Exome variant prioritization in a large cohort of hearing-impaired individuals indicates IKZF2 to be associated with non-syndromic hearing loss and guides future research of unsolved cases DOI Creative Commons
Hedwig M. Velde, Maryam Vaseghi‐Shanjani, Jeroen J. Smits

и другие.

Human Genetics, Год журнала: 2024, Номер 143(11), С. 1379 - 1399

Опубликована: Окт. 16, 2024

Abstract Although more than 140 genes have been associated with non-syndromic hereditary hearing loss (HL), at least half of the cases remain unexplained in medical genetic testing. One reason is that pathogenic variants are located ‘novel’ deafness genes. A variant prioritization approach was used to identify novel (candidate) for HL. Exome-wide sequencing data were assessed subjects presumed HL remained testing by gene-panel analysis. Cases group AD had autosomal dominantly inherited (n = 124), and AR, recessive 337). Variants known candidate prioritized based on allele frequencies predicted effects. Selected tested their co-segregation Two solved recently identified ( ABHD12 , TRRAP ). Variant also revealed potentially causative X-linked Importantly, missense IKZF2 found co-segregate three families. These specifically affected Zn 2+ -coordinating cysteine or histidine residues zinc finger motifs 2 3 encoded protein Helios. This finding indicates a complex genotype–phenotype correlation defects, as this gene previously dysfunction immune system ICHAD syndrome, including The designed strategy can underlie large number therein stress importance inclusion family members prioritization.

Язык: Английский

Whole exome sequencing of 491 individuals with inherited retinal diseases reveals a large spectrum of variants and identification of novel candidate genes DOI
Tamar Hayman, Talya Millo,

Karen Hendler

и другие.

Journal of Medical Genetics, Год журнала: 2023, Номер unknown, С. jmg - 109482

Опубликована: Окт. 5, 2023

Background Inherited retinal diseases (IRDs) include a range of vision loss conditions caused by variants in different genes. The clinical and genetic heterogeneity make identification the cause challenging. Here, cohort 491 unsolved cases from our Israeli Palestinian families with IRDs underwent whole exome sequencing (WES), including detection CNVs as well single nucleotide (SNVs). Methods All participants examinations. Following WES on DNA samples 3 billion, initial SNV analysis was performed billion CNV Franklin Genoox. indicated programme were confirmed PCR followed gel electrophoresis. Results IRD revealed disease 51% cases, which 11% due wholly or part to CNVs. In two we clarified previously incorrect unclear diagnoses. This also identified ESRRB DNM1 potential novel Conclusion is most extensive one examine causing genes populations. It has allowed us identify causative variant many patients ones diagnoses

Язык: Английский

Процитировано

8
Identification of novel 3D-genome altering and complex structural variants underlying retinitis pigmentosa type 17 through a multistep and high-throughput approach DOI Creative Commons
Suzanne E. de Bruijn, Daan M. Panneman, Nicole Weisschuh

и другие.

Frontiers in Genetics, Год журнала: 2024, Номер 15

Опубликована: Окт. 23, 2024

Introduction Autosomal dominant retinitis pigmentosa type 17 (adRP, RP17) is caused by complex structural variants (SVs) affecting a locus on chromosome (chr17q22). The SVs disrupt the 3D regulatory landscape altering topologically associating domain (TAD) structure of locus, creating novel TAD structures (neo-TADs) and ectopic enhancer-gene contacts. Currently, screening for RP17-associated not included in routine diagnostics given complexity lack cost-effective detection methods. aim this study was to accurately detect RP17-SVs establishing systematic efficient workflow. Methods Genetically unexplained probands diagnosed with adRP (n = 509) from an international cohort were screened using smMIPs or genomic qPCR-based approach tailored RP17 locus. Suspected copy number changes validated high-density SNP-array genotyping, SV breakpoint characterization performed mutation-specific PCR, genome sequencing and, if required, optical mapping. In silico modeling predict formation neo-TADs whether contacts between retinal enhancers GDPD1 -promoter could be formed. Results Using workflow, potential detected eight which seven confirmed. Two identified that are predicted cause rearrangement enhancer- contact, one Germany (DE-SV9) three same United States (US-SV10). Previously reported also Australian probands, UK-SV2 two SA-SV3. Discussion summary, we describe multi-step pipeline reliable RP17-SV discovery expand range disease-associated SVs. Based these data, can considered frequent warrants inclusion RP17-screening as standard diagnostic test disease.

