Publications by authors named "Gwenael le Guyader"
Article Synopsis
- KBG syndrome is an autosomal dominant genetic disorder characterized by neurodevelopmental issues, intellectual disability, behavioral problems, epilepsy, and distinct physical features.
- This study aimed to analyze the diagnostic pathway for individuals with KBG syndrome, focusing on the healthcare professionals involved and the reasons for referrals.
- Results indicated that pediatricians were the primary referrers for genetic consultation, mainly due to concerns about learning delays or intellectual disabilities in children.
FOXG1 variants can be associated with milder phenotypes than congenital Rett syndrome with unassisted walking and language development.
Am J Med Genet B Neuropsychiatr Genet
September 2024
Since 2008, FOXG1 haploinsufficiency has been linked to a severe neurodevelopmental phenotype resembling Rett syndrome but with earlier onset. Most patients are unable to sit, walk, or speak. For years, FOXG1 sequencing was only prescribed in such severe cases, limiting insight into the full clinical spectrum associated with this gene.
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- The study investigates the concept of incomplete penetrance in neurodevelopmental disorders, where some individuals carry pathogenic genetic variants but remain asymptomatic.
- Between 2020 and 2022, researchers collaborated with a French network to analyze families where affected individuals had inherited these variants from symptom-free parents, finding 12 cases with significant genetic findings.
- The results suggest that incomplete penetrance may be more common than previously acknowledged, highlighting its importance for genetic interpretation, counseling, and future research into its underlying mechanisms.
Article Synopsis
- Duplications of the 3q29 chromosomal region are rare genetic variations linked to diverse neurodevelopmental disorders, often causing learning disabilities and neuropsychiatric issues.
- A study involving 31 families revealed different sizes of 3q29 duplications: 14 recurrent, 8 overlapping, and 9 smaller ones, with some patients showing additional genetic factors influencing their conditions.
- Most patients exhibited mild neurodevelopmental disorders, with many duplications being inherited and associated with low rates of intellectual disabilities, suggesting that severe cases might require more detailed genetic examination.
Purpose: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD).
Methods: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients.
Background: Molecular diagnosis of neurodevelopmental disorders (NDDs) is mainly based on exome sequencing (ES), with a diagnostic yield of 31% for isolated and 53% for syndromic NDD. As sequencing costs decrease, genome sequencing (GS) is gradually replacing ES for genome-wide molecular testing. As many variants detected by GS only are in deep intronic or non-coding regions, the interpretation of their impact may be difficult.
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- * New cases revealed individuals with microdeletions in AGAP1 exhibited various neurodevelopmental issues, including intellectual disability and autism, along with other physical and developmental challenges.
- * Research in fruit flies suggested that AGAP1 disruption leads to problems in cellular transport processes, increased susceptibility to stress, and highlights the interaction between genetic vulnerabilities and environmental factors in neurodevelopmental disorders.
Article Synopsis
- Common obesity is a major global health issue, but studying its rare monogenic forms has provided insights into the genetic mechanisms involved, particularly those affecting appetite regulation in the brain.
- A variant in the POU3F2 gene, linked to neurodevelopmental disorders and obesity, was identified in a family showing symptoms of both syndromic obesity and autism spectrum disorder.
- Research suggests that dysfunctional variants of POU3F2 contribute to difficulties in appetite control and weight gain during adolescence, indicating its role not just in monogenic forms, but possibly also in common obesity cases.
Article Synopsis
- Microduplications of the MYT1L gene are linked mainly to isolated schizophrenia, but detailed phenotypic characteristics are not well-defined due to limited reports.
- The study involved 16 new patients with 2p25.3 microduplications and reviewed 27 existing cases, revealing a wide range of clinical features including developmental delays, autism, intellectual disabilities, and schizophrenia.
- Findings indicate that MYT1L microduplications can vary significantly in expression and may be influenced by unknown genetic and environmental factors, helping clinicians with assessment and management.
Article Synopsis
- Dominant variants in the RARB gene cause MCOPS12, a type of microphthalmia that comes with various birth defects and developmental delays, impacting 25 individuals in this study.
- The research employed transcriptional assays and structural analysis to evaluate how these RARB variants affect its typical function, revealing both gain-of-function and loss-of-function activities.
- Findings indicate that while RARB disruption leads to a variety of clinical outcomes, some affected individuals may not show key symptoms like eye abnormalities or motor issues, highlighting the complexity of these genetic variations.
Purpose: Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder.
Methods: Cases with YWHAE variants were collected through international data sharing networks.
Unlabelled: is an Arf1 GAP that regulates endolysosomal trafficking. Damaging variants have been linked to cerebral palsy and autism. We report 3 new individuals with microdeletion variants in .
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- * The deletion was caused by a unique genetic event involving a dicentric chromosome during early development, resulting in a combination of an inverted duplication and deletion in a mosaic pattern in the placenta.
