Publications by authors named "James Lespinasse"
Background: Aarskog-Scott syndrome (AAS) is a rare condition with multiple congenital anomalies, caused by hemizygote variants in the gene. Its description was based mostly on old case reports, in whom a molecular diagnosis was not always available, or on small series. The aim of this study was to better delineate the phenotype and the natural history of AAS and to provide clues for the diagnosis and the management of the patients.
View Article and Find Full Text PDFAn increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.
View Article and Find Full Text PDFPossible incomplete penetrance of Xq28 int22h-1/int22h-2 duplication.
Alexis Billes
,
Mathilde Pujalte
,
Guillaume Jedraszak
,
Daniel Amsallem
,
Elise Boudry-Labis
,
James Lespinasse
Clin Genet
September 2024
Article Synopsis
- Xq28 int22h-1/int22h-2 duplication results from recombination between specific genetic repeats and is linked to a form of intellectual disability along with recurrent infections and atopic diseases.
- In a study involving 15 families, many carriers exhibited mild or no symptoms, suggesting that the condition can manifest variably.
- The findings point towards potential incomplete penetrance, meaning not all carriers show obvious signs of the condition, indicating a need for further research to understand the genetic implications better.
Cat eye syndrome: Clinical, cytogenetics and familial findings in a large cohort of 43 patients highlighting the importance of congenital heart disease and inherited cases.
Guillaume Jedraszak
,
Florence Jobic
,
Aline Receveur
,
Frédéric Bilan
,
Brigitte Gilbert-Dussardier
,
James Lespinasse
Am J Med Genet A
April 2024
Article Synopsis
- - Cat Eye Syndrome (CES) is a rare genetic disorder linked to a marker chromosome from chromosome 22, leading to diverse symptoms including iris coloboma, anal atresia, and preauricular tags, but these are present in less than half of the cases.
- - An international study of 43 CES patients found that only 16% displayed all three classic symptoms, while 9% showed none; additional issues such as cardiac anomalies (51%) and intellectual disabilities (47%) were also common.
- - The study highlights the significance of supernumerary marker chromosomes (sSMC), found in 91% of cases, with many parents showing mild traits, emphasizing the need for genetic counseling regarding recurrence risks.
Article Synopsis
- Variants of uncertain significance (VUS) present challenges in diagnosing rare diseases, and episignatures have emerged as potential biomarkers to help classify these variants.
- A study analyzed DNA methylation data from different groups, including carriers of pathogenic variants and healthy controls, using a k-nearest-neighbour classifier to assess the predictive abilities of various episignatures.
- Results revealed that while some signatures (ATRX, DNMT3A, KMT2D, NSD1) achieved 100% sensitivity, others (CREBBP-RSTS, CHD8) showed lower performance, indicating that not all episignatures are equally reliable for diagnostic use and highlighting the need for further validation with larger sample sizes.
Article Synopsis
- - The study investigates the increasing frequency of multiple molecular diagnoses (MMDs) in individuals with congenital anomalies/intellectual disability (CA/ID) through clinical exome/genome sequencing, highlighting rates between 1.8% to 7.1% previously documented.
- - Out of 880 positive exome sequencing diagnoses analyzed from 2014 to 2021, MMDs were found in 3.5% of cases, with additional potential MMDs identified in 4.4% of individuals, indicating their significance in disease comprehension.
- - Emphasizing the necessity for reanalysis of sequencing data and collaboration among clinicians and biologists, the study underlines the importance of updated clinical information and enhanced bio
Article Synopsis
- Exome sequencing has a high diagnostic yield (25%-70%) for rare diseases, revealing novel gene associations, but retrospective data reanalysis can be challenging for labs.
- The study employed a systematic reanalysis strategy utilizing daily PubMed searches and the GREP command-line tool to track new disease-gene associations over 18 months.
- From their queries, they identified 128 genes of interest and confirmed causal diagnoses in 21 individuals, showcasing that this efficient reanalysis method can enhance diagnostic outcomes in genetic research.
Article Synopsis
- Pathogenic variants in KMT5B, a lysine methyltransferase, are linked to global developmental issues, macrocephaly, autism, and other congenital anomalies, but the disorder is still not fully understood.
- A study examining 43 patients revealed new significant features like hypotonia and congenital heart defects not previously associated with this condition.
- Research using patient cell lines and KMT5B knockout mice showed that these variants lead to slow growth and highlighted alterations in pathways related to nervous system development, enhancing our understanding of the disorder's molecular mechanisms.
The different clinical facets of -related neurodevelopmental disorders.
