Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and ...different genes have been demonstrated to be causative of syndromic and non‐syndromic forms of AM. We screened seven AM genes GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y‐box 2), and VSX2 (visual system homeobox 2 gene) in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi‐quantitative multiplex polymerase chain reaction (PCR) quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF). The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.
The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such ...as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.
BACKGROUND Genome-wide screening of large patient cohorts with mental retardation using microarray-based comparative genomic hybridisation (array-CGH) has recently led to identification several novel ...microdeletion and microduplication syndromes. METHODS Owing to the national array-CGH network funded by the French Ministry of Health, shared information about patients with rare disease helped to define critical intervals and evaluate their gene content, and finally determine the phenotypic consequences of genomic array findings. RESULTS In this study, nine unrelated patients with overlapping de novo interstitial microdeletions involving 4q21 are reported. Several major features are common to all patients, including neonatal muscular hypotonia, severe psychomotor retardation, marked progressive growth restriction, distinctive facial features and absent or severely delayed speech. The boundaries and the sizes of the nine deletions are different, but an overlapping region of 1.37 Mb is defined; this region contains five RefSeq genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL and ENOPH1. DISCUSSION Adding new individuals with similar clinical features and 4q21 deletion allowed us to reduce the critical genomic region encompassing two genes, PRKG2 and RASGEF1B. PRKG2 encodes cGMP-dependent protein kinase type II, which is expressed in brain and in cartilage. Information from genetically modified animal models is pertinent to the clinical phenotype. RASGEF1B is a guanine nucleotide exchange factor for Ras family proteins, and several members have been reported as key regulators of actin and microtubule dynamics during both dendrite and spine structural plasticity. CONCLUSION Clinical and molecular delineation of 4q21 deletion supports a novel microdeletion syndrome and suggests a major contribution of PRKG2 and RASGEF1B haploinsufficiency to the core phenotype.
To assess the safety and efficacy of submucosal radiofrequency (RF) treatment for hereditary hemorrhagic telangiectasia (HHT) with mild or moderate epistaxis.
We carried out a prospective pilot study ...of 16 consecutive patients with HHT-related epistaxis from June 2010 to April 2012. Under local anesthesia, RF was applied to one or both sides of the nose from the columella beneath the septal mucosal (50 joules per puncture). Patients were sent a questionnaire at least six months after the procedure.
RF under local anesthesia was well tolerated, according to visual analog scale scores. Neither crusting nor pain was reported one week after the intervention. The frequency of epistaxis per day and per month was significantly lower after RF. The duration of bleeding also decreased from more than 10 minutes to less than 5 minutes in two thirds of patients. Thirteen of the 16 patients were satisfied with the technique and would request it for subsequent procedures to treat repeated bleeding.
Submucosal RF treatment for HHT is a safe, well tolerated procedure with significant efficacy in the short term. It should be considered as an alternative technique for managing HHT-related epistaxis, although long-term results remain to be evaluated.
Petit F, Holder‐Espinasse M, Duban‐Bedu B, Bouquillon S, Boute‐Benejean O, Bazin A, Rouland V, Manouvrier‐Hanu S, Delobel B. Trisomy 7 mosaicism prenatally misdiagnosed and maternal uniparental ...disomy in a child with pigmentary mosaicism and Russell–Silver syndrome.
Prenatal diagnosis of true mosaic trisomy 7 is rare in amniotic fluid and can be misinterpreted as pseudomosaic. The phenotype is highly variable and may be modified by a maternal uniparental disomy of chromosome 7 leading to mild Russell–Silver syndrome (RSS). We report here the third postnatal case of mosaic trisomy 7 with maternal uniparental disomy of chromosome 7 in a boy presenting a mild RSS. Fetal karyotype performed in amniocentