5, highlighting causal genes, inheritance, mechanisms, and renal/extrarenal phenotypes. It is useful for quickly comparing subtype-defining features and the strongest supporting citations from the gathered evidence.*