New insights from trio whole-exome sequencing in the children with kidney disease: A single-center retrospective cohort study.

BACKGROUND: Kidney disease of children markedly affects their health and development. Limited clinical data of early-stage kidney disease render a tremendous challenge for the accurate diagnosis. Trio whole-exome sequencing (Trio-WES) is emerging as a first-line diagnostic strategy in pediatric kidney disease, and shows important implications for the precision medicine strategies of children with kidney disease. METHODS: Trio-WES was performed in 133 Chinese children with kidney disease and their parents. The results for casual variants in genes known to cause kidney disease were analyzed. We further assessed the genetic diagnostic yield and the clinical implications of genetic testing. RESULTS: An overall diagnostic yield of 52.63% (70/133) was found, and the diagnostic rates ranged from 44.74% to 59.62% in different clinical phenotypes. The diagnostic yield of the three groups of simple proteinuria, renal insufficiency, and "other" was 50%, 50%, and 54.55%, respectively. Eight-seven diagnostic variants were identified in 70 probands with variants spanning 30 genes. The top 7 genes with diagnostic variants were COL4A5 (23, 26.44%), COL4A4 (13, 14.94%), ADCK4 (7, 8.05%), CLCN5 (3, 3.45%), ACE (3, 3.45%), PKD1 (3, 3.45%), and SLC12A3 (3, 3.45%), accounting for 63.22% of all variations in the cohort. CONCLUSIONS: The retrospective cohort study summarized the clinical utility of genetic testing in 133 probands, and expanded the phenotypic and genetic profiles of kidney disease in children. Trio-WES is an efficient diagnostic tool for children with kidney disease, which facilitates the clinical diagnosis and treatment. Our findings have important implications for the precise diagnosis of childhood nephropathy and may provide clinical guideline for disease management.

Metabolomics-driven gene mining and genetic improvement of tolerance to salt-induced osmotic stress in maize.

The farmland of the world's main corn-producing area is increasingly affected by salt stress. Therefore, the breeding of salt-tolerant cultivars is necessary for the long-term sustainability of global corn production. Previous studies have shown that natural maize varieties display a large diversity of salt tolerance, yet the genetic variants underlying such diversity remain poorly discovered and applied, especially those mediating the tolerance to salt-induced osmotic stress (SIOS). Here we report a metabolomics-driven understanding and genetic improvement of maize SIOS tolerance. Using a LC-MS-based untargeted metabolomics approach, we profiled the metabolomes of 266 maize inbred lines under control and salt conditions, and then identified 37 metabolite biomarkers of SIOS tolerance (METO1-37). Follow-up metabolic GWAS (mGWAS) and genotype-to-phenotype modeling identified 10 candidate genes significantly associating with the SIOS tolerance and METO abundances. Furthermore, we validated that a citrate synthase, a glucosyltransferase and a cytochrome P450 underlie the genotype-METO-SIOS tolerance associations, and showed that their favorable alleles additively improve the SIOS tolerance of elite maize inbred lines. Our study provides a novel insight into the natural variation of maize SIOS tolerance, which boosts the genetic improvement of maize salt tolerance, and demonstrates a metabolomics-based approach for mining crop genes associated with this complex agronomic trait.

Natural variation of an EF-hand Ca2+-binding-protein coding gene confers saline-alkaline tolerance in maize.

Sodium (Na+) toxicity is one of the major damages imposed on crops by saline-alkaline stress. Here we show that natural maize inbred lines display substantial variations in shoot Na+ contents and saline-alkaline (NaHCO3) tolerance, and reveal that ZmNSA1 (Na+ Content under Saline-Alkaline Condition) confers shoot Na+ variations under NaHCO3 condition by a genome-wide association study. Lacking of ZmNSA1 promotes shoot Na+ homeostasis by increasing root Na+ efflux. A naturally occurred 4-bp deletion decreases the translation efficiency of ZmNSA1 mRNA, thus promotes Na+ homeostasis. We further show that, under saline-alkaline condition, Ca2+ binds to the EF-hand domain of ZmNSA1 then triggers its degradation via 26S proteasome, which in turn increases the transcripts levels of PM-H+-ATPases (MHA2 and MHA4), and consequently enhances SOS1 Na+/H+ antiporter-mediated root Na+ efflux. Our studies reveal the mechanism of Ca2+-triggered saline-alkaline tolerance and provide an important gene target for breeding saline-alkaline tolerant maize varieties.