A5002049999- Retinal Development and Disorders
- Retinal Diseases and Treatments
- RNA regulation and disease
- Photoreceptor and optogenetics research
- Connexins and lens biology
- Genomics and Rare Diseases
- Genetic and Kidney Cyst Diseases
- CRISPR and Genetic Engineering
- Advanced biosensing and bioanalysis techniques
- Fetal and Pediatric Neurological Disorders
- Cellular transport and secretion
- Hedgehog Signaling Pathway Studies
- Genomic variations and chromosomal abnormalities
- Congenital heart defects research
- Oral microbiology and periodontitis research
- Infant Nutrition and Health
- Oral and gingival health research
- Neuroscience and Neural Engineering
- Cerebrovascular and genetic disorders
- Ocular Disorders and Treatments
- Cell Adhesion Molecules Research
- Metabolism and Genetic Disorders
- Helicobacter pylori-related gastroenterology studies
- Oral and Craniofacial Lesions
- Amino Acid Enzymes and Metabolism
Massachusetts Eye and Ear Infirmary
2019-2025
Harvard University
2019-2025
Boston University
2024
Genomics (United Kingdom)
2024
Radboud University Nijmegen
2014-2020
Radboud University Medical Center
2014-2020
Radboud Institute for Molecular Life Sciences
2014-2020
University Medical Center
2017-2020
Sapienza University of Rome
2020
Telethon Institute Of Genetics And Medicine
2012-2017
PurposeUsing exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored Stargardt disease (STGD1) as a model to identify missing heritability.MethodsSequencing of ABCA4 was performed 8 STGD1 cases one variant and p.Asn1868Ile trans, 25 variant, 3 no variant. The effect intronic analyzed using vitro splice assays HEK293T cells patient-derived fibroblasts. Antisense oligonucleotides were used correct defects.ResultsIn 24 probands...
Stargardt disease is caused by variants in the ABCA4 gene, a significant part of which are noncanonical splice site (NCSS) variants. In case gene interest not expressed available somatic cells, small genomic fragments carrying potential disease-associated tested for abnormalities using vitro assays. We recently discovered that when minigenes lacking proper context, results do correlate with defects observed patient cells. therefore devised novel strategy bacterial artificial chromosome was...
<h2>Abstract</h2><h3>Purpose</h3> <i>ABCA4</i>-associated disease, a recessive retinal dystrophy, is hallmarked by large proportion of patients with only one pathogenic <i>ABCA4</i> variant, suggestive for missing heritability. <h3>Methods</h3> By locus-specific analysis <i>ABCA4</i>, combined extensive functional studies, we aimed to unravel the alleles in cohort 67 (<i>p</i>), (<i>p</i> = 64) or no 3) identified coding variants <i>ABCA4</i>. <h3>Results</h3> We eight (deep-)intronic splice...
To assess the occurrence and disease expression of common p.Asn1868Ile variant in patients with Stargardt (STGD1) harboring known, monoallelic causal ABCA4 variants.The coding noncoding regions were sequenced 67 63 STGD1 probands respectively, variants. In case was detected, segregation analysis performed whenever possible. Probands affected siblings without additional variants cis clinically evaluated retrospectively. Two asymptomatic carrying same as their examined. The penetrance...
Variants in ABCA4 are responsible for autosomal-recessive Stargardt disease and cone-rod dystrophy. Sequence analysis of exons previously revealed one causative variant each 45 probands. To identify the "missing" variants these cases, we performed multiplex ligation-dependent probe amplification-based deletion scanning ABCA4. In addition, sequenced promoter region, fragments containing five deep-intronic splice variants, 15 regions weak sites. Heterozygous deletions spanning exon 5 or 20-22...
Purpose: To investigate the role of two deep-intronic ABCA4 variants, that showed a mild splice defect in vitro and can occur on same allele as low penetrant c.5603A>T, Stargardt disease (STGD1). Methods: Ophthalmic data were assessed 18 STGD1 patients who harbored c.769-784C>T or c.4253+43G>A combination with severe variant. Subjects carrying c.[769-784C>T; 5603A>T] clinically compared cohort previously published c.5603A>T noncomplex. We calculated penetrances intronic variants using...
