Uniparental isodisomy of chromosome 1 involving NPHS2 in steroid-resistant nephrotic syndrome with renal failure

Steroid-resistant nephrotic syndrome is a rare condition defined by early severe proteinuria associated with hypoalbuminemia, hyperlipidemia and possible edema, is usually caused by pathogenic variants in genes affecting the establishment and maintenance of the glomerular filtration barrier; among these NPHS1 (19q13.12) and NPHS2 (1q25.2) are by far the two main autosomal recessive genes implicated. We report on a 23-year-old girl referred to our hospital for Steroid-resistant nephrotic syndrome secondary to focal segmental glomerulosclerosis, onset at the age of 5 months. Next Generation Sequencing analysis showed the homozygous pathogenic variant c.413G > A in the NPHS2 gene, leading to the amino acid change p.Arg138Gln (rs74315342). By segregation study the father resulted heterozygous carrier of the same variants, while the mother emerged as wild-type. In order to investigate a possible chromosomal rearrangement in the maternal allele, SNP-array analysis was performed, revealing a paternally chromosome 1 isodisomy in the proband. Uniparental disomy of chromosome 1 is not associated with a specific phenotype but unmasks the autosomal recessive NPHS2 mutation paternally inherited and bring it to a homozygosity state. In conclusion, this clinical report demonstrates the importance of parental segregation analysis, especially in patients with recessive conditions, both to search for the disease specific genetic cause and to appropriately estimate the risk of recurrence in the family.