52 research outputs found
Barber-Say/Ablepharon-Macrostomia : Patientâs View
Barber-Say syndrome (BSS) and ablepharon-macrostomia syndrome (AMS) are infrequently reported congenital malformation disorders caused by mutations in the TWIST2 gene. Both are characterized by abnormalities in ectoderm-derived structures and cause a very unusual morphology of mainly the face in individuals with otherwise normal cognition and normal physical functioning. We studied the impact that the presence of BSS and AMS has on psychosocial functioning of affected individuals and their families, using their point of view to start with. We tabulated frequently asked questions from affected individuals and families, and a parent of an affected child and an affected adult woman offered personal testimonies. We focused on perception of illness, body satisfaction, and the consequences for an otherwise normal individual who has a disorder that interferes with body image. The importance of paying particular attention to the management of both the physical appearance and the consequences of these entities on the quality of life is stressed by the affected individuals themselves
Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity
ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized. International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing. We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity. We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy
Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
Background
In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking.
Methods
We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires.
Results
We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected.
Conclusions
This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research FoundationâFlanders and the Chief Scientist OfficeâMinistry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and â5 per milleâ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009â003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network
Genetic landscape of a large cohort of Primary Ovarian Insufficiency : New genes and pathways and implications for personalized medicine
Background Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yield-ing infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology.Methods 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. Findings A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromo-somal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link.Interpretation We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogene-sis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility.Funding Universite? Paris Saclay, Agence Nationale de Biome?decine.Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe
Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis
Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making
A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing
Purpose
Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the âClinVar low-hanging fruitâ reanalysis, reasons for the failure of previous analyses, and lessons learned.
Methods
Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted.
Results
We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency).
Conclusion
The âClinVar low-hanging fruitâ analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock
Increased oxytocin release precedes hyponatremia after pituitary surgery
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a well-known complication of transsphenoidal pituitary surgery, related to inappropriate secretion of arginine vasopressin (AVP). Its diagnosis is based on hyponatremia, with a peak of occurrence around day 7 after surgery and, to date, no early marker has been reported. In particular, copeptin levels are not predictive of hyponatremia in this case. Oxytocin (OXT) is secreted into the peripheral blood by axon terminals adjacent to those of AVP neurons in the posterior pituitary. Besides its role in childbirth and lactation, recent evidences suggested a role for OXT in sodium balance. The contribution of this hormone in the dysnatremias observed after pituitary surgery has however never been investigated
Description clinique et analyse de corrĂ©lation phĂ©notype/gĂ©notype dans une cohorte de patients atteints dâune dĂ©ficience intellectuelle liĂ©e Ă des mutations du gĂšne PAK3
International audienceLa prĂ©valence de la dĂ©ficience intellectuelle (DI) est estimĂ©e entre 2 Ă 3% de la population gĂ©nĂ©rale. Chez les individus de sexe masculin 5 Ă 10% des DI seraient liĂ©es Ă lâX. On connait actuellement 146 gĂšnes de DI sur le chromosome X. Le premier variant pathogĂšne retrouvĂ© dans le gĂšne PAK3 (P21-Activated Kinase 3) est un variant faux-sens identifiĂ© par Allen et al. en 1998 dans une famille de patients atteints dâune DI liĂ©e Ă lâX. Les patients, dĂ©crits comme peu dysmorphiques, avaient une microcĂ©phalie et des troubles du comportement, hyperactivitĂ© dans lâenfance et hĂ©tĂ©roagressivitĂ© Ă lâĂąge adulte. Notre Ă©tude multicentrique rĂ©trospective avait pour objectif de dĂ©crire les caractĂ©ristiques cliniques des patients ayant une mutation dans le gĂšne PAK3 puis de faire une analyse de corrĂ©lation phĂ©notype/gĂ©notype. Elle a portĂ© sur dix patients recrutĂ©s en France et quarante-cinq patients de la littĂ©rature. Nous avons retrouvĂ© une DI non spĂ©cifique associĂ©e Ă une hypotonie dans 92% des cas, un retard de langage dans 91%, une microcĂ©phalie dans 46% et des rĂ©flexes vifs dans 32% des cas. Les troubles du comportement prĂ©sents chez 97% des patients sont au-devant du tableau clinique avec une auto- ou une hĂ©tĂ©roagressivitĂ© dans 58% des cas et