Monogenic causes of chronic kidney disease in adults

Abstract

Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.

Keywords: chronic kidney disease; genetic kidney disease; whole exome sequencing.

Figure 1.. Percentage of the 114 families in Ireland with CKD in whom whole exome sequencing (WES) established a molecular genetic diagnosis (i.e. a pathogenic or likely pathogenic monogenic mutation in a known CKD gene was detected following WES)

(A) The 37% of families (42/114) in whom a pathogenic or likely pathogenic mutation in a known CKD disease gene was detected (i.e. molecular genetic diagnosis established following WES) is denoted by a navy blue colour. The 12% of families (14/114) in whom a variant of uncertain significance (VUS) in a known CKD gene was detected, is denoted by the light blue colour. Yellow colour indicates that no meaningful genetic variant could be detected in a known CKD gene following WES (i.e. no molecular genetic diagnosis established following WES). (B) The category and percentage of monogenic mutations detected in the 42 families in whom we identified a pathogenic or likely pathogenic mutation in a known CKD gene (i.e. families in whom we established a molecular genetic diagnosis). Each colour represents a different molecular genetic diagnostic group. i) Mutations in known cystic kidney disease including nephronophthisis genes (red) ii) Mutations in known syndromic CAKUT genes (light blue) iii) Mutations in known isolated CAKUT genes (dark blue) iv) Mutations in known chronic glomerulonephritis (GN) genes (orange) v) Mutations in known tubulo-interstitial kidney disease (TIKD) genes (brown) vi) Mutations in known renal tubulopathy genes (purple) vii) Mutations in known nephrolithiasis/nephrocalcinosis (NLNC) genes (pink) viii) Mutations in known steroid resistant nephrotic syndrome (SRNS) genes (green) ix) Mutations in known rare chronic kidney disease genes (miscellaneous category) (cream) identified

Figure 2.. Percentage of the 114 families in Ireland with CKD in whom whole exome sequencing established a molecular genetic diagnosis (i.e. a pathogenic or likely pathogenic monogenic mutation in a known CKD gene was detected following WES) stratified by recruitment group

Navy blue colour denotes families in whom a pathogenic or likely pathogenic mutation in a known CKD gene was detected (i.e. molecular genetic diagnosis established following WES). Light blue colour denotes families in whom we identified a variant of uncertain significance (VUS) in a known CKD gene following WES. Yellow colour indicates that no meaningful genetic variant could be detected in a known CKD gene following WES (i.e. no molecular genetic diagnosis established following WES). A) Positive family history cohort denotes families with CKD who report CKD in either a 1^st or 2^nd degree relative (78/144 families) B) Negative family history but extra-renal features cohort (16/114 families) C) Negative family history and no extra-renal features cohort (20/114 families)

Figure 3.. Specific mutation category identified by whole exome sequencing in 114 families with chronic kidney disease

The X-axis displays the 7 a priori clinical diagnostic groups listed horizontally and includes cystic kidney disease (KD), congenital anomalies of the kidney and urinary tract (CAKUT), chronic glomerulonephritis (GN), tubulo-interstitial kidney disease (TIKD), steroid resistant nephrotic syndrome (SRNS), renal tubulopathy (tubulopathy) and CKD - aetiology unknown. The Y-axis displays the molecular genetic diagnosis established following whole exome sequencing and includes the following: i) Mutations in known cystic kidney disease including nephronophthisis genes (red) identified ii) Mutations in known syndromic CAKUT genes (light blue) identified iii) Mutations in known isolated CAKUT genes (dark blue) identified iv) Mutations in known chronic glomerulonephritis (GN) genes (orange) identified v) Mutations in known tubulo-interstitial kidney disease (TIKD) genes (brown) identified vi) Mutations in known renal tubulopathy genes (purple) identified vii) Mutations in known steroid resistant nephrotic syndrome (SRNS) genes (green) identified viii) Mutations in known nephrolithiasis/nephrocalcinosis (NLNC) genes (pink) identified ix) Mutations in known rare chronic kidney disease genes (miscellaneous category) (cream) identified x) No molecular genetic diagnosis established following WES (yellow)