Open Access Research Article

NPHS1 and NPHS2 Variants Associated with Early-Onset Frequently Relapsing or Steroid-Dependent Nephrotic Syndrome

Ahmad O Babalghith1, Nasser A Elhawary1*, Iman S Abumansour1, Ehab M Melibary1, Ghydda Alghamdi1, Ikhlas A Sindi2, Ezzeldin N Elhawary3, Najiah M Alyamani4, Ibtesam S Almami5, Hind Naffadi6, Afnan Shakoori7, Luai Zamil8, Nasser Alenezy9 and Mohammed Dandini10

1Department of Medical Genetics, College of Medicine, Umm Al-Qura University, Mecca, SA

2Department of Biotechnology, Faculty of Science, King Abdulaziz University, SA

3MS Genomic Medicine Program, Faculty of Medicine, University of Southampton, Southampton General Hospital, UK

4Department of Biology, College of Science, University of Jeddah, Jeddah, SA

5Department of Biology, College of Science, Qassim University, SA

6Common Science, First Year Deanship, Umm Al-Qura University, Mecca, SA

7Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Mecca, SA

8Department of Laboratory and Blood Bank, King Abdulaziz Hospital, Mecca, SA

9Rumah General Hospital, Ministry of Health; Riyadh, SA

10Department of Laboratory and Blood Bank, Maternity and Children Hospital, Mecca, SA

Corresponding Author

Received Date: June 17, 2022;  Published Date: June 29, 2022


Background: Glomerular podocytes and slit diaphragms remain the major causes of progressive proteinuria and nephrotic syndrome (NS).

Objective: Here, we analyzed genetic variants in the nephrin (NPHS1) and podocin (NPHS2) genes in cases with early-onset presentation of NS in Saudi Arabia.

Subjects and methods: Clinical characteristics and genomic DNA were collected from 35 unrelated NS cases (mean age of onset, 3.0 years; range, stillbirth-8 years). Cases were diagnosed based on histologic kidney biopsy and biochemical parameters. Enzymatic digestion was performed on PCR amplicons for the frameshift L41NfsX50 and nonsense R1109X variants of NPHS1, and the entire coding regions of NPHS2 were sequenced.

Results: We identified 15 cases of frequently relapsing NS or steroid-dependent NS (FRNS/SDNS) (42.9%), 12 cases of steroid-resistant NS (SRNS) (34.3%), and 8 cases of steroid-sensitive NS (SSNS) (22.9%). Cases with FRNS/SDNS (46.2%) had a younger age at presentation than cases with SSNS (38.5%; P = 0.52) or SRNS (15.4%; P = 0.0056). one SSNS case, three FRNS/SDNS, and three SRNS carried the NPHS1 R1109X (Finminor) variant. For NPHS2, one SSNS case carried a homozygote R168H variant, and another SSNS case carried a compound heterozygote R229Q variant. The allele frequencies of the NPHS1 R1109X variant and the NPHS2 R168H and R229Q variants were 14% and 4.3%, respectively. No cases carried the NPHS1 L41NfsX50 variant. Available kidney biopsy reports revealed that minimal change disease was most frequent in FRNS/SDNS cases (56.7%) and focal segmental glomerulosclerosis, most common in SRNS cases (75%).

Conclusion: A significant proportion of the youngest SSNS cases may develop FRNS/SDNS.

Keywords: Nephrotic syndrome; NPHS1; NPHS2; Nephrin; Podocin; Frequently-relapsing or Steroid-dependent; Steroid-resistance

Abbreviations: CRF -chronic kidney failure; FATHMM-Functional Analysis through Hidden Markov Models; FRNS -Frequently Relapsing Nephrotic Syndrome; FSGS- Focal Segmental Glomerulosclerosis; GFR- Glomerular Filtration Rate; IgA- Immunoglobulin A; ISKDC-International Study of Kidney Disease in Children; Lo Ftool- loss-of-Function Tool; MCD-Minimal Change Disease; MCNS-Minimal change Nephrotic Syndrome; MsPGNMesangioproliferative glomerulonephritis; NPHS1-Nephrin; NPHS2-podocin; NS- Nephrotic Syndrome; PolyPhen-2- Polymorphism Phenotyping v2, SA- Saudi Arabia SDNS- Steroid-dependent Nephrotic Syndrome; SIFT- Sorting Intolerant from Tolerant, SRNS -steroid-Resistant Nephrotic Syndrome; SSNS- Steroid-Sensitive Nephrotic Syndrome

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