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Background <p>Apolipoprotein L1 (APOL1)-mediated kidney disease is causally associated with the G1/G2 risk alleles of the <i>APOL1</i> 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 <i>APOL1</i> 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 <i>cis</i> configuration with G2 allele (on the same polypeptide), or can also act in <i>trans</i> (on the opposite allele), an issue of potential future clinical diagnostic and therapeutic relevance when phase is unknown for certain genotypes.</p> Case presentation <p>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reduction in proteinuria; therapy was complicated by reversible insulin-requiring hyperglycemia and subsequently withdrawn.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 <i>APOL1</i> G0/G2 with N264K on the paternal G0 allele (<i>trans</i> 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 <i>cis</i> (same construct as G2) and not in <i>trans</i> (on G0), despite comparable expression; the effect was stronger on an EIK than a KIK haplotype backbone.</p> Conclusions <p>Taken together the clinical findings and the in vitro experimental laboratory results suggest that <i>APOL</i>1 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.</p>

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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

  • 期刊论文

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  • 发表日期：

    2026年5月4日

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  • Meidad Greenberg,
  • Orly Tabachnikov,
  • Dror Ben-Ruby,
  • Asaf Vivante,
  • Karl Skorecki

摘要

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.