To identify the genetic cause for disease in individuals affected with inherited retinal (IRD), to characterize their phenotype and properties of underlying gene. Participants underwent a comprehensive ophthalmological evaluation, including best-corrected visual acuity, field testing, fundus autofluorescence, optical coherence tomography electroretinography. Genetic analyses included exome, genome Sanger sequencing. Gene expression pattern was analyzed by reverse transcription-PCR....
<title>Abstract</title> Inherited retinal degenerations (IRDs) are a group of clinically and genetically heterogeneous blinding disorders. In this retrospective study, we describe five families with non-syndromic IRD in which affected probands carried rare bi-allelic variants <italic>SCLT1</italic>, gene previously associated multiple recessive ciliopathies. Seven the eight identified were novel, four them splicing, including known missense p.(Lys544Arg), detected heterozygously three East...
Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases large cohort sequencing studies, clear association non-syndromic inherited degenerations (IRDs) has not been made. We validate this by reporting 16 IRD patients from ten families bi-allelic mutations INPP5E. Additional two showed early onset limited JBTS features. Detailed phenotypic description for all probands is presented. report 14 rare variants, 12 of which...
Inherited retinal degenerations (IRDs) are at the focus of current genetic therapeutic advancements. For a treatment such as gene therapy to be successful, an accurate diagnostic is required. Genetic diagnostics relies on assessment probability that given DNA variant pathogenic. Non-coding variants present unique challenge for assessments compared coding variants. one, non-coding much higher number in genome than In addition, our understanding rules govern regions less complete regions....
Importance Despite advances in next-generation sequencing (NGS), a significant proportion of patients with inherited retinal disease (IRD) remain undiagnosed after initial genetic testing. Exome (ES) reanalysis the clinical setting has been suggested as one method for improving diagnosis IRD. Objective To investigate association clinician-led ES data, which incorporates updated information and comprehensive bioinformatic analysis, diagnostic yield cohort IRDs Korea. Design, Setting,...
Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream start codon ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]), in South Asian and African ancestry, respectively. Genotypes included 71 homozygotes 3 mixed heterozygotes trans with a predicted loss-of-function allele. Haplotype showed single-nucleotide variants (SNVs)...
Despite advances in sequencing technologies, a molecular diagnosis remains elusive many Mendelian disease patients. Current short-read clinical approaches cannot provide chromosomal phase information or epigenetic without further sample processing, which is not routinely done and can result an incomplete The ability to phased genetic from single run would improve the diagnostic rate of conditions. Here we describe Targeted Long-read Sequencing Disease genes (TaLon-SeqMD) using real-time...
Noncanonical splice-site mutations are an important cause of inherited diseases. Based on in vitro and stem-cell-based studies, some variants show a stronger splice defect than expected based their predicted effects, suggesting that other sequence motifs influence the outcome. We investigated whether defects due to human-inherited-disease-associated noncanonical sequences ABCA4, DMD, TMC1 could be rescued by strengthening site side exon. 5′- 3′-splice-site were selected. Rescue introduced...
Familial occurrence of Ménétrier disease is rare and has been reported only in few instances.Affected patients from a large pedigree were evaluated at the clinical, endoscopic, pathological levels.Affected members presented with gastropathy variable severity but without protein loss. Endoscopy pathology findings consistent disease; however, gastric transforming growth factor α (TGF-α) immunohistochemistry real-time polymerase chain reaction showed no increase TGF-α expression.We describe...
We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Ménétrier disease, premalignant gastric disorder epithelial hyperplasia and enhanced EGFR signalling. disease is believed to be an acquired disorder, but its aetiology unknown. In affected members, we found missense p.V742G variant MIB2, gene regulating NOTCH signalling that has not been previously linked human diseases. The segregated the pedigree, highly conserved amino acid...