Nephroplex: a kidney-focused NGS panel highlights the challenges of PKD1 sequencing and identifies a founder BBS4 mutation

Abstract

Background Genetic testing of patients with inherited kidney diseases has emerged as a tool of clinical utility by improving the patients’ diagnosis, prognosis, surveillance and therapy. Methods The present study applied a Next Generation Sequencing (NGS)-based panel, named NephroPlex, testing 115 genes causing renal diseases, to 119 individuals, including 107 probands and 12 relatives. Thirty-five (poly)cystic and 72 non (poly)cystic individuals were enrolled. The latter subgroup of patients included Bardet-Biedl syndrome (BBS) patients, as major components. Results Disease-causing mutations were identified in 51.5 and 40% of polycystic and non-polycystic individuals, respectively. Autosomal dominant polycystic kidney disease (ADPKD) patients with truncating PKD1 variants showed a trend towards a greater slope of the age-estimated glomerular filtration rate (eGFR) regression line than patients with (i) missense variants, (ii) any PKD2 mutations and (iii) no detected mutations, according to previous findings. The analysis of BBS individuals showed a similar frequency of BBS4,9,10 and 12 mutations. Of note, all BBS4-mutated patients harbored the novel c.332+1G>GTT variant, which was absent in public databases, however, in our internal database, an additional heterozygote carrier was found. All BBS4-mutated individuals originated from the same geographical area encompassing the coastal provinces of Naples. Discussion In conclusion, these findings indicate the potential for a genetic panel to provide useful information at both clinical and epidemiological levels. Graphic abstract

Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook

“…50 However, mutations in BBS1 to BBS18 account for about 70-80% of cases worldwide 73 and about 50% of diagnosis in the western countries are due to mutations in three genes: BBS1, BBS2 and BBS10. 19,74 In Caucasian populations, indeed, mutations in BBS1 and BBS10 are detected in 21-30% of patients, 75 a percentage rising to 40-50% in Northern European patients. 76 A founder effect is responsible for the two most common mutations in Northern Europe: p.M390R (BBS1, accounting for 50% of BBS1 cases) and p.C91Lfs*5 (BBS10).…”

“…BBS1, BBS3, and BBS4 mutations are commonly reported in Saudi Arabia, 72,79 while pathogenic variants in BBS1, BBS2 and BBS8 are common in Tunisia; 80 Middle Eastern and North African individuals have a high frequency of BBS4, BBS5, and TTC8 variants. 81 A possible bias is the underdiagnosis and scarcity of large studies from some areas of the world; 74,[82][83][84] in isolated populations characterized by a high frequency of marriages among consanguineous, the frequency of the disease is higher and founder effects are common; the Faroe Islands (c.1091 + 3G>C in BBS1), 5 Tunisia (p.R189* in BBS2 and c.459 + 1G>A in BBS8) 80,85,86 and the Hutterite population (c.472-2A>G in BBS2) are some examples. 32,73,87 Similarly, we have recently found a possible BBS4 (c.332+1G>GTT) founder mutation in a restricted geographic area of the province of Naples.…”

“…32,73,87 Similarly, we have recently found a possible BBS4 (c.332+1G>GTT) founder mutation in a restricted geographic area of the province of Naples. 74 Most BBS genes have a low tissue specificity. Few exceptions are BBIP1, which is mainly expressed in the testis, LZTFL1, expressed in lymphoid tissue and NPHP1, in the skeletal muscle.…”

Next-Generation Sequencing (NGS) Analysis Illustrates the Phenotypic Variability of Collagen Type IV Nephropathies

“…The α5 subunit is encoded by COL4A5 , located on the X-chromosome, and is associated with the classic X-linked Alport syndrome (AS) in male patients. The α3 or α4 subunits are encoded by COL4A3 and COL4A4 , respectively; their mutations cause either autosomal dominant/recessive Alport syndrome and thin basement membrane nephropathy (TBMN) [ 1 , 2 ]. Typically, AS patients’ phenotype is characterized by hematuria from infancy, with subsequent onset of glomerular filtration rate (GFR) decline up to end-stage renal disease (ESRD) in young-adults; extra-renal features include sensorineural hearing loss and sometimes lenticonus or retinal/corneal dystrophy [ 3 ].…”

Metabolomic fingerprinting of renal disease progression in Bardet-Biedl syndrome reveals mitochondrial dysfunction in kidney tubular cells

“…There is significant evidence that energy metabolism is impaired in both genetic and acquired kidney disorders ( Zacchia et al., 2020 , 2021b ). Moreover, metabolomics has emerged as a valid tool to analyze metabolites within biological fluids, aiming at detecting disease-related biomarkers as well as molecular aberrations underlying pathologic conditions.…”