Case report of a child with kidney disease: consideration of the risk of a single APOL1 G2 allele with a protective N264K variant on the G0 parental chromosome.
| Title: | Case report of a child with kidney disease: consideration of the risk of a single APOL1 G2 allele with a protective N264K variant on the G0 parental chromosome. |
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| Authors: | Greenberg M; Pediatric Nephrology Unit, Meir Medical Center, Kfar Saba, Israel. meidad.greenberg@clalit.org.il.; Tabachnikov O; Department of Nephrology, Rambam Healthcare Campus, Haifa, Israel. o_tabachnikov@rmc.gov.il.; Ben-Ruby D; Genetic Kidney Diseases Research Laboratory, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.; Gray Faculty of Medical and Health Sciences, Tel-Aviv University, Tel- Aviv, Israel.; Vivante A; Genetic Kidney Diseases Research Laboratory, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.; Gray Faculty of Medical and Health Sciences, Tel-Aviv University, Tel- Aviv, Israel.; Skorecki K; Department of Nephrology, Rambam Healthcare Campus, Haifa, Israel.; Departments of Genetics and Developmental Biology and Rappaport, Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.; The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel. |
| Source: | BMC nephrology [BMC Nephrol] 2026 May 04. Date of Electronic Publication: 2026 May 04. |
| Publication Model: | Ahead of Print |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: BioMed Central Country of Publication: England NLM ID: 100967793 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1471-2369 (Electronic) Linking ISSN: 14712369 NLM ISO Abbreviation: BMC Nephrol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London : BioMed Central, [2000- |
| Abstract: | Background: Apolipoprotein L1 (APOL1)-mediated kidney disease is causally associated with the G1/G2 risk alleles of the APOL1 gene, and shows incomplete penetrance shaped by environmental and genomic modifiers. A rare coding variant, N264K, observed on G0 or G2 variants, has been associated with protection in high-risk genotypes. Importantly, emerging data indicate that in some settings a single APOL1 risk allele can confer risk, including reports of end stage kidney disease in G0/G2 individuals, underscoring the need to determine whether N264K protection requires cis configuration with G2 allele (on the same polypeptide), or can also act in trans (on the opposite allele), an issue of potential future clinical diagnostic and therapeutic relevance when phase is unknown for certain genotypes.; Case Presentation: A previously healthy 10-year-old Muslim Arab male developed edema during laboratory-confirmed influenza. He had sub-nephrotic-range proteinuria with hypoalbuminemia, preserved kidney function, and normal blood pressure. Treatment with prednisone according to Kidney Disease: Improving Global Outcomes (KDIGO) pediatric guidelines did not induce remission. Kidney biopsy showed diffuse mesangial hypercellularity with prominent IgM deposition. In patients with steroid non-remitting disease, this finding is compatible with IgM nephropathy that can herald focal segmental glomerulosclerosis. Tacrolimus was started, and later pulse methyl-prednisolone was administered, achieving only transient reduction in proteinuria; therapy was complicated by reversible insulin-requiring hyperglycemia and subsequently withdrawn. Subsequent administration of Rituximab in combination with angiotensin-converting enzyme (ACE) inhibition resulted in significant reduction of proteinuria. Trio exome sequencing demonstrated APOL1 G0/G2 with N264K on the paternal G0 allele (trans to G2) and no other monogenic cause of steroid-resistant nephrotic syndrome. At follow-up, the child has preserved kidney function with normal plasma albumin level and without proteinuria. In human embryonic kidney (HEK-293) cultured cells co-transfection assays modeling heterozygosity, N264K reduced G2-dependent cytotoxicity only in cis (same construct as G2) and not in trans (on G0), despite comparable expression; the effect was stronger on an EIK than a KIK haplotype backbone.; Conclusions: Taken together the clinical findings and the in vitro experimental laboratory results suggest that APOL1 allele phasing may be informative in selected cases where both G2 and N264K are reported, and support development of APOL1-mediated kidney disease biomarkers and genotype-informed therapies.; (© 2026. The Author(s).) |
| Competing Interests: | Declarations. Ethics approval and consent to participate: In accordance with the Declaration of Helsinki, a waiver was granted by the Institutional Review Board at the Meir Medical Center for this retrospective case report on the basis of patient anonymity. Consent for publication: Written informed consent was obtained from the patient’s parents for publication of this case report and accompanying images, and such signed consent is and will be maintained on file in the offices of author MG. Competing interests: The authors declare no competing interests. |
| Grant Information: | 101040267-GeneCKD StG ERC grant; 3911/24 Israel Science Foundation |
| Contributed Indexing: | Keywords: AMKD; APOL1; FSGS; Heterozygous risk variants; Nephropathy |
| Entry Date(s): | Date Created: 20260504 Latest Revision: 20260504 |
| Update Code: | 20260505 |
| DOI: | 10.1186/s12882-026-05006-9 |
| PMID: | 42082919 |
| Database: | MEDLINE |
Journal Article