Abstract Recent advances in the understanding of infantile developmental epileptic encephalopathies (IDEE) have revealed the association of biallelic pathogenic variants in UGDH . In this study, we ...report two novel combinations identified by exome sequencing: p.(Arg135Trp) with p.(Arg65*) and p.(Arg102Trp) with p.(Arg65*). Both combinations share a common pathogenic nonsense variant, with the missense variants strategically located in the NAD‐binding domain of the UGDH protein, predicted in structural models to create new interactions with the central domain. The first patient exhibited the typical UGDH‐related disease phenotype and progressive microcephaly, a rarely reported feature. In contrast, the second patient presented an atypical phenotype, including absence of seizure, severe intellectual disability, ataxic gait, and abnormal eye movements. This comprehensive analysis extends the phenotypic spectrum of UGDH syndrome beyond early infantile intractable encephalopathy to include intellectual disability without epilepsy.
Thrombocytopenia‐absent radius (TAR) syndrome is characterized by radial defect and neonatal thrombocytopenia. It is caused by biallelic variants of RBM8A gene (1q21.1) with the association of a null ...allele and a hypomorphic noncoding variant. RBM8A encodes Y14, a core protein of the exon junction complex involved in messenger RNA maturation. To date, only two hypomorphic variants have been identified. We report on a cohort of 26 patients affected with TAR syndrome and carrying biallelic variants in RBM8A. Half patients carried a 1q21.1 deletion and one of the two known hypomorphic variants. Four novel noncoding variants of RBM8A were identified in the remaining patients. We developed experimental models enabling their functional characterization in vitro. Two variants, located respectively in the 5′‐untranslated region (5′‐UTR) and 3′‐UTR regions, are responsible for a diminished expression whereas two intronic variants alter splicing. Our results bring new insights into the molecular knowledge of TAR syndrome and enabled us to propose genetic counseling for patients' families.
Congenital limb malformations (CLM) comprise many conditions affecting limbs and more than 150 associated genes have been reported. Due to this large heterogeneity, a high proportion of patients ...remains without a molecular diagnosis. In the last two decades, advances in high throughput sequencing have allowed new methodological strategies in clinical practice. Herein, we report the screening of 52 genes/regulatory sequences by multiplex high‐throughput targeted sequencing, in a series of 352 patients affected with various CLM, over a 3‐year period of time. Patients underwent a clinical triage by expert geneticists in CLM. A definitive diagnosis was achieved in 35.2% of patients, the yield varying considerably, depending on the phenotype. We identified 112 single nucleotide variants and 26 copy‐number variations, of which 52 are novel pathogenic or likely pathogenic variants. In 6% of patients, variants of uncertain significance have been found in good candidate genes. We showed that multiplex targeted high‐throughput sequencing works as an efficient and cost‐effective tool in clinical practice for molecular diagnosis of congenital limb malformations. Careful clinical evaluation of patients may maximize the yield of CLM panel testing.
Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido‐lenticulo‐corneal adhesions. Several genes are involved in syndromic or isolated PA ...(B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro‐anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.
PITX1 is a homeobox transcription factor essential for hindlimb morphogenesis. Two PITX1‐related human disorders have been reported to date: PITX1 ectopic expression causes Liebenberg syndrome, ...characterized by malformation of upper limbs showing a “lower limb” appearance; PITX1 deletions or missense variation cause a syndromic picture including clubfoot, tibial hemimelia, and preaxial polydactyly. We report two novel PITX1 missense variants, altering PITX1 transactivation ability, in three individuals from two unrelated families showing a distinct recognizable autosomal dominant syndrome, including first branchial arch, pelvic, patellar, and male genital abnormalities. This syndrome shows striking similarities with the Pitx1−/− mouse model. A partial phenotypic overlap is also observed with Ischiocoxopodopatellar syndrome caused by TBX4 haploinsufficiency, and with the phenotypic spectrum caused by SOX9 anomalies, both genes being PITX1 downstream targets. Our study findings expand the spectrum of PITX1‐related disorders and suggest a common pattern of developmental abnormalities in disorders of the PITX1–TBX4–SOX9 signaling pathway.
Background: Introduction of script concordance tests (SCT) in the graduating French national ranking examination, so-called ECNi, is discussed. SCT has never been used to evaluate medical genetics in ...graduate medical studies. Objective: Develop a medical genetics SCT and administer it to graduate students and residents in medical genetics. Determine the ability of SCT to discriminate the expertise of participants. Method: Creation of a specific SCT for medical genetics and administration of it to graduate students and residents in medical genetics. The ECNi-type test includes 3 clinical case scenarios and 12 isolated questions. Internal consistency was measured with Cronbach’s alpha. Construct validity was evaluated by comparing scores obtained by the different groups and measuring the correlation between the score obtained at the SCT and the students’ overall ranking at the ECNi. Results: A total of 18 experts and 129 students (105 graduate students and 24 residents in medical genetics) participated. Cronbach’s alpha was 0.67. The test was able to discriminate between mastery level in students. There was a correlation between the SCT scores and the ECNi ranking. Conclusion: This study focused on a standardized SCT available to evaluate medical genetics’ learning by graduate students. The SCT score is correlated with the results obtained in clinical case scenarios and with the ECNi ranking, indicating an excellent ability to assess clinical reasoning and discriminate students’ level.