Язык: Английский

Процитировано

2
A proteogenomic atlas of the human neural retina DOI Open Access
Tabea Riepe, Merel Stemerdink, Renee Salz

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 24, 2024

The human neural retina is a complex tissue with abundant alternative splicing and more than 10% of genetic variants linked to inherited retinal diseases (IRDs) alter splicing. Traditional short-read RNA-sequencing methods have been used for understanding retina-specific but limitations in detailing transcript isoforms. To address this, we generated proteogenomic atlas that combines PacBio long-read data mass spectrometry whole genome sequencing three healthy samples. We identified nearly 60,000 isoforms, which approximately one-third are novel. Additionally, ten novel peptides confirmed For instance, IMPDH1 isoform combination known exons supported by peptide evidence. Our research underscores the potential in-depth tissue-specific transcriptomic analysis enhance our grasp underlying available via EGA identifier EGAD50000000101, ProteomeXchange PXD045187, accessible through UCSC browser.

Язык: Английский

Процитировано

1
Next-generation sequencing to genetically diagnose a diverse range of inherited eye disorders in 15 consanguineous families from Pakistan. DOI Creative Commons
Rabia Basharat, Suzanne E. de Bruijn, Muhammad Zahid

и другие.

Experimental Eye Research, Год журнала: 2024, Номер 244, С. 109945 - 109945

Опубликована: Май 28, 2024

Inherited retinal dystrophies (IRDs) are characterized by photoreceptor dysfunction or degeneration. Clinical and phenotypic overlap between IRDs makes the genetic diagnosis very challenging comprehensive genomic approaches for accurate frequently required. While there previous studies on in Pakistan, causative genes variants still unknown a significant portion of patients. Therefore, is need to expand knowledge spectrum Pakistan. Here, we recruited 52 affected 53 normal individuals from 15 consanguineous Pakistani families presenting non-syndromic syndromic forms IRDs. We employed single molecule Molecular Inversion Probes (smMIPs) based panel sequencing whole genome identify probable disease-causing these families. Using this approach, obtained 93% solve rate identified 16 (likely) 14 families, which seven novel were ATOH7, COL18A1, MERTK, NDP, PROM1, PRPF8 USH2A while nine recurrent CNGA3, CNGB1, HGSNAT, NMNAT1, SIX6 TULP1. The MERTK variant one TULP1 explained intra-familial locus heterogeneity screened two CNGA3 compound heterozygosity another family. identification known disease-associated emphasizes utilization time cost-effective screening rapid diagnosis. timely will not only any associated systemic issues case IRDs, but also aid acceleration personalized medicine patients with

Язык: Английский

Процитировано

1
Exome variant prioritization in a large cohort of hearing-impaired individuals indicates IKZF2 to be associated with non-syndromic hearing loss and guides future research of unsolved cases DOI Creative Commons
Hedwig M. Velde, Maryam Vaseghi‐Shanjani, Jeroen J. Smits

и другие.

Human Genetics, Год журнала: 2024, Номер 143(11), С. 1379 - 1399

Опубликована: Окт. 16, 2024

Abstract Although more than 140 genes have been associated with non-syndromic hereditary hearing loss (HL), at least half of the cases remain unexplained in medical genetic testing. One reason is that pathogenic variants are located ‘novel’ deafness genes. A variant prioritization approach was used to identify novel (candidate) for HL. Exome-wide sequencing data were assessed subjects presumed HL remained testing by gene-panel analysis. Cases group AD had autosomal dominantly inherited (n = 124), and AR, recessive 337). Variants known candidate prioritized based on allele frequencies predicted effects. Selected tested their co-segregation Two solved recently identified ( ABHD12 , TRRAP ). Variant also revealed potentially causative X-linked Importantly, missense IKZF2 found co-segregate three families. These specifically affected Zn 2+ -coordinating cysteine or histidine residues zinc finger motifs 2 3 encoded protein Helios. This finding indicates a complex genotype–phenotype correlation defects, as this gene previously dysfunction immune system ICHAD syndrome, including The designed strategy can underlie large number therein stress importance inclusion family members prioritization.

Язык: Английский

Процитировано

1