Dataset Information

Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life.

ABSTRACT:

Introduction

Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause of chronic kidney disease (CKD) and the need for kidney replacement therapy (KRT) in children. Although more than 60 genes are known to cause CAKUT if mutated, genetic etiology is detected, on average, in only 16% of unselected CAKUT cases, making genetic testing unproductive.

Methods

Whole exome sequencing (WES) was performed in 100 patients with CAKUT diagnosed in the first 1000 days of life with CKD stages 1 to 5D/T. Variants in 58 established CAKUT-associated genes were extracted, classified according to the American College of Medical Genetics and Genomics guidelines, and their translational value was assessed.

Results

In 25% of these mostly sporadic patients with CAKUT, a rare likely pathogenic or pathogenic variant was identified in 1 or 2 of 15 CAKUT-associated genes, including GATA3, HNF1B, LIFR, PAX2, SALL1, and TBC1D1. Of the 27 variants detected, 52% were loss-of-function and 18.5% de novo variants. The diagnostic yield was significantly higher in patients requiring KRT before 3 years of age (43%, odds ratio 2.95) and in patients with extrarenal features (41%, odds ratio 3.5) compared with patients lacking these criteria. Considering that all affected genes were previously associated with extrarenal complications, including treatable conditions, such as diabetes, hyperuricemia, hypomagnesemia, and hypoparathyroidism, the genetic diagnosis allowed preventive measures and/or early treatment in 25% of patients.

Conclusion

WES offers significant advantages for the diagnosis and management of patients with CAKUT diagnosed before 3 years of age, especially in patients who require KRT or have extrarenal anomalies.

SUBMITTER: Werfel L

PROVIDER: S-EPMC10658255 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life.

Werfel Lina L Martens Helge H Hennies Imke I Gjerstad Ann Christin AC Fröde Kerstin K Altarescu Gheona G Banerjee Sushmita S Valenzuela Palafoll Irene I Geffers Robert R Kirschstein Martin M Christians Anne A Bjerre Anna A Haffner Dieter D Weber Ruthild G RG

Kidney international reports 20230814 11

<h4>Introduction</h4>Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause of chronic kidney disease (CKD) and the need for kidney replacement therapy (KRT) in children. Although more than 60 genes are known to cause CAKUT if mutated, genetic etiology is detected, on average, in only 16% of unselected CAKUT cases, making genetic testing unproductive.<h4>Methods</h4>Whole exome sequencing (WES) was performed in 100 patients with CAKUT diagnosed in the first 1000 d ...[more]

PMID: 38025229

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Project description:BackgroundAutism spectrum disorder (ASD) affects 1 in 100 children globally with a rapidly increasing prevalence. To the best of our knowledge, no data exists on the genetic architecture of ASD in India. This study aimed to identify the genetic architecture of ASD in India and to assess the use of whole exome sequencing (WES) as a first-tier test instead of chromosomal microarray (CMA) for genetic diagnosis.MethodsBetween 2020 and 2022, 101 patient-parent trios of Indian origin diagnosed with ASD according to the Diagnostic and Statistical Manual, 5th edition, were recruited. All probands underwent a sequential genetic testing pathway consisting of karyotyping, Fragile-X testing (in male probands only), CMA and WES. Candidate variant validation and parental segregation analysis was performed using orthogonal methods.ResultsOf 101 trios, no probands were identified with a gross chromosomal anomaly or Fragile-X. Three (2.9%) and 30 (29.7%) trios received a confirmed genetic diagnosis from CMA and WES, respectively. Amongst diagnosis from WES, SNVs were detected in 27 cases (90%) and CNVs in 3 cases (10%), including the 3 CNVs detected from CMA. Segregation analysis showed 66.6% (n = 3 for CNVs and n = 17 for SNVs) and 16.6% (n = 5) of the cases had de novo and recessive variants respectively, which is in concordance with the distribution of variant types and mode of inheritance observed in ASD patients of non-Hispanic white/ European ethnicity. MECP2 gene was the most recurrently mutated gene (n = 6; 20%) in the present cohort. Majority of the affected genes identified in the study cohort are involved in synaptic formation, transcription and its regulation, ubiquitination and chromatin remodeling.ConclusionsOur study suggests de novo variants as a major cause of ASD in the Indian population, with Rett syndrome as the most commonly detected disorder. Furthermore, we provide evidence of a significant difference in the diagnostic yield between CMA (3%) and WES (30%) which supports the implementation of WES as a first-tier test for genetic diagnosis of ASD in India.

Project description:ImportanceWhole-exome sequencing (WES) has the potential to reveal tumor and germline mutations of clinical relevance, but the diagnostic yield for pediatric patients with solid tumors is unknown.ObjectiveTo characterize the diagnostic yield of combined tumor and germline WES for children with solid tumors.DesignUnselected children with newly diagnosed and previously untreated central nervous system (CNS) and non-CNS solid tumors were prospectively enrolled in the BASIC3 study at a large academic children's hospital during a 23-month period from August 2012 through June 2014. Blood and tumor samples underwent WES in a certified clinical laboratory with genetic results categorized on the basis of perceived clinical relevance and entered in the electronic health record.Main outcomes and measuresClinical categorization of somatic mutations; frequencies of deleterious germline mutations related to patient phenotype and incidental medically-actionable mutations.ResultsOf the first 150 participants (80 boys and 70 girls, mean age, 7.4 years), tumor samples adequate for WES were available from 121 patients (81%). Somatic mutations of established clinical utility (category I) were reported in 4 (3%) of 121 patients, with mutations of potential utility (category II) detected in an additional 29 (24%) of 121 patients. CTNNB1 was the gene most frequently mutated, with recurrent mutations in KIT, TSC2, and MAPK pathway genes (BRAF, KRAS, and NRAS) also identified. Mutations in consensus cancer genes (category III) were found in an additional 24 (20%) of 121 tumors. Fewer than half of somatic mutations identified were in genes known to be recurrently mutated in the tumor type tested. Diagnostic germline findings related to patient phenotype were discovered in 15 (10%) of 150 cases: 13 pathogenic or likely pathogenic dominant mutations in adult and pediatric cancer susceptibility genes (including 2 each in TP53, VHL, and BRCA1), 1 recessive liver disorder with hepatocellular carcinoma (TJP2), and 1 renal diagnosis (CLCN5). Incidental findings were reported in 8 (5%) of 150 patients. Most patients harbored germline uncertain variants in cancer genes (98%), pharmacogenetic variants (89%), and recessive carrier mutations (85%).Conclusions and relevanceTumor and germline WES revealed mutations in a broad spectrum of genes previously implicated in both adult and pediatric cancers. Combined reporting of tumor and germline WES identified diagnostic and/or potentially actionable findings in nearly 40% of newly diagnosed pediatric patients with solid tumors.

Dataset Information

Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life.

Introduction

Methods

Results

Conclusion

Publications

Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life.

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