Combining a prioritization strategy and functional studies nominates 5’UTR variants underlying inherited retinal disease DOI Creative Commons
Alfredo Dueñas Rey, Marta Del Pozo‐Valero, Manon Bouckaert

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 27, 2023

Abstract Background 5’ untranslated regions (5’UTRs) are essential modulators of protein translation. Predicting the impact 5’UTR variants is challenging and typically not performed in routine diagnostics. Here, we present a combined approach comprehensive prioritization strategy subsequent functional assays to evaluate variation two large cohorts patients with inherited retinal diseases (IRDs). Methods We an isoform-level re-analysis RNA-seq data identify protein-coding transcripts 378 IRD genes highest expression retina. evaluated coverage these 5’UTRs by different whole exome sequencing (WES) capture kits. The selected were analyzed genome (WGS) WES from sub-cohorts 100,000 Genomes Project (n = 2,417 WGS) in-house database 1,682 WES), respectively. Identified annotated for 5’UTR-relevant features classified into 7 distinct categories based on their predicted consequence. developed variant integrating population frequency, specific criteria each category, family phenotypic data. A selection candidate underwent validation using diverse experimental approaches. Results Isoform-level re-quantification gene revealed 76 non-canonical retina-enriched isoform, which 20 display fully compared that canonical isoform. Depending probe-design 3-20% have captured WES. After analyzing both prioritized 11 (likely) pathogenic 10 ( ARL3 , MERTK NDP NMNAT1 NPHP4 PAX6 PRPF31 PRPF4 RDH12 RD3 ), 8 novel. Functional analyses further supported pathogenicity 2 variants. :c.-125G>A variant, overlapping transcriptional start site, was shown significantly reduce luciferase mRNA levels activity. :c.-123C>T found cis reported hypomorphic :c.701G>A (p.Arg234His) patients. This introduce upstream open reading frame, result reduced but unaltered levels. Conclusions study demonstrates importance implicated IRDs provides systematic annotation applicable other diseases.

Language: Английский

The expanding diagnostic toolbox for rare genetic diseases DOI
Kristin D. Kernohan, Kym M. Boycott

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(6), P. 401 - 415

Published: Jan. 18, 2024

Language: Английский

Citations

29
The Genetics of Intellectual Disability DOI Creative Commons
Sandra Jansen, Lisenka E.L.M. Vissers, Bert B.A. de Vries

et al.

Brain Sciences, Journal Year: 2023, Volume and Issue: 13(2), P. 231 - 231

Published: Jan. 30, 2023

Intellectual disability (ID) has a prevalence of ~2–3% in the general population, having large societal impact. The underlying cause ID is largely genetic origin; however, identifying this past often led to long diagnostic Odysseys. Over decades, improvements technologies and strategies have these causes being more detectable: from cytogenetic analysis 1959, we moved first decade 21st century genomic microarrays with yield ~20% next-generation sequencing platforms up 60%. In review, discuss various developments, as well their associated challenges implications for field ID, which highlight revolutionizing shift clinical practice phenotype-first into genotype-first approach.

Language: Английский

Citations

36
Whole genome sequencing enables new genetic diagnosis for inherited retinal diseases by identifying pathogenic variants DOI Creative Commons
Xubing Liu,

Fangyuan Hu,

Daowei Zhang

et al.

npj Genomic Medicine, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 20, 2024

Language: Английский

Citations

16
Portuguese Society of Ophthalmology and Portuguese Society of Human Genetics Joint Clinical Practice Guidelines for Genetic Testing in Inherited Retinal Dystrophies DOI Creative Commons
João Pedro Marques, Célia Azevedo Soares, Ana Luísa Carvalho

et al.

Clinical Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

ABSTRACT The Portuguese Society of Ophthalmology and the Human Genetics developed clinical practice guidelines to streamline genetic testing for inherited retinal dystrophies (IRDs), underlining critical role molecular diagnosis in enhancing patient care. Genetic is pivotal diagnosis, counselling, prognosis access trials, new gene‐specific therapies. These recommend all IRD patients provide a detailed assessment available methods, ensuring that counselling integrated into ophthalmic Essential this process inclusion at least one session effectively communicate discuss implications test results with families/carers. Key recommendations include cascade identify at‐risk family members standardisation variant classification according international criteria ensure consistency Ophthalmological follow‐up generally prescribed intervals 1–2 years adults 6 months paediatric patients, monitor disease progression complications. Paediatric considerations are addressed, reflecting complexities ethical concerns associated minors. aim elevate diagnostic accuracy, guide therapeutic decisions ultimately improve outcomes, marking significant advance management IRDs.

Language: Английский

Citations

1
A comprehensive genetic landscape of inherited retinal diseases in a large Pakistani cohort DOI Creative Commons
Mukhtar Ullah, Atta Ur Rehman, Mathieu Quinodoz

et al.

npj Genomic Medicine, Journal Year: 2025, Volume and Issue: 10(1)

Published: April 4, 2025

Language: Английский

Citations

1
Whole genome sequencing for USH2A-associated disease reveals several pathogenic deep-intronic variants that are amenable to splice correction DOI Creative Commons
Janine Reurink, Nicole Weisschuh,

Alejandro Garanto

et al.

