Multicenter study on the genetics of glomerular diseases among southeast and south Asians: Deciphering Diversities ‐ Renal Asian Genetics Network (DRAGoN)

Abstract

Multinational studies have reported monogenic etiologies in 25%–30% of children with steroid‐resistant nephrotic syndrome. Such large studies are lacking in Asia. We established Deciphering Diversities: Renal Asian Genetics Network (DRAGoN) and aimed to describe the genetic and clinical spectrums in Asians. We prospectively studied a cohort of 183 probands with suspected genetic glomerulopathies from South and Southeast Asia, of whom 17% had positive family history. Using multi‐gene panel sequencing, we detected pathogenic variants in 26 (14%) probands, of whom one‐third had COL4A4 or COL4A5 variants (n = 9, 5%). Of those with COL4A5 defects, only 25% had features suggestive of Alport syndrome. Besides traditional predictors for genetic disease (positive family history and extrarenal malformations), we identified novel predictors, namely older age (6.2 vs. 2.4 years; p = 0.001), hematuria (OR 5.6; 95% CI 2.1–14.8; p < 0.001), and proteinuria in the absence of nephrotic syndrome (OR 4.6; 95% CI 1.8–11.8; p = 0.001) at first manifestation. Among patients who first presented with proteinuria without nephrotic syndrome, the genetic diagnostic rates were >60% when a second risk factor (positive family history or extrarenal manifestation) co‐existed. The genetic spectrum of glomerulopathies appears different in Asia. Collagen IV genes may be included in sequencing panels even when suggestive clinical features are absent.

Genetic stratification reveals COL4A variants and spontaneous remission in Egyptian children with proteinuria in the first 2 years of life

“…In accordance with our findings, but within an older age range, COL4A variants are emerging as the leading cause of genetic SRNS in south and southeast Asian children. 10,12 Unlike other studies where FSGS was observed in all children with SRNS and COL4A variants, 8,10 our patients had mesangial proliferation only. These findings may correlate with their earlier presentation and subsequent earlier biopsies or represents unsampled FSGS.…”

“…However, NPHS2 variants accounted for 51.4% of Central European patients with CNS, 9 whereas Asian children with SRNS rarely carried a podocin mutation 6,10,11 . Alternatively, they clustered variants of WT1 , 11 COQ8B , 6 or COL4A 10,12 …”

“…6,10,11 Alternatively, they clustered variants of WT1, 11 COQ8B, 6 or COL4A. 10,12 Kidney biopsies from patients with SRNS typically exhibit focal and segmental glomerulosclerosis (FSGS). 4,6,8 Other lesion patterns can also be observed, including minimal changes, diffuse mesangial sclerosis and collapsing glomerulopathy.…”

Clinical practice guidelines for nephrotic syndrome: consensus is emerging

“…The outcome in patients with CNI-refractory disease is not satisfactory [38]. While there are limited studies in Asian patients, these variations are perhaps less common, approaching ~ 15% [39]. Advances in exome sequencing and bioinformatics and standardization of reporting have enabled rapid and inexpensive screening for these variations.…”

“…Apart from identifying an alternative histopathology, the biopsy helps define the extent of tubulointerstitial fibrosis and pattern of glomerulosclerosis that may influence prognosis. Given reports of significant variations in COL4A genes in patients with steroid resistance, electron microscopy is necessary [4,5,39]. ISPN advises kidney biopsy in all patients with steroid resistance, except where histological diagnosis is considered unnecessary, e.g., in patients with known or strongly suspected monogenic disease, such as congenital nephrotic syndrome and familial steroid resistance [4].…”