- * This case is significant as it is the first instance of a terminal deletion consistently found in the blood of a patient, linked to a similar genetic anomaly in the placenta, prompting considerations for genetic counseling in similar prenatal findings.
Article Synopsis
- The blood-brain barrier is essential for protecting the central nervous system (CNS) and maintaining its balance, with Claudin-5 (CLDN5) being a key factor in its integrity.
- Researchers discovered new mutations in the CLDN5 gene in 15 unrelated patients, who exhibited symptoms like developmental delays, seizures, and specific brain abnormalities.
- By studying these variants in zebrafish, they found that these mutations likely disrupt the normal function of CLDN5, leading to a new neurodevelopmental disorder that affects both the blood-brain barrier and neuronal health.
Article Synopsis
- Recent research highlights that new missense variants in the SLC32A1 gene are linked to severe epilepsy and neurodevelopmental issues in individuals with the condition.
- Four individuals were studied and identified with these genetic variations, showing traits like intellectual disability and early-onset epilepsy.
- The findings suggest these variants could disrupt the normal function of GABA neurotransmission, potentially causing epilepsy through two main mechanisms related to synaptic vesicle function.
Article Synopsis
- Peters' anomaly (PA) is a rare eye condition marked by issues like corneal opacity and adhesions related to the eye's anterior segment, linked to several genes such as B3GLCT and PAX6.
- Researchers studied 95 PA patients using advanced genetic techniques and found genetic defects in about one-third of them, with B3GLCT and PAX6 being the most common culprits.
- Notably, they discovered SOX2, a gene associated with microphthalmia, in some PA patients, highlighting its unexpected role in this condition and the need for further genetic exploration in PA cases.
Purpose: Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder characterized by developmental delay and/or intellectual disability, hypotonia, feeding difficulties, and distinct facial features. To refine the phenotype and to better understand the molecular basis of the syndrome, we analyzed clinical data and performed genome-wide DNA methylation analysis of a series of individuals carrying a YY1 variant.
Methods: Clinical data were collected for 13 individuals not yet reported through an international call for collaboration.
Aim: KCNB1 encephalopathy encompasses a broad phenotypic spectrum associating intellectual disability, behavioral disturbances, and epilepsies of various severity. Using standardized parental questionnaires, we aimed to capture the heterogeneity of the adaptive and behavioral features in a series of patients with KCNB1 pathogenic variants.
Methods: We included 25 patients with a KCNB1 encephalopathy, aged from 3.
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.
Article Synopsis
- The study investigated the clinical characteristics and genetic variations associated with the DHX30-related neurodevelopmental disorder, especially focusing on new missense variants in the gene.
- Researchers collected clinical and genetic data from affected individuals via social media, collaboration networks, and analyzed the effects of these variants on cellular functions and development using various experimental models, including zebrafish.
- Findings revealed that individuals with missense variants presented with severe developmental issues, while those with variants leading to milder haploinsufficiency showed less severe symptoms, suggesting the presence of two distinct clinical subtypes based on the type and location of the genetic variants.
Article Synopsis
- The CHD5 gene, found in the critical 1p36 microdeletion region, is part of the NuRD complex essential for brain development, and variants in this gene are linked to neurodevelopmental disorders.
- A study identified 16 individuals with heterozygous CHD5 variants via exome sequencing, revealing that most had new (de novo) mutations associated with conditions such as speech delays and learning disabilities.
- The most common issues among these patients included language deficits (81%), behavioral problems (69%), intellectual disabilities (64%), and epilepsy (62%), indicating that CHD5 variants lead to a varied spectrum of neurodevelopmental disorders.
Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.
Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants.
Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy.
Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE).
Article Synopsis
- Atypical fetal chromosomal anomalies (ACAs) are more common than thought and can impact fetal development, hence a new screening strategy for non-invasive prenatal testing (NIPT) was developed.
- The screening was tested on two cohorts: Cohort A with 192 plasma samples (42 with ACAs) evaluated the test's performance, showing an 88.1% sensitivity and 99.3% specificity.
- In Cohort B, involving 3,097 pregnant women, there was a 1.2% positive result rate for anomalies, indicating that this genome-wide NIPT can effectively screen for ACAs while requiring minimal additional invasive tests, especially for at-risk women.
De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.
Genet Med
November 2020
Article Synopsis
- Nontruncating variants in the SMARCA2 gene are linked to Nicolaides-Baraitser syndrome (NCBRS), characterized by intellectual disability and congenital anomalies, but other disorders associated with SMARCA2 were unclear.
- Researchers found SMARCA2 variants in 20 individuals with syndromic neurodevelopmental disorders that did not fit the criteria for NCBRS and analyzed these variants functionally and through genetic testing.
- Results revealed a new syndrome called blepharophimosis intellectual disability syndrome (BIS), which shares some features with NCBRS but is distinct both phenotypically and at the molecular level, primarily due to the location of the SMARCA2 variants.