Abstract:Background
A considerable minority of patients on waiting lists for kidney transplantation either have no diagnosis (and fall into the subset of undiagnosed cases) because kidney biopsy was not performed or histological findings were non-specific, or do not fall into any well-defined clinical category. Some of these patients might be affected by a previously unrecognised monogenic disease.
Methods
Through a multidisciplinary cooperative effort, we built an analytical pipeline to identify patients with chronic… Show more
“…We previously reported on the design and set-up of a “kidney” gene panel that comprises > 400 genes all involved in different forms of kidney diseases [ 14 ]. For this study, we implemented analysis with subpanels focused on the specific clinical category of suspicion (e.g., CAKUT, glomerulopathy, tubulopathy, etc.)…”
Section: Resultsmentioning
confidence: 99%
“…Nucleic acid extraction from peripheral blood, analysis of DNA quality, library preparation and sequencing were performed as previously reported [ 14 ]. Raw data obtained from sequencing were converted in FASTQ files and then aligned with Enrichment 3.1.0 or DRAGEN Enrichment tools (Illumina) and mapped on TruSightOne Expanded v2.0 manifest using Homo Sapiens UCSC GRCh37 genome as reference to obtain single nucleotide variants, copy number variants (CNV) and structural variants vcf files.…”
Purpose
Inherited kidney diseases are among the leading causes of kidney failure in children, resulting in increased mortality, high healthcare costs and need for organ transplantation. Next-generation sequencing technologies can help in the diagnosis of rare monogenic conditions, allowing for optimized medical management and therapeutic choices.
Methods
Clinical exome sequencing (CES) was performed on a cohort of 191 pediatric patients from a single institution, followed by Sanger sequencing to confirm identified variants and for family segregation studies.
Results
All patients had a clinical diagnosis of kidney disease: the main disease categories were glomerular diseases (32.5%), ciliopathies (20.4%), CAKUT (17.8%), nephrolithiasis (11.5%) and tubular disease (10.5%). 7.3% of patients presented with other conditions. A conclusive genetic test, based on CES and Sanger validation, was obtained in 37.1% of patients. The highest detection rate was obtained for ciliopathies (74.4%), followed by nephrolithiasis (45.5%), tubular diseases (45%), while most glomerular diseases and CAKUT remained undiagnosed.
Conclusions
Results indicate that genetic testing consistently used in the diagnostic workflow of children with chronic kidney disease can (i) confirm clinical diagnosis, (ii) provide early diagnosis in the case of inherited conditions, (iii) find the genetic cause of previously unrecognized diseases and (iv) tailor transplantation programs.
“…We previously reported on the design and set-up of a “kidney” gene panel that comprises > 400 genes all involved in different forms of kidney diseases [ 14 ]. For this study, we implemented analysis with subpanels focused on the specific clinical category of suspicion (e.g., CAKUT, glomerulopathy, tubulopathy, etc.)…”
Section: Resultsmentioning
confidence: 99%
“…Nucleic acid extraction from peripheral blood, analysis of DNA quality, library preparation and sequencing were performed as previously reported [ 14 ]. Raw data obtained from sequencing were converted in FASTQ files and then aligned with Enrichment 3.1.0 or DRAGEN Enrichment tools (Illumina) and mapped on TruSightOne Expanded v2.0 manifest using Homo Sapiens UCSC GRCh37 genome as reference to obtain single nucleotide variants, copy number variants (CNV) and structural variants vcf files.…”
Purpose
Inherited kidney diseases are among the leading causes of kidney failure in children, resulting in increased mortality, high healthcare costs and need for organ transplantation. Next-generation sequencing technologies can help in the diagnosis of rare monogenic conditions, allowing for optimized medical management and therapeutic choices.
Methods
Clinical exome sequencing (CES) was performed on a cohort of 191 pediatric patients from a single institution, followed by Sanger sequencing to confirm identified variants and for family segregation studies.
Results
All patients had a clinical diagnosis of kidney disease: the main disease categories were glomerular diseases (32.5%), ciliopathies (20.4%), CAKUT (17.8%), nephrolithiasis (11.5%) and tubular disease (10.5%). 7.3% of patients presented with other conditions. A conclusive genetic test, based on CES and Sanger validation, was obtained in 37.1% of patients. The highest detection rate was obtained for ciliopathies (74.4%), followed by nephrolithiasis (45.5%), tubular diseases (45%), while most glomerular diseases and CAKUT remained undiagnosed.
Conclusions
Results indicate that genetic testing consistently used in the diagnostic workflow of children with chronic kidney disease can (i) confirm clinical diagnosis, (ii) provide early diagnosis in the case of inherited conditions, (iii) find the genetic cause of previously unrecognized diseases and (iv) tailor transplantation programs.
