Blog entry by Meguid El Nahas
Anyone in the world
Comments by Professor Neveen Soliman, head of EGORD (Egypt Group for Orphan Renal Diseases):
It is actually a pilot study where Gharavi and his coauthors tested the clinical utility of WES in 92 adults with undiagnosed/familial CKD.
They identified many known or undiagnosed genetic disorders in 22 of 92 cohort patients (24%).
Among these theyidentified PARN mutations (implicated in lung fibrosis) in 2 probands with tubulointerstitial fibrosis,
thereby extending the phenotype of PARN mutations to renal fibrosis.
They also confirmed the variable phenotypic expression of type IV collagen gene (previously reported by our group and others)
as they identified AR and XL forms of Alport syndrome among patients with the clinical diagnosis of FSGS.
This again supports the categorization of FSGS ad pathological and not an etiological diagnosis. As such WES had immediate clinical implications:
i) for surveillance for extrarenal manifestations; and ii) avoidance of unnecessary immunosupressive therapy in cases misdiagnosed as FSGS.
This work lends support to Prof Soliman own work in collaboration with Prof Hildebrandt in Boston on the value of application of WES to CKD, as they investigated genetic mutations in patients with CAKUT and detected recessive mutations in nine known disease-causing genes: ZBTB24, WFS1, HPSE2, ATRX, ASPH, AGXT, AQP2, CTNS, and PKHD1 notably, when mutated, these genes cause multiorgan syndromes that may include CAKUT as a feature (syndromic CAKUT) or cause renal diseases that may manifest as phenocopies of CAKUT. None of the above monogenic disease-causing genes were suspected on clinical grounds before this study. Follow-up clinical characterization of those patients allowed them to revise and detect relevant new clinical features in a more appropriate pathogenetic context.
They concluded that applying WES to the diagnostic approach in CAKUT provides opportunities for an accurate and early etiology-based diagnosis and improved clinical management.
Also, one of the most exciting associations between CKD and genetic mutations has been that involving the UMOD loci coding for Uromodulin (Tamm-Horsfall protein), that showed an association between such mutation and the incidence as well as the progression of CKD.
In addition, rare mutations in UMOD seem to be major causes of autosomal dominant tubulointerstitial kidney disease, a condition that leads to CKD and ESRD. https://www.ncbi.nlm.nih.gov/pubmed/29180396
In summary new and streamlined genetic approaches to the diagnosis and management of CKD are well underway and may unravel genetic mutations associations that shed light onto the mechanism of underlying nephropathies as well as open the way to the genetic manipulations of such abnormalities.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]