Finnish congenital nephrotic syndrome: genes and variants

Genes linked to Finnish congenital nephrotic syndrome

• NPHS1: Nephrin

  It forms a key structural and signaling component of the slit diaphragm between glomerular podocyte foot processes. Biallelic loss-of-function variants cause congenital nephrotic syndrome of the Finnish type with massive protein loss beginning early in life.

  70 disease-causing and 211 uncertain variants in NPHS1 are linked to Finnish congenital nephrotic syndrome.

• NPHS2: Podocin

  It organizes nephrin-containing slit-diaphragm complexes in podocytes and helps maintain the glomerular filtration barrier. Biallelic pathogenic variants are a major cause of steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis.

  1 disease-causing and 1 uncertain variants in NPHS2 are linked to Finnish congenital nephrotic syndrome.

Where Finnish congenital nephrotic syndrome variants cluster

• NPHS1 Ig-like C2-type 7 (positions 740–821): 8 of 70 disease-causing changes, 1.7× more than its size predicts.
• NPHS1 Ig-like C2-type 6 (positions 544–635): 8 of 70 disease-causing changes, 1.5× more than its size predicts.

Known disease-causing variants in Finnish congenital nephrotic syndrome

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Uncertain variants in Finnish congenital nephrotic syndrome that look disease-causing

Which prediction tools work for Finnish congenital nephrotic syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 91 out of 100
• SIFT: 90 out of 100
• phyloP: 87 out of 100
• MetaLR: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Nephrotic syndrome is also caused by NPHS2 variants; they fall mostly in different places as the Finnish congenital nephrotic syndrome variants (30 disease-causing).
• Steroid-resistant nephrotic syndrome is also caused by NPHS2 variants; they fall mostly in different places as the Finnish congenital nephrotic syndrome variants (8 disease-causing).
• Idiopathic nephrotic syndrome is also caused by NPHS2 variants; they fall mostly in different places as the Finnish congenital nephrotic syndrome variants (5 disease-causing).

Diseases related to Finnish congenital nephrotic syndrome

• Nephrotic syndrome, also linked to NPHS1 and NPHS2
• Focal segmental glomerulosclerosis, also linked to NPHS1 and NPHS2
• Steroid-resistant nephrotic syndrome, also linked to NPHS2
• Idiopathic nephrotic syndrome, also linked to NPHS2
• Kidney disorder, also linked to NPHS1

Frequently asked questions

Which genes are linked to Finnish congenital nephrotic syndrome?

In CATVariant, Finnish congenital nephrotic syndrome is linked to 2 analyzed proteins: NPHS1 (Nephrin) and NPHS2 (Podocin).

How many genetic variants are linked to Finnish congenital nephrotic syndrome?

287 variants: 71 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 212 are of uncertain significance or have conflicting reports.

Which uncertain variants in Finnish congenital nephrotic syndrome look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example NPHS1 S572G. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Finnish congenital nephrotic syndrome?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.91, based on 47 disease-causing and 41 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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