scholarly journals Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus

2021 ◽  
Vol 9 ◽  
Author(s):  
Panli Liao ◽  
Tianchao Xiang ◽  
Hongxia Li ◽  
Ye Fang ◽  
Xiaoyan Fang ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Isotonic Saline ◽  
Treatment Strategies ◽  
Clinical Genetic ◽  
Pathogenic Variants ◽  
Protein Structural Analysis

Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder characterized by renal inability to concentrate urine. We utilized a multicenter strategy to investigate the genotype and phenotype in a cohort of Chinese children clinically diagnosed with NDI from 2014 to 2019. Ten boys from nine families were identified with mutations in AVPR2 or AQP2 along with dehydration, polyuria–polydipsia, and severe hypernatremia. Genetic screening confirmed the diagnosis of seven additional relatives with partial or subclinical NDI. Protein structural analysis revealed a notable clustering of diagnostic mutations in the transmembrane region of AVPR2 and an enrichment of diagnostic mutations in the C-terminal region of AQP2. The pathogenic variants are significantly more likely to be located inside the domain compared with population variants. Through the structural analysis and in silico prediction, the eight mutations identified in this study were presumed to be disease-causing. The most common treatments were thiazide diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Emergency treatment for hypernatremia dehydration in neonates should not use isotonic saline as a rehydration fluid. Genetic analysis presumably confirmed the diagnosis of NDI in each patient in our study. We outlined methods for the early identification of NDI through phenotype and genotype, and outlined optimized treatment strategies.

scholarly journals Integrating population variation and protein structural analysis to improve the clinical genetic diagnosis and treatment in children with congenital nephrogenic diabetes insipidus

2020 ◽  
Author(s):  
Panli LIAO ◽  
Tianchao XIANG ◽  
Hongxia LI ◽  
Ye FANG ◽  
Xiaoyan FANG ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Isotonic Saline ◽  
Population Variation ◽  
Pathogenic Mutations ◽  
Protein Structural Analysis ◽  
Congenital Nephrogenic Diabetes Insipidus

Abstract Background and Objectives: Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder characterized by renal inability to concentrate urine. Establishing the genetic diagnosis appears particularly important to NDI for early detection and differential diagnosis.Method: We utilized a Chinese multicenter registry to investigate genotype and phenotype in children with NDI from 2014 to 2019. The structural locations of the pathogenic mutations from this study and the literature, as well as population variants retried from gnomAD were analyzed. Results: A total of 10 boys from 9 families carried mutations in AVPR2 (8/10) or AQP2 (2/10). Another 7 relatives of the families were diagnosed by sequencing for partial or subclinical NDI. Patients presented with dehydration, polyuria-polydipsia, and severe hypernatremia with a median age at diagnosis of 1.0 month (IQR 0.16, 18). Protein structural analysis revealed a notable clustering of diagnostic mutations in the transmembrane regions of AVPR2, and enrichment of diagnostic mutations by autosomal dominant inheritance (AD) in the C terminal region of AQP2. The pathogenic mutations are significantly more likely to be buried inside the domain comparing the population variants. Through structural analysis and in silico prediction, the eight mutations identified in this study were considered as presumably disease causative. The most common treatments were thiazide diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Emergency treatment of hypernatremic dehydration in neonates should not choose the isotonic saline as a rehydration fluid.Conclusion: Genetic analysis presumably confirmed the diagnosis of NDI in every patient of the studied cohort. A plea of early identifying NDI confirmed by phenotype and genotype, and consequently optimize the treatment.

scholarly journals Valine-279 Deletion–Mutation on Arginine Vasopressin Receptor 2 Causes Obstruction in G-Protein Binding Site: A Clinical Nephrogenic Diabetes Insipidus Case and Its Sub-Molecular Pathogenic Analysis

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 301
Author(s):  
Ming-Chun Chen ◽  
Yu-Chao Hsiao ◽  
Chun-Chun Chang ◽  
Sheng-Feng Pan ◽  
Chih-Wen Peng ◽  
...  
Keyword(s):  
Structural Analysis ◽  
Protein Binding ◽  
Diabetes Insipidus ◽  
Binding Site ◽  
G Protein ◽  
Arginine Vasopressin ◽  
Nephrogenic Diabetes Insipidus ◽  
Md Simulations ◽  
Protein Binding Site ◽  
Vasopressin Receptor

Congenital nephrogenic diabetes insipidus (CNDI) is a genetic disorder caused by mutations in arginine vasopressin receptor 2 (AVPR2) or aquaporin 2 genes, rendering collecting duct cells insensitive to the peptide hormone arginine vasopressin stimulation for water reabsorption. This study reports a first identified AVPR2 mutation in Taiwan and demonstrates our effort to understand the pathogenesis caused by applying computational structural analysis tools. The CNDI condition of an 8-month-old male patient was confirmed according to symptoms, family history, and DNA sequence analysis. The patient was identified to have a valine 279 deletion–mutation in the AVPR2 gene. Cellular experiments using mutant protein transfected cells revealed that mutated AVPR2 is expressed successfully in cells and localized on cell surfaces. We further analyzed the pathogenesis of the mutation at sub-molecular levels via long-term molecular dynamics (MD) simulations and structural analysis. The MD simulations showed while the structure of the extracellular ligand-binding domain remains unchanged, the mutation alters the direction of dynamic motion of AVPR2 transmembrane helix 6 toward the center of the G-protein binding site, obstructing the binding of G-protein, thus likely disabling downstream signaling. This study demonstrated that the computational approaches can be powerful tools for obtaining valuable information on the pathogenesis induced by mutations in G-protein-coupled receptors. These methods can also be helpful in providing clues on potential therapeutic strategies for CNDI.