Human Genetics and Genomics Advances, Journal Year: 2023, Volume and Issue: 4(2), P. 100181 - 100181

Published: Jan. 18, 2023

A significant number of individuals with a rare disorder such as Usher syndrome (USH) and (non-)syndromic autosomal recessive retinitis pigmentosa (arRP) remain genetically unexplained. Therefore, we assessed subjects suspected

Language: Английский

Citations

19
Loss-of-function variants in UBAP1L cause autosomal recessive retinal degeneration DOI
Ji Hoon Han, Kim Rodenburg, Tamar Hayman

et al.

Genetics in Medicine, Journal Year: 2024, Volume and Issue: 26(6), P. 101106 - 101106

Published: Feb. 28, 2024

Language: Английский

Citations

8
Optical genome mapping unveils hidden structural variants in neurodevelopmental disorders DOI Creative Commons
Isabelle Schrauwen,

Yasmin Rajendran,

Anushree Acharya

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: May 16, 2024

Abstract While short-read sequencing currently dominates genetic research and diagnostics, it frequently falls short of capturing certain structural variants (SVs), which are often implicated in the etiology neurodevelopmental disorders (NDDs). Optical genome mapping (OGM) is an innovative technique capable SVs that undetectable or challenging-to-detect via methods. This study aimed to investigate NDDs using OGM, specifically focusing on cases remained unsolved after standard exome sequencing. OGM was performed 47 families ultra-high molecular weight DNA. Single-molecule maps were assembled de novo, followed by SV copy number variant calling. We identified 7 interest, 5 (10.6%) classified as likely pathogenic pathogenic, located BCL11A, OPHN1 , PHF8, SON NFIA. also inversion disrupting NAALADL2 a gene previously found harbor complex rearrangements two NDD cases. Variants known genes candidate interest missed mainly consisted larger insertions (> 1kbp), inversions, deletions/duplications low exons (1–4 exons). In conclusion, addition improving diagnosis NDDs, this may reveal novel techniques.

Language: Английский

Citations

7
Combining a prioritization strategy and functional studies nominates 5’UTR variants underlying inherited retinal disease DOI Creative Commons
Alfredo Dueñas Rey, Marta Del Pozo‐Valero, Manon Bouckaert

et al.

Genome Medicine, Journal Year: 2024, Volume and Issue: 16(1)

Published: Jan. 6, 2024

Abstract Background 5’ untranslated regions (5’UTRs) are essential modulators of protein translation. Predicting the impact 5’UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach comprehensive prioritization strategy functional assays to evaluate variation two large cohorts patients with inherited retinal diseases (IRDs). Methods We an isoform-level re-analysis RNA-seq data identify protein-coding transcripts 378 IRD genes highest expression retina. evaluated coverage their 5’UTRs by different whole exome sequencing (WES) kits. The selected were analyzed genome (WGS) WES from sub-cohorts 100,000 Genomes Project ( n = 2397 WGS) in-house database 1682 WES), respectively. Identified annotated for 5’UTR-relevant features classified into seven categories based on predicted consequence. developed variant integrating population frequency, specific criteria each category, family phenotypic data. A selection candidate underwent validation using diverse approaches. Results Isoform-level re-quantification gene revealed 76 non-canonical retina-enriched isoform, which 20 display fully distinct compared that canonical isoform. Depending probe design, 3–20% have captured WES. After analyzing these both cohorts, prioritized 11 (likely) pathogenic 10 ARL3 , MERTK NDP NMNAT1 NPHP4 PAX6 PRPF31 PRPF4 RDH12 RD3 ), 7 novel. Functional analyses further supported pathogenicity three variants. Mis-splicing was demonstrated :c.-9+1G>T variant. :c.-125G>A variant, overlapping transcriptional start site, shown significantly reduce luciferase mRNA levels activity. :c.-123C>T found cis hypomorphic :c.701G>A (p.Arg234His) patients. This introduce upstream open reading frame, result reduced but unaltered levels. Conclusions study demonstrates importance implicated IRDs provides systematic annotation applicable other diseases.

Language: Английский

Citations

6
Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene DOI Creative Commons
Elena Fernández-Suárez, María González‐del Pozo,

Cristina Méndez‐Vidal

et al.

Mobile DNA, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 4, 2024

Abstract Background Biallelic variants in EYS are the major cause of autosomal recessive retinitis pigmentosa (arRP) certain populations, a clinically and genetically heterogeneous disease that may lead to legal blindness. is one largest genes (~ 2 Mb) expressed retina, which structural (SVs) represent common disease. However, their identification using short-read sequencing (SRS) not always feasible. Here, we conducted targeted long-read (T-LRS) adaptive sampling on MinION platform (Oxford Nanopore Technologies) definitively diagnose an arRP family, whose affected individuals ( n = 3) carried heterozygous pathogenic deletion exons 32–33 gene. As this was recurrent variant identified three additional families our cohort, also aimed characterize known at nucleotide level assess possible founder effect. Results T-LRS family A unveiled AluYa5 insertion coding exon 43 (chr6(GRCh37):g.64430524_64430525ins352), segregated with compound heterozygosity previously deletion. Visual inspection previous SRS alignments IGV revealed several reads containing soft-clipped bases, accompanied by slight drop coverage Alu site. This prompted us develop simplified program grep command investigate recurrence cohort from data. Moreover, LRS allowed characterization CNV as ~ 56.4kb spanning (chr6(GRCh37):g.64764235_64820592del). The results further Sanger linkage analysis four were consistent variant. Conclusions To knowledge, first report mobile element into sequence EYS, likely family. Our study highlights value technology characterizing identifying hidden SVs, such retrotransposon insertions, contribution etiopathogenesis rare diseases be underestimated.

Language: Английский

Citations

5