une psychose dans 26% des cas. Sur le plan morphologique, il nâexiste pas de caractĂšres spĂ©cifiques, mais des oreilles longues sont retrouvĂ©es chez 60% des patients et un palais creux chez 71%. Enfin, une agĂ©nĂ©sie du corps calleux est retrouvĂ©e dans 42% des cas mais peu de patients ont eu une IRM cĂ©rĂ©brale. Au total, 14 patients issus de 4 familles ont une mutation nulle et 40 patients issus de 12 familles ont une mutation faux-sens. Nous nâavons pas mis en Ă©vidence de corrĂ©lation gĂ©notype-phĂ©notype significative, notamment les patients ayant une mutation nulle nâont pas une atteinte clinique plus sĂ©vĂšre que les autres. Une nouvelle Ă©tude avec un plus grand nombre de patients et davantage de donnĂ©es dâimagerie cĂ©rĂ©brale serait intĂ©ressante pour Ă©valuer la frĂ©quence de lâagĂ©nĂ©sie du corps calleux et dĂ©finir si elle est liĂ©e Ă certains types de mutations
Description clinique et analyse de corrĂ©lation phĂ©notype/gĂ©notype dans une cohorte de patients atteints dâune dĂ©ficience intellectuelle liĂ©e Ă des mutations du gĂšne PAK3
International audienceLa prĂ©valence de la dĂ©ficience intellectuelle (DI) est estimĂ©e entre 2 Ă 3% de la population gĂ©nĂ©rale. Chez les individus de sexe masculin 5 Ă 10% des DI seraient liĂ©es Ă lâX. On connait actuellement 146 gĂšnes de DI sur le chromosome X. Le premier variant pathogĂšne retrouvĂ© dans le gĂšne PAK3 (P21-Activated Kinase 3) est un variant faux-sens identifiĂ© par Allen et al. en 1998 dans une famille de patients atteints dâune DI liĂ©e Ă lâX. Les patients, dĂ©crits comme peu dysmorphiques, avaient une microcĂ©phalie et des troubles du comportement, hyperactivitĂ© dans lâenfance et hĂ©tĂ©roagressivitĂ© Ă lâĂąge adulte. Notre Ă©tude multicentrique rĂ©trospective avait pour objectif de dĂ©crire les caractĂ©ristiques cliniques des patients ayant une mutation dans le gĂšne PAK3 puis de faire une analyse de corrĂ©lation phĂ©notype/gĂ©notype. Elle a portĂ© sur dix patients recrutĂ©s en France et quarante-cinq patients de la littĂ©rature. Nous avons retrouvĂ© une DI non spĂ©cifique associĂ©e Ă une hypotonie dans 92% des cas, un retard de langage dans 91%, une microcĂ©phalie dans 46% et des rĂ©flexes vifs dans 32% des cas. Les troubles du comportement prĂ©sents chez 97% des patients sont au-devant du tableau clinique avec une auto- ou une hĂ©tĂ©roagressivitĂ© dans 58% des cas et une psychose dans 26% des cas. Sur le plan morphologique, il nâexiste pas de caractĂšres spĂ©cifiques, mais des oreilles longues sont retrouvĂ©es chez 60% des patients et un palais creux chez 71%. Enfin, une agĂ©nĂ©sie du corps calleux est retrouvĂ©e dans 42% des cas mais peu de patients ont eu une IRM cĂ©rĂ©brale. Au total, 14 patients issus de 4 familles ont une mutation nulle et 40 patients issus de 12 familles ont une mutation faux-sens. Nous nâavons pas mis en Ă©vidence de corrĂ©lation gĂ©notype-phĂ©notype significative, notamment les patients ayant une mutation nulle nâont pas une atteinte clinique plus sĂ©vĂšre que les autres. Une nouvelle Ă©tude avec un plus grand nombre de patients et davantage de donnĂ©es dâimagerie cĂ©rĂ©brale serait intĂ©ressante pour Ă©valuer la frĂ©quence de lâagĂ©nĂ©sie du corps calleux et dĂ©finir si elle est liĂ©e Ă certains types de mutations
Description clinique et analyse de corrĂ©lation phĂ©notype/gĂ©notype dans une cohorte de patients atteints dâune dĂ©ficience intellectuelle liĂ©e Ă des mutations du gĂšne PAK3
International audienceLa prĂ©valence de la dĂ©ficience intellectuelle (DI) est estimĂ©e entre 2 Ă 3% de la population gĂ©nĂ©rale. Chez les individus de sexe masculin 5 Ă 10% des DI seraient liĂ©es Ă lâX. On connait actuellement 146 gĂšnes de DI sur le chromosome X. Le premier variant pathogĂšne retrouvĂ© dans le gĂšne PAK3 (P21-Activated Kinase 3) est un variant faux-sens identifiĂ© par Allen et al. en 1998 dans une famille de patients atteints dâune DI liĂ©e Ă lâX. Les patients, dĂ©crits comme peu dysmorphiques, avaient une microcĂ©phalie et des troubles du comportement, hyperactivitĂ© dans lâenfance et hĂ©tĂ©roagressivitĂ© Ă lâĂąge adulte. Notre Ă©tude multicentrique rĂ©trospective avait pour objectif de dĂ©crire les caractĂ©ristiques cliniques des patients ayant une mutation dans le gĂšne PAK3 puis de faire une analyse de corrĂ©lation phĂ©notype/gĂ©notype. Elle a portĂ© sur dix patients recrutĂ©s en France et quarante-cinq patients de la littĂ©rature. Nous avons retrouvĂ© une DI non spĂ©cifique associĂ©e Ă une hypotonie dans 92% des cas, un retard de langage dans 91%, une microcĂ©phalie dans 46% et des rĂ©flexes vifs dans 32% des cas. Les troubles du comportement prĂ©sents chez 97% des patients sont au-devant du tableau clinique avec une auto- ou une hĂ©tĂ©roagressivitĂ© dans 58% des cas et une psychose dans 26% des cas. Sur le plan morphologique, il nâexiste pas de caractĂšres spĂ©cifiques, mais des oreilles longues sont retrouvĂ©es chez 60% des patients et un palais creux chez 71%. Enfin, une agĂ©nĂ©sie du corps calleux est retrouvĂ©e dans 42% des cas mais peu de patients ont eu une IRM cĂ©rĂ©brale. Au total, 14 patients issus de 4 familles ont une mutation nulle et 40 patients issus de 12 familles ont une mutation faux-sens. Nous nâavons pas mis en Ă©vidence de corrĂ©lation gĂ©notype-phĂ©notype significative, notamment les patients ayant une mutation nulle nâont pas une atteinte clinique plus sĂ©vĂšre que les autres. Une nouvelle Ă©tude avec un plus grand nombre de patients et davantage de donnĂ©es dâimagerie cĂ©rĂ©brale serait intĂ©ressante pour Ă©valuer la frĂ©quence de lâagĂ©nĂ©sie du corps calleux et dĂ©finir si elle est liĂ©e Ă certains types de mutations
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