| Domain | Best current finding/statistic | Evidence type | Key source/date/DOI |
|---|---|---|---|
| Definition and cause | SPLIS, also called nephrotic syndrome type 14 (NPHS14), is an ultra-rare autosomal-recessive sphingolipid-metabolism disorder caused by biallelic inactivating **SGPL1** variants. SGPL1 encodes the pyridoxal-5′-phosphate-dependent sphingosine-1-phosphate lyase. | Human genetic cohorts; biochemical studies | Lovric et al., March 2017, DOI: [10.1172/JCI89626](https://doi.org/10.1172/JCI89626); Sedillo et al., published online October 30, 2023, DOI: [10.1016/j.gimo.2023.100840](https://doi.org/10.1016/j.gimo.2023.100840) (pqac-00000003, pqac-00000019) |
| Modeled prevalence | Estimated worldwide prevalence: **0.015 per 100,000** (95% CI 0.010–0.021), corresponding to approximately **11,707 affected people worldwide**. This is a population-genetic model, not observed case prevalence. | Population-genetic modeling using curated variants and gnomAD v2.1.1 | Sedillo et al., Genetics in Medicine Open, 2024; online October 30, 2023; DOI: [10.1016/j.gimo.2023.100840](https://doi.org/10.1016/j.gimo.2023.100840) (pqac-00000003, pqac-00000004) |
| Major phenotype frequencies | In the 76-patient cohort: **kidney involvement 78%**, **primary adrenal insufficiency 63%**, **ESKD 35%**, **hypothyroidism 33%**, and **lymphopenia 30%**. Presentation ranged from prenatal disease to age 15 years; 54% presented in the first year. | Worldwide retrospective cross-sectional natural-history cohort | Keller et al., September 2024, DOI: [10.1186/s13023-024-03311-w](https://doi.org/10.1186/s13023-024-03311-w) (pqac-00000001, pqac-00000007) |
| Survival and early-onset risk | Overall survival at last report was **50%**. Among non-transplanted patients with nephropathy, diagnosis before age one identified a high-risk group: fewer than 30% were alive two years after diagnosis and 17% were alive at last report; mean age at death among deceased cohort members was 7.5 months. Prenatal presentations were also associated with early mortality. | Human natural-history cohort | Keller et al., September 2024, DOI: [10.1186/s13023-024-03311-w](https://doi.org/10.1186/s13023-024-03311-w) (pqac-00000001, pqac-00000007, pqac-00000010) |
| Genotype and prognosis | Homozygous **p.Arg222Gln (R222Q)** was associated with better survival: reported survival was approximately **85%**, and median age at last report among non-transplanted patients was 6.8 years versus 1.9 years for other genotypes. This association is prognostic, not proof that R222Q alone determines outcome. | Human genotype–phenotype association | Keller et al., 2024, DOI: [10.1186/s13023-024-03311-w](https://doi.org/10.1186/s13023-024-03311-w) (pqac-00000007, pqac-00000008, pqac-00000011) |
| Kidney transplantation | Kidney transplantation significantly extended survival relative to dialysis or palliative care. Median age at last report was 8 years after transplantation, 4.4 years with dialysis, and 1.3 years with palliative care; dialysis did not show a significant survival benefit over palliative care in the reported analysis. | Retrospective treatment-outcome comparison; nonrandomized | Keller et al., September 2024, DOI: [10.1186/s13023-024-03311-w](https://doi.org/10.1186/s13023-024-03311-w) (pqac-00000008, pqac-00000010, pqac-00000011) |
| Core mechanism | Loss of ER-localized S1P-lyase activity blocks irreversible cleavage of S1P into hexadecenal and ethanolamine phosphate, disturbing sphingolipid homeostasis. Patient samples show increased S1P/sphingosine; fibroblasts can retain less than 10% of normal activity. Downstream mechanisms include abnormal S1P-receptor signaling, impaired mesangial migration, podocyte injury, immune-cell trafficking defects, and altered steroidogenesis; several organ-specific links remain partly inferred. | Human biochemical, cellular, mouse, yeast, and Drosophila evidence | Janecke et al., April 2017, DOI: [10.1002/humu.23192](https://doi.org/10.1002/humu.23192); Lovric et al., March 2017, DOI: [10.1172/JCI89626](https://doi.org/10.1172/JCI89626) (pqac-00000014, pqac-00000015, pqac-00000016, pqac-00000021) |
| Diagnostic approach | Molecular confirmation requires **biallelic pathogenic or likely pathogenic SGPL1 variants**, typically detected by exome/genome sequencing or an SGPL1-containing nephrotic-syndrome/adrenal-insufficiency panel. Supporting assessments include proteinuria, serum albumin/lipids, kidney function and biopsy, cortisol/ACTH and mineralocorticoid testing, lymphocyte subsets, neurologic evaluation/MRI, and sphingolipid or enzyme assays where available. | Human cohort practice; observational biomarker development | Keller et al., 2024, DOI: [10.1186/s13023-024-03311-w](https://doi.org/10.1186/s13023-024-03311-w); NCT06669949 (pqac-00000007, pqac-00000022, pqac-00000026) |
| Observational research | Two recruiting UCSF records were identified: **NCT04885179**, an international registry with estimated enrollment of 120, and **NCT06669949**, a three-year natural-history study with estimated enrollment of 28. They collect clinical, imaging, pathological and biospecimen data; neither assigns an investigational treatment. | Prospective observational studies/registries | [NCT04885179](https://clinicaltrials.gov/study/NCT04885179), started April 22, 2025; [NCT06669949](https://clinicaltrials.gov/study/NCT06669949), started April 22, 2025 (pqac-00000022, pqac-00000023, pqac-00000024, pqac-00000026) |


*Table: Compact summary of the strongest current evidence on SPLIS genetics, epidemiology, manifestations, prognosis, mechanism, diagnosis, transplantation, and ongoing observational research. Modeled estimates and nonrandomized clinical associations are explicitly distinguished from directly observed outcomes.*