Contexte : Dans les prochaines années, il est prévu d’introduire le test de concordance de script (TCS) dans le cadre des épreuves classantes nationales informatisées (ECNi). Le TCS n’a jamais été évalué pour l’enseignement de la génétique médicale du deuxième cycle. But : Élaborer un TCS pour les étudiants de deuxième cycle et évaluer ses qualités psychométriques. Déterminer les arguments docimologiques étayant la pertinence d’introduire le TCS aux ECNi. Méthode : Création d’un TCS spécifique à la discipline et administration aux étudiants de deuxième cycle et internes de génétique médicale. Administration d’une épreuve type ECNi comportant 3 dossiers progressifs (DP) et 12 questions isolées (QI) aux étudiants de deuxième cycle. Analyse du caractère discriminant du TCS par comparaison des scores obtenus par les différents groupes. Analyse de corrélation entre les scores aux TCS et DP, QI et rang de classement aux ECNi. Résultats : Les réponses de 18 experts et 129 étudiants ont été obtenues. Après optimisation, le TCS contient 15 vignettes cliniques et 34 items. Le coefficient alpha de Cronbach est de 0,67. Le test a pu discriminer le niveau des étudiants et il existe une corrélation entre les scores obtenus au TCS, aux DP, ainsi qu’avec le rang de classement aux ECNi. Conclusion : Cette étude montre la faisabilité d’un TCS standardisé pour évaluer l’enseignement de la génétique médicale, qui pourrait être aisément intégré aux ECNi. Il s’agit d’un exemple supplémentaire de la pertinence de ce type d’épreuve dans l’évaluation du raisonnement clinique des étudiants de médecine.
Contexte :
Dans les prochaines années, il est prévu d’introduire le test de concordance de script (TCS) dans le cadre des épreuves classantes nationales informatisées (ECNi). Le TCS n’a jamais été ...évalué pour l’enseignement de la génétique médicale du deuxième cycle.
But :
Élaborer un TCS pour les étudiants de deuxième cycle et évaluer ses qualités psychométriques. Déterminer les arguments docimologiques étayant la pertinence d’introduire le TCS aux ECNi.
Méthode :
Création d’un TCS spécifique à la discipline et administration aux étudiants de deuxième cycle et internes de génétique médicale. Administration d’une épreuve type ECNi comportant 3 dossiers progressifs (DP) et 12 questions isolées (QI) aux étudiants de deuxième cycle. Analyse du caractère discriminant du TCS par comparaison des scores obtenus par les différents groupes. Analyse de corrélation entre les scores aux TCS et DP, QI et rang de classement aux ECNi.
Résultats :
Les réponses de 18 experts et 129 étudiants ont été obtenues. Après optimisation, le TCS contient 15 vignettes cliniques et 34 items. Le coefficient alpha de Cronbach est de 0,67. Le test a pu discriminer le niveau des étudiants et il existe une corrélation entre les scores obtenus au TCS, aux DP, ainsi qu’avec le rang de classement aux ECNi.
Conclusion :
Cette étude montre la faisabilité d’un TCS standardisé pour évaluer l’enseignement de la génétique médicale, qui pourrait être aisément intégré aux ECNi. Il s’agit d’un exemple supplémentaire de la pertinence de ce type d’épreuve dans l’évaluation du raisonnement clinique des étudiants de médecine.
Background:
Introduction of script concordance tests (SCT) in the graduating French national ranking examination, so-called ECNi, is discussed. SCT has never been used to evaluate medical genetics in graduate medical studies.
Objective:
Develop a medical genetics SCT and administer it to graduate students and residents in medical genetics. Determine the ability of SCT to discriminate the expertise of participants.
Method:
Creation of a specific SCT for medical genetics and administration of it to graduate students and residents in medical genetics. The ECNi-type test includes 3 clinical case scenarios and 12 isolated questions. Internal consistency was measured with Cronbach’s alpha. Construct validity was evaluated by comparing scores obtained by the different groups and measuring the correlation between the score obtained at the SCT and the students’ overall ranking at the ECNi.
Results:
A total of 18 experts and 129 students (105 graduate students and 24 residents in medical genetics) participated. Cronbach’s alpha was 0.67. The test was able to discriminate between mastery level in students. There was a correlation between the SCT scores and the ECNi ranking.
Conclusion:
This study focused on a standardized SCT available to evaluate medical genetics’ learning by graduate students. The SCT score is correlated with the results obtained in clinical case scenarios and with the ECNi ranking, indicating an excellent ability to assess clinical reasoning and discriminate students’ level.
Martineau Louis Simon, Regnaud de Saint-Jean d'Angely Michel Louis Etienne, Bourdon Antoine, Gouttes Jean-Louis, Boussion Pierre. Discussion du projet de décret sur la contribution patriotique des ...ci-devant bénéficiers, lors de la séance du 12 février 1791. In: Tome XXIII - Du 6 février 1791 au 9 mars 1791. pp. 139-140.
Boussion Pierre, Prieur de la Marne Pierre Louis, La Révellière-Lépeaux Louis Marie de, Goupil de Préfeln Guillaume François, Martineau Louis Simon. Lecture de différentes adresses, lors de la séance ...du 1er février 1791. In: Tome XXII - Du 3 janvier au 5 février 1791. pp. 664-665.
Vernier Théodore, Charrier de La Roche Louis, Dellay-d'Agier ou Delay Claude Pierre de, Martineau Louis Simon, Féraud, Roederer Pierre Louis, Dubois-Crancé Edmond Louis, Boussion Pierre. Discussion ...sur l'impôt en nature, lors de la séance du 6 octobre 1790. In: Tome XIX - Du 16 septembre au 23 octobre 1790. pp. 476-479.
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