Look Alike, Sound Alike: Phenocopies in Steroid-Resistant Nephrotic Syndrome

Becherucci, Francesca; Landini, Samuela; Cirillo, Luigi; Mazzinghi, Benedetta; Romagnani, Paola

doi:10.3390/ijerph17228363

Cited by 12 publications

(10 citation statements)

References 94 publications

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“…More than 50% patients with Dent disease will present with nephrotic-range proteinuria, which is the important reason for misdiagnosis as SRNS. One mutation in the CLCN5 gene (c.2000delC) was reported in a family of SRNS by the PodoNet cohort ( 34 ), and our case illustrated similar phenotypic traits at all ( 35 ). To our knowledge, 3 different mechanisms might explain patients with phenocopies: one for misdiagnosis: clinical or genetic misdiagnosis; the second for concomitant of two different diseases; the third one is the real phenocopy as causality was not established between certain phenotypes and genotypes.…”

Section: Discussionsupporting

confidence: 68%

The Clinical and Genetic Features in Chinese Children With Steroid-Resistant or Early-Onset Nephrotic Syndrome: A Multicenter Cohort Study

Zhu

Zhang

et al. 2022

Front. Med.

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Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage kidney disease (ESKD) in children and young adults. For approximately 30% of children with SRNS results from a genetic cause. In this study, genotype-phenotype correlations in a cohort of 283 pediatric patients with SRNS or early-onset NS (nephrotic syndrome presenting within the first year of life) from 23 major pediatric nephrology centers in China were analyzed. All patients were performed with next-generation sequencing and Sanger sequencing. The overall mutation detection rate was 37.5% (106 of 283 patients). WT1 was the most frequently detected mutation, followed by NPHS1, NPHS2, and ADCK4, and these four major causative genes (WT1, NPHS1, NPHS2, and ADCK4) account for 73.6% of patients with monogenic SRNS. Thirteen of 106 individuals (12.3%) carried mutations in ADCK4 that function within the coenzyme Q10 biosynthesis pathway. In the higher frequently ADCK4-related SRNS, two mutations, c.737G>A (p.S246N) and c.748G>C (p.D250H), were the most prevalent. Our study provides not only definitive diagnosis but also facilitate available targeted treatment for SRNS, and prediction of prognosis and renal outcome. Our indications for genetic testing are patients with FSGS, initial SRNS, cases of positive family history or those with extra-renal manifestations.

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Section: Discussionsupporting

confidence: 68%

The Clinical and Genetic Features in Chinese Children With Steroid-Resistant or Early-Onset Nephrotic Syndrome: A Multicenter Cohort Study

Zhu

Zhang

et al. 2022

Front. Med.

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“…8 Reverse phenotyping is an approach in which specific clinical features are interrogated in a subsequent clinical examination once a likely molecular genetic diagnosis has been established. 29 This method has been shown to detect causative genetic variants in genes that cause syndromic Mendelian diseases, including renal diseases such as pediatric-onset steroid-resistant nephrotic syndrome, 30,31 renal cystic ciliopathies, 32 and also CAKUT. 15 Another major weakness of ES is the long list of potentially deleterious variants after initial filtering.…”

Section: Introductionmentioning

confidence: 99%

Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT

Seltzsam

Wang

Zheng

et al. 2022

Genetics in Medicine

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Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES. Methods: We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping. Results: In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype-phenotype correlation. Conclusion:We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.

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“…Reverse genetics (i.e., reframing clinical diagnosis in view of genetic results) and identification of phenocopies have already proved efficacious in guiding this process in other fields of nephrology (e.g., podocytopathies and steroid-resistant nephrotic syndrome, ciliopathies, congenital anomalies of the kidney and urinary tract, etc.) [ 33 , 34 , 35 ], paving the way for a profound revision of disease ontology. Previous studies reported on disease reclassification based on reverse genetics, including in tubulopathies [ 14 , 18 , 28 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Characterization of Patients with Bartter and Gitelman Syndrome

Palazzo

Raglianti

Landini

et al. 2022

IJMS

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Bartter (BS) and Gitelman (GS) syndrome are autosomal recessive inherited tubulopathies, whose clinical diagnosis can be challenging, due to rarity and phenotypic overlap. Genotype–phenotype correlations have important implications in defining kidney and global outcomes. The aim of our study was to assess the diagnostic rate of whole-exome sequencing (WES) coupled with a bioinformatic analysis of copy number variations in a population of 63 patients with BS and GS from a single institution, and to explore genotype-phenotype correlations. We obtained a diagnostic yield of 86% (54/63 patients), allowing disease reclassification in about 14% of patients. Although some clinical and laboratory features were more commonly reported in patients with BS or GS, a significant overlap does exist, and age at onset, preterm birth, gestational age and nephro-calcinosis are frequently misleading. Finally, chronic kidney disease (CKD) occurs in about 30% of patients with BS or GS, suggesting that the long-term prognosis can be unfavorable. In our cohort the features associated with CKD were lower gestational age at birth and a molecular diagnosis of BS, especially BS type 1. The results of our study demonstrate that WES is useful in dealing with the phenotypic heterogeneity of these disorders, improving differential diagnosis and genotype-phenotype correlation.

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Look Alike, Sound Alike: Phenocopies in Steroid-Resistant Nephrotic Syndrome

Cited by 12 publications

References 94 publications

The Clinical and Genetic Features in Chinese Children With Steroid-Resistant or Early-Onset Nephrotic Syndrome: A Multicenter Cohort Study

The Clinical and Genetic Features in Chinese Children With Steroid-Resistant or Early-Onset Nephrotic Syndrome: A Multicenter Cohort Study

Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT

Clinical and Genetic Characterization of Patients with Bartter and Gitelman Syndrome

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