Novel mutations associated with nephrogenic diabetes insipidus. A clinical-genetic study

2015 ◽  
Vol 174 (10) ◽  
pp. 1373-1385 ◽  
Author(s):  
Alejandro García Castaño ◽  
◽  
Gustavo Pérez de Nanclares ◽  
Leire Madariaga ◽  
Mireia Aguirre ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Genetic Study ◽  
Nephrogenic Diabetes Insipidus ◽  
Novel Mutations ◽  
Clinical Genetic

Importance of Early Genetic Sequencing in Neonates Admitted to NICU with Recurrent Hypernatremia: Results of a Prospective Cohort Study

Neonatology ◽  
2021 ◽  
pp. 1-8
Author(s):  
Liyuan Hu ◽  
Lin Yang ◽  
Kai Yan ◽  
Bingbing Wu ◽  
Huijun Wang ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Single Gene ◽  
Genetic Diagnosis ◽  
Plasma Sodium ◽  
Onset Age ◽  
Genetic Etiology ◽  
Genetic Characteristics ◽  
Genetic Sequencing ◽  
Congenital Nephrogenic Diabetes Insipidus

<b><i>Objectives:</i></b> The genetic characteristics in neonates admitted to the NICU with recurrent hypernatremia remained unknown. We aimed to implement early genetic sequencing to identify possible genetic etiologies, optimize the treatment, and improve the outcome. <b><i>Methods:</i></b> We prospectively performed exome sequencing or targeted panel sequencing on neonates diagnosed with recurrent hypernatremia (plasma sodium ≥150 mEq/L, ≥2 episodes) from January 1, 2016, to June 30, 2020. <b><i>Results:</i></b> Among 22,375 neonates admitted to the NICU, approximately 0.33% (73/22,375) developed hypernatremia. The incidence of hypernatremia &#x3e;14 days and ≤14 days was 0.03% and 0.3%, respectively. Among 38 neonates who had ≥2 hypernatremia episodes, parents of 28 patients consented for sequencing. Genetic diagnosis was achieved in 25% neonates (7/28). Precision medicine treatment was performed in 85.7% (6/7) of the patients, including hydrochlorothiazide and indomethacin for 57.1% (4/7) with arginine vasopressin receptor 2 (<i>AVPR2</i>) deficiency-associated congenital nephrogenic diabetes insipidus; a special diet of fructose formula for 1 patient with solute carrier family 5 member 1 deficiency-associated congenital glucose-galactose malabsorption (1/7, 14.3%); and kallikrein-inhibiting ointment for 1 patient with serine protease inhibitor of Kazal-type <i>5</i> deficiency-associated Netherton syndrome (1/7, 14.3%). Only hypernatremia onset age (adjusted odds ratio 1.32 [1.01–1.72], <i>p</i> = 0.040) independently predicted the underlying genetic etiology. The risk of a genetic etiology of hypernatremia was 9.0 times higher for neonates with a hypernatremia onset age ≥17.5 days (95% confidence interval, 1.1–73.2; <i>p</i> = 0.038). <b><i>Conclusions:</i></b> Single-gene disorders are common in neonates with recurrent hypernatremia, and &#x3e;50% of cases are caused by <i>AVPR2</i> deficiency-associated congenital nephrogenic diabetes insipidus. Early genetic testing can aid the diagnosis of unexplained recurrent neonatal hypernatremia and improve therapy and outcome.

scholarly journals Contribution of SLC22A12 on hypouricemia and its clinical significance for screening purposes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Do Hyeon Cha ◽  
Heon Yung Gee ◽  
Raul Cachau ◽  
Jong Mun Choi ◽  
Daeui Park ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Kidney Injury ◽  
Genetic Identification ◽  
Diagnostic Screening ◽  
Renal Hypouricemia ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Causal Variants ◽  
Coding Variants ◽  
Independent Cohort

Abstract Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (<1.3 mg/dl) from a Korean urban cohort of 179,381 subjects without underlying conditions. WES and corresponding downstream analyses were performed for the discovery of rare causal variants for hypouricemia. Two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.

scholarly journals One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation

2021 ◽  
Author(s):  
Stephen E. Lincoln ◽  
Tina Hambuch ◽  
Justin M. Zook ◽  
Sara L. Bristow ◽  
Kathryn Hatchell ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Copy Number Variants ◽  
Low Complexity ◽  
Clinical Genetic ◽  
Clinical Sensitivity ◽  
Pathogenic Variants ◽  
Wide Range ◽  
Large Indels ◽  
Next Generation Sequencing Ngs ◽  
The Impact

Abstract Purpose To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions. Methods An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)–based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients. Results In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests. Conclusion The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.

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