Front Cell Dev Biol
December 2022
Article Synopsis
- This study introduces 31 new individuals with 22 unique genetic variants related to SYN1 disorders, detailing the prevalence of symptoms like autism, epilepsy, and intellectual disability across these cases.
- The research also identifies specific triggers for seizures, such as water contact and routine activities, and suggests that the type of genetic mutation can influence the severity of symptoms, particularly the relationship between early seizure onset and greater intellectual challenges.
Article Synopsis
- The study reports on seven patients with Marbach-Schaaf neurodevelopmental syndrome, all sharing the same genetic variant in the PRKAR1B gene, which affects their neurological development.
- Key symptoms include global developmental delay, reduced pain sensitivity, and some behavioral issues, with only one patient formally diagnosed with autism spectrum disorder (ASD), suggesting a lower prevalence of ASD in this syndrome than previously thought.
- The findings indicate that PRKAR1B plays a significant role in neuron function and highlights the need to explore molecular mechanisms to better understand the disorder's diverse clinical presentations.
Article Synopsis
- Rare genetic variants in the CDK13 gene cause CDK13-related disorder (CDK13-RD), which includes symptoms like developmental delays, facial abnormalities, and seizures; this paper presents 18 new cases with detailed disease characterization.
- The study involved clinical data analysis, comparison of DNA methylation between CDK13-RD individuals and controls, and the development of a machine learning model to differentiate CDK13-RD from other disorders.
- The findings reveal new symptoms associated with CDK13-RD, establish a specific DNA methylation profile as a diagnostic tool, and highlight similarities with another disorder related to the CCNK gene.
A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder.
Livia O Loureiro
,
Jennifer L Howe
,
Miriam S Reuter
,
Alana Iaboni
,
Kristina Calli
,
James Lespinasse
NPJ Genom Med
November 2021
Article Synopsis
- - Autism Spectrum Disorder (ASD) is influenced by a complex array of genetic factors, with around 100 known copy number variants and genes associated with the condition, prompting researchers to explore specific damaging mutations in affected genes.
- - The study identified a common mutation in the SHANK3 gene (c.3679dup; p.Ala1227Glyfs*69) present in 18 individuals from 16 families, which is found in about 0.08% of those with ASD, with many individuals having new mutations while some inherited it through somatic mosaicism.
- - Analysis of individuals with the SHANK3 mutation revealed that all tested had an ASD diagnosis, but the expression of core ASD features varied significantly
Severe Phenotype in Patients with Large Deletions of .
Laurence Pacot
,
Dominique Vidaud
,
Audrey Sabbagh
,
Ingrid Laurendeau
,
Audrey Briand-Suleau
,
James Lespinasse
Cancers (Basel)
June 2021
Article Synopsis
- Complete gene deletion occurs in 5-10% of neurofibromatosis type 1 (NF1) patients, with a significant representation (4%) observed in a large French cohort of 3,479 cases.
- A comprehensive clinical evaluation revealed that 93% of patients with gene deletion met the NIH criteria for NF1, showing a higher incidence of symptoms like café-au-lait spots, neurofibromas, and learning disabilities.
- Compared to typical NF1 cases, the -deleted cohort displayed more severe symptoms, including a higher percentage of spinal neurofibromas, dysmorphism, and various systemic abnormalities.
Article Synopsis
- - Tenorio syndrome (TNORS) is a recently identified genetic disorder characterized by symptoms such as macrocephaly, intellectual disability, hypotonia, enlarged ventricles, and autoimmune diseases, with few cases documented so far.
- - The underlying genetic issues include missense variants and a large deletion in the RNF125 gene, which is important for protein regulation, and further investigations have identified 14 new cases, enriching the understanding of the syndrome's clinical features.
- - While not all patients exhibited significant overgrowth, a common trend among them includes neurodevelopmental challenges and macrocephaly, with families showing varying severity of symptoms, indicating a need for more research on the syndrome's genetics and clinical presentation.
Article Synopsis
- Molecular diagnosis using singleton exome sequencing (sES) in fetuses with multiple congenital abnormalities (MCA) shows a lower diagnostic yield (20%) compared to live births with developmental issues (30%), indicating potential underestimation of genetic variant impact in fetal cases.
- In a study of 95 fetuses with MCA, a genotype-first strategy was employed, blending variant analysis and bioinformatics with reverse phenotyping to determine the clinical significance of genetic variations.
- The results revealed causal variants in 25% of fetuses, unknown significance variants in 8%, and identified six novel candidate genes, highlighting the importance of prenatal genetic studies for understanding complex disorders.
Article Synopsis
- - Segmental progeroid syndromes are rare genetic disorders that speed up certain aging features and have been researched since the 20th century.
- - The Molecular Genetics Laboratory in Marseille has been using NGS sequencing for four years to diagnose these syndromes in 66 patients, achieving a diagnostic success rate over 60% when there's a specific clinical suspicion.
- - The study identified significant genetic variants in many patients, proposed prenatal testing for some families, and emphasized that this method is an effective first step towards diagnosing these disorders before considering whole genome sequencing.
Article Synopsis
- Nijmegen breakage syndrome is linked to mutations in the NBN gene and leads to severe health issues like microcephaly, cancer risk, and infertility.
- A new study identified a specific NBN variant in Lebanese patients that is primarily associated with infertility, differing from the usual severe symptoms of the syndrome.
- Functional tests showed that, despite reduced NBN levels and some cell cycle defects, these patients retained certain protein functions that may explain their milder symptoms compared to typical Nijmegen breakage syndrome cases.
Background: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified defects, as no external validation was available.
View Article and Find Full Text PDFArticle Synopsis
- The 15q11.2 deletion is linked to neurodevelopmental disorders and its clinical implications are challenging due to confusing literature surrounding it.
- This study aimed to determine the effect size of this deletion using meta-analysis of various case-control studies, revealing a decrease in IQ by 4.3 points among carriers.
- The findings suggested that while the deletion has some association with disorders like intellectual disabilities and epilepsy, it is not significant enough to warrant discussion in clinical settings, as it mostly shows mild effects.
Article Synopsis
- The text refers to a correction made to a previously published article with the DOI 10.1038/s41525-017-0035-2.
- The correction likely addresses errors or omissions in the original publication.
- This ensures that readers have access to accurate and updated information related to the research discussed in the article.
Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders.
Caroline Schluth-Bolard
,
Flavie Diguet
,
Nicolas Chatron
,
Pierre-Antoine Rollat-Farnier
,
Claire Bardel
,
James Lespinasse
J Med Genet
August 2019
Article Synopsis
- A study investigated balanced chromosomal rearrangements in patients with intellectual disabilities and congenital anomalies using next-generation sequencing to identify breakpoints at a molecular level.
- The research characterized breakpoints in 55 patients, revealing that 89% of chromosomal rearrangements were detected, with non-homologous end-joining identified as the primary repair mechanism.
- The study found that a diagnosis could be established in about 44.8% of patients, revealing disruptions in genes and suggesting that paired-end whole genome sequencing is effective for clinical applications in structural variation analysis.
Article Synopsis
- Robertsonian translocations (RobT) are common chromosome rearrangements where carriers often produce mostly balanced sperm through a process called alternate segregation, raising questions about the relevance of sperm FISH analysis for these individuals.* -
- A study analyzed 23 patients from 2003-2017 alongside 187 cases from literature, finding that 73.45% of spermatozoa from RobT carriers were chromosomally balanced, in line with existing data, although some translocation types, particularly der(13;15), showed lower rates.* -
- Results suggest that despite some variations in sperm quality among RobT carriers, sperm FISH analysis remains important for genetic counseling and assessing reproductive options for these patients.*
Cutis laxa and excessive bone growth due to de novo mutations in PTDSS1.
Am J Med Genet A
March 2018
Article Synopsis
- - The cutis laxa syndromes are a group of disorders characterized by loose, wrinkled skin and involve various genetic mutations related to elastic fiber formation.
- - This report focuses on three patients with a specific rare disorder known as Lenz-Majewski syndrome (LMS), marked by unique symptoms like facial dysmorphism, severe growth retardation, and intellectual disability, linked to mutations in the PTDSS1 gene.
- - The study highlights LMS as a clear example of a cutis laxa syndrome and notes distinctive early signs such as brachydactyly, emphasizing the need for further research on the connection between the PTDSS1 gene and the body's extracellular matrix structure.
A framework to identify contributing genes in patients with Phelan-McDermid syndrome.
Anne-Claude Tabet
,
Thomas Rolland
,
Marie Ducloy
,
Jonathan Lévy
,
Julien Buratti
,
James Lespinasse
NPJ Genom Med
October 2017
Article Synopsis
- Phelan-McDermid syndrome (PMS) is a genetic condition linked to deletions on chromosome 22q13, leading to symptoms like intellectual disability, speech delays, and autism spectrum disorders, with severity varying across individuals.
- The study involved analyzing 85 patients and found that 28% had abnormalities in the corpus callosum, a brain structure important for communication between hemispheres, and identified genomic regions that may contribute to specific symptoms like lack of speech.
- Additionally, researchers found significant genetic variations that might influence the severity of PMS and noted that some family members with the deletion could remain unaffected, indicating potential compensatory mechanisms for managing the disorder.