“…This increase is mainly due to the enhanced ability to diagnose genetic disorders and a consequent surge in the reporting of such disorders within the past decade. With the advent and ease of access to technologies such as Whole Exome Sequencing (WES) and gene panel sequencing, diagnostic rates of genetic disorders have increased significantly ( Vaisitti et al, 2021 ; Sanchez-Luquez et al, 2022 ; Moundir et al, 2023 ). In fact, within our set of genetic disorders reported in the UAE, a significant portion comes from the utilization of such sequencing techniques on fairly large patient populations ( Al-Shamsi et al, 2016 ; Alsamri et al, 2020 ; Mahfouz et al, 2020 ; Saleh et al, 2021 ).…”
Like many other Arab countries, the United Arab Emirates (UAE) has a relatively high prevalence of genetic disorders. Here we present the first review and analysis of all genetic disorders and gene variants reported in Emirati nationals and hosted on the Catalogue for Transmission Genetics in Arabs (CTGA), an open-access database hosting bibliographic data on human gene variants associated with inherited or heritable phenotypes in Arabs. To date, CTGA hosts 665 distinct genetic conditions that have been described in Emiratis, 621 of which follow a clear Mendelian inheritance. Strikingly, over half of these are extremely rare according to global prevalence rates, predominantly with an autosomal recessive mode of inheritance. This is likely due to the relatively high consanguinity rates within the Emirati population. The 665 conditions include disorders that are unique to the Emirati population, as well as clearly monogenic disorders that have not yet been mapped to a causal genetic locus. We also describe 1,365 gene variants reported in Emiratis, most of which are substitutions and over half are classified as likely pathogenic or pathogenic. Of these, 235 had not been reported on the international databases dbSNP and Clinvar, as of December 2022. Further analysis of this Emirati variant dataset allows a comparison of clinical significance as reported by Clinvar and CTGA, where the latter is derived from the study cited. A total of 307 pathogenic/likely pathogenic variants from CTGA’s Emirati dataset, were classified as benign, variants of uncertain significance, or were missing a clinical significance or had not been reported by Clinvar. In conclusion, we present here the spectrum of genetic disorders and gene variants reported in Emiratis. This review emphasizes the importance of ethnic databases such as CTGA in addressing the underrepresentation of Arab variant data in international databases and documenting population-specific discrepancies in variant interpretation, reiterating the value of such repositories for clinicians and researchers, especially when dealing with rare disorders.
“…This increase is mainly due to the enhanced ability to diagnose genetic disorders and a consequent surge in the reporting of such disorders within the past decade. With the advent and ease of access to technologies such as Whole Exome Sequencing (WES) and gene panel sequencing, diagnostic rates of genetic disorders have increased significantly (Vaisitti et al, 2021; Sanchez-Luquez et al, 2022; Moundir et al, 2023). In fact, within our set of genetic disorders reported in the UAE, a significant portion comes from the utilization of such high-throughput sequencing techniques on fairly large patient populations (Al-Shamsi et al, 2016; Alsamri et al, 2020; Mahfouz et al, 2020; Saleh et al, 2021).…”
Like many other Arab countries, the United Arab Emirates (UAE) has a relatively high prevalence of genetic disorders. Here we present the first review and analysis of all genetic disorders and gene variants reported in Emirati nationals and hosted on the Catalogue for Transmission Genetics in Arabs (CTGA), an open-access database hosting bibliographic data on human gene variants associated with inherited or heritable phenotypes in Arabs. To date, CTGA hosts 665 distinct genetic conditions that have been described in Emiratis, 621 of which follow a clear Mendelian inheritance. Strikingly, over half of these are extremely rare according to global prevalence rates, predominantly with an autosomal recessive mode of inheritance. This is likely due to the relatively high consanguinity rates within the Emirati population. The 665 conditions include disorders that are unique to the Emirati population, as well as clearly monogenic disorders that have not yet been mapped to a causal genetic locus. We also describe 1,365 gene variants reported in Emiratis, most of which are substitutions and over half are classified as likely pathogenic or pathogenic. Of these, 235 had not been reported on the international databases dbSNP and Clinvar, as of December 2022. Further analysis of this Emirati variant dataset allows a comparison of clinical significance as reported by Clinvar and CTGA, where the latter is derived from the study cited. A total of 306 pathogenic/likely pathogenic variants from CTGA's Emirati dataset, were classified as benign, variants of uncertain significance, or were missing a clinical significance or had not been reported by Clinvar. In conclusion, we present here the spectrum of genetic disorders and gene variants reported in Emiratis. This review emphasizes the importance of ethnic databases such as CTGA in addressing the underrepresentation of Arab variant data in international databases and documenting population-specific discrepancies in variant interpretation, reiterating the value of such repositories for clinicians and researchers, especially when dealing with rare disorders.
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