Genotype First Approach as a Diagnostic Strategy for Precision Medicine in Moroccan Families with Nephronophthisis

Abstract

Nephronophthisis is a group of autosomal recessive kidney diseases characterized by chronic tubulointerstitial abnormalities leading to kidney failure. The incidence of nephronophthisis varies globally, and its genetic heterogeneity presents significant difficulties in diagnosis. Herein, we present a molecular diagnosis of four unrelated Moroccan families fulfilling the clinical criteria of nephronophthisis. As first diagnosis step, screening for a homozygous NPHP1 gene deletion, the most common mutation, was performed by using multiplex polymerase chain reaction. Additionally, clinical exome sequencing was carried out on patients in whom no NPHP1 deletion was identified. Three novel pathogenic variants in NPHP1, INVS, and NPHP4 genes were identified and confirmed by Sanger sequencing in the proband and other family members. These variants are absent from genetic databases of patients and controls of Moroccan origin. The bioinformatics analysis classified these variants as pathogenic. Our findings expand the genotypic spectrum of nephronophthisis and highlight the importance of genetic testing in patients from low- and middle-income countries to obtain a precise diagnosis of nephronophthisis. This helps facilitate an appropriate and personalized genetic counseling and improves clinical outcomes for patients with this condition.

Keywords

nephronophthisis - NPHP1 - INVS - NPHP4 - novel mutation - clinical exome sequencing

• References

• 1 Gupta S, Ozimek-Kulik JE, Phillips JK. Nephronophthisis-pathobiology and molecular pathogenesis of a rare kidney genetic disease. Genes (Basel) 2021; 12 (11) 1762
• 2 Braun DA, Hildebrandt F. Ciliopathies. Cold Spring Harb Perspect Biol 2017; 9 (03) a028191
• 3 Luo F, Tao YH. Nephronophthisis: a review of genotype-phenotype correlation. Nephrology (Carlton) 2018; 23 (10) 904-911
• 4 Petzold F, Billot K, Chen X. et al; INSERM–Necker Hospital NPH collaborative group. The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies. Kidney Int 2023; 104 (02) 378-387
• 5 Soliman NA, Hildebrandt F, Otto EA. et al. Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: a single center experience. Saudi J Kidney Dis Transpl 2012; 23 (05) 1090-1098
• 6 Stokman MF, van der Zwaag B, van de Kar NCAJ. et al. Clinical and genetic analyses of a Dutch cohort of 40 patients with a nephronophthisis-related ciliopathy. Pediatr Nephrol 2018; 33 (10) 1701-1712
• 7 Srivastava S, Molinari E, Raman S, Sayer JA. Many Genes-One Disease? Genetics of Nephronophthisis (NPHP) and NPHP-Associated Disorders. Front Pediatr 2018; 5: 287
• 8 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 9 Salomon R, Saunier S, Niaudet P. Nephronophthisis. Pediatr Nephrol 2009; 24 (12) 2333-2344
• 10 Hildebrandt F, Strahm B, Nothwang H-G. et al. Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft für Pädiatrische Nephrologie. Kidney Int 1997; 51 (01) 261-269
• 11 Halbritter J, Porath JD, Diaz KA. et al; GPN Study Group. Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet 2013; 132 (08) 865-884
• 12 Tory K, Rousset-Rouvière C, Gubler M-C. et al. Mutations of NPHP2 and NPHP3 in infantile nephronophthisis. Kidney Int 2009; 75 (08) 839-847
• 13 Otto EA, Helou J, Allen SJ. et al. Mutation analysis in nephronophthisis using a combined approach of homozygosity mapping, CEL I endonuclease cleavage, and direct sequencing. Hum Mutat 2008; 29 (03) 418-426
• 14 Chaki M, Hoefele J, Allen SJ. et al. Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies. Kidney Int 2011; 80 (11) 1239-1245
• 15 König J, Kranz B, König S. et al; Gesellschaft für Pädiatrische Nephrologie (GPN). Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies. Clin J Am Soc Nephrol 2017; 12 (12) 1974-1983
• 16 Li J, Su X, Zhang H. et al. Genotype and phenotype analysis and transplantation strategy in children with kidney failure caused by NPHP. Pediatr Nephrol 2023; 38 (05) 1609-1620