Publications by authors named "Claude Houdayer"

Article Synopsis
  • * A case study highlights a 30-year-old man who has JPS, characterized by multiple polyps, colon cancer, and persistent nosebleeds, and has a mosaic variant of the SMAD4 gene associated with his symptoms.
  • * The findings suggest that mosaic mutations of SMAD4 might be a common cause for some cases of JPS, which often go undiagnosed, emphasizing the need for detailed genetic testing to identify these difficult-to-detect mutations.
View Article and Find Full Text PDF

Variants which disrupt splicing are a frequent cause of rare disease that have been under-ascertained clinically. Accurate and efficient methods to predict a variant's impact on splicing are needed to interpret the growing number of variants of unknown significance (VUS) identified by exome and genome sequencing. Here, we present the results of the CAGI6 Splicing VUS challenge, which invited predictions of the splicing impact of 56 variants ascertained clinically and functionally validated to determine splicing impact.

View Article and Find Full Text PDF

About half of the human genome is composed of repeated sequences derived from mobile elements, mainly retrotransposons, generally without pathogenic effect. Familial forms of retinoblastoma are caused by germline pathogenic variants in gene. Here, we describe a family with retinoblastoma affecting a father and his son.

View Article and Find Full Text PDF
Article Synopsis
  • Breast cancer detection and prognosis are difficult due to the need for effective biomarkers, and the role of circRNAs in this process is being explored.
  • Researchers created a new method called SEALigHTS to study the interplay between circular RNAs and mRNAs in breast tissue samples.
  • Their findings indicate that the balance between circRNAs and mRNAs is disrupted in tumor tissues, supporting the idea that this imbalance contributes to the development of breast cancer.
View Article and Find Full Text PDF
Article Synopsis
  • Many variants found in disease susceptibility genes are classified as variants of uncertain significance (VUS), making their interpretation critical for clinical decisions.
  • This study introduces a new likelihood ratio-based method that takes into account gene-specific age-related penetrance to better analyze the pathogenicity of these variants.
  • The method outperformed traditional approaches in simulated and real datasets, allowing for clearer classifications of variants as pathogenic or non-pathogenic for conditions like breast cancer, and includes user-friendly tools for researchers.
View Article and Find Full Text PDF
Article Synopsis
  • Modeling pre-mRNA splicing is crucial for understanding how nucleotide variations can affect gene expression and lead to diseases, as these variations can disrupt or create important splicing motifs.
  • Existing tools typically specialize in specific splicing motifs, which led to the development of the Splicing Prediction Pipeline (SPiP), a machine learning-based analysis that assesses the impact of variants on various splicing motifs simultaneously.
  • SPiP achieved impressive results with 83.13% sensitivity and 99% specificity in detecting spliceogenic variants, outperforming other existing tools and providing a comprehensive prediction approach for genomic medicine.
View Article and Find Full Text PDF

Background: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks.

View Article and Find Full Text PDF
Article Synopsis
  • Inversions, which are DNA orientation changes, can cause human diseases but are often overlooked because they do not produce an obvious imbalance in genetic material.* -
  • The study highlights two families: one with constitutional mismatch repair deficiency and history of colon cancer (F1), and another with a severe history of Lynch syndrome (F2), showcasing the impact of inversions on gene expression.* -
  • Utilizing a whole gene panel approach allowed for the detection of significant inversions in the PMS2 and MSH6 genes, emphasizing the importance of genomic sequencing in improving diagnosis rates.*
View Article and Find Full Text PDF
Article Synopsis
  • Pathogenic variants in the MYT1L gene lead to a neurodevelopmental disorder characterized by features like developmental delays, intellectual disabilities, and behavioral disorders.
  • A study analyzed genetic data from 40 previously unreported patients, adding to a total of 62 patients to better understand the clinical characteristics and genotype-phenotype correlations.
  • The research confirmed key phenotypic traits, introduced new clinical features, and emphasized that patients with certain genetic variants do not show distinct clinical differences, aiding in improved diagnosis and management of the disorder.
View Article and Find Full Text PDF

Retinoblastoma is a malignant tumor of the infant retina. Nearly half of patients are predisposed to retinoblastoma by a germline RB1 pathogenic variant. Nonhereditary retinoblastoma is mainly caused by inactivation of both RB1 alleles at a somatic level.

View Article and Find Full Text PDF

Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs.

View Article and Find Full Text PDF
Article Synopsis
  • Retinoblastoma is the most common eye cancer in children, originating from developing retinal cells, but its molecular behavior is not well understood.* -
  • Researchers identified two distinct subtypes of retinoblastoma: Subtype 1 is characterized by early onset and less genetic alteration, while Subtype 2 has recurrent genetic changes, is less differentiated, and has a higher likelihood of spreading.* -
  • Understanding these two subtypes can offer new insights into the biology and treatment of retinoblastoma, with subtype 1 being less aggressive and subtype 2 showing more aggressive traits and stem cell-like features.*
View Article and Find Full Text PDF

Assessment of age-dependent cancer risk for carriers of a predicted pathogenic variant (PPV) is often hampered by biases in data collection, with a frequent under-representation of cancer-free PPV carriers. TUMOSPEC was designed to estimate the cumulative risk of cancer for carriers of a PPV in a gene that is usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France.

View Article and Find Full Text PDF

Purpose: The analysis of circulating tumor DNA (ctDNA), a fraction of total cell-free DNA (cfDNA), might be of special interest in retinoblastoma patients. Because the accessibility to tumor tissue is very limited in these patients, either for histopathological diagnosis of suspicious intraocular masses (biopsies are proscribed) or for somatic RB1 studies and genetic counseling (due to current successful conservative approaches), we aim to validate the detection of ctDNA in plasma of non-hereditary retinoblastoma patients by molecular analysis of RB1 gene.

Experimental Design: In a cohort of 19 intraocular unilateral non-hereditary retinoblastoma patients for whom a plasma sample was available at diagnosis, we performed high-deep next-generation sequencing (NGS) of RB1 in cfDNA.

View Article and Find Full Text PDF

Background: Large genomic rearrangements (LGR) in consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5' region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families.

Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing.

View Article and Find Full Text PDF
Article Synopsis
  • Biallelic pathogenic variants in the NTHL1 gene are linked to a hereditary cancer syndrome, increasing risks for adenomatous polyposis and colorectal cancer, as well as other tumors like breast and brain cancers.
  • The study, using data from the French oncogenetic consortium, describes 10 patients with these variants, identifying them as the second-largest series on NTHL1, all of whom showed signs of adenomatous polyps.
  • The findings suggest that testing for NTHL1 should be included in diagnostic panels for hereditary cancers, with recommendations for colon and extra-colonic cancer surveillance based on existing guidelines.
View Article and Find Full Text PDF

Background: Reverse transcription-quantitative PCR on nasopharyngeal swabs is currently the reference COVID-19 diagnosis method but exhibits imperfect sensitivity.

Methods: We developed a multiplex reverse transcription-digital droplet PCR (RT-ddPCR) assay, targeting 6 SARS-CoV-2 genomic regions, and evaluated it on nasopharyngeal swabs and saliva samples collected from 130 COVID-19 positive or negative ambulatory individuals, who presented symptoms suggestive of mild or moderate SARS-CoV2 infection.

Results: For the nasopharyngeal swab samples, the results obtained using the 6-plex RT-ddPCR and RT-qPCR assays were all concordant.

View Article and Find Full Text PDF

is a clinically actionable gene implicated in breast and ovarian cancer predisposition that has become a high priority target for improving the classification of variants of unknown significance (VUS). Among all VUS, those causing partial/leaky splicing defects are the most challenging to classify because the minimal level of full-length (FL) transcripts required for normal function remains to be established. Here, we explored exon 3 (e3) as a model for calibrating variant-induced spliceogenicity and estimating thresholds for haploinsufficiency.

View Article and Find Full Text PDF

Importance: Retinoblastoma (RB) is the most common pediatric intraocular neoplasm. RB is a complex model in which atypical pathogenic variants, modifier genes, imprinting, and mosaicism are known to be associated with the phenotype. In-depth understanding of RB therefore requires large genotype-phenotype studies.

View Article and Find Full Text PDF

CDK12 variants were investigated as a genetic susceptibility to ovarian cancer in a series of 416 unrelated and consecutive patients with ovarian carcinoma and who carry neither germline BRCA1 nor BRCA2 pathogenic variant. The presence of CDK12 variants was searched in germline DNA by massive parallel sequencing on pooled DNAs. The lack of detection of deleterious variants and the observed proportion of missense variants in the series of ovarian carcinoma patients as compared with all human populations strongly suggests that CDK12 is not an ovarian cancer predisposing gene.

View Article and Find Full Text PDF

Germline nonsense and canonical splice site variants identified in disease-causing genes are generally considered as loss-of-function (LoF) alleles and classified as pathogenic. However, a fraction of such variants could maintain function through their impact on RNA splicing. To test this hypothesis, we used the alternatively spliced exon 12 (E12) as a model system because its in-frame skipping leads to a potentially functional protein.

View Article and Find Full Text PDF
Article Synopsis
  • Branch points (BPs) are crucial for the splicing of pre-mRNA and are located in short motifs upstream of acceptor splice sites (3'ss); several bioinformatics tools for detecting BPs have been developed recently.
  • In a study utilizing a large dataset of human 3'ss, Branchpointer was found to be the most accurate tool for identifying BPs, showing 99.48% accuracy for constitutive and 65.84% for alternative 3'ss.
  • Additionally, BPP was the best performer for predicting the impact of variants in BP regions on mRNA splicing, achieving an accuracy of 89.17%.
View Article and Find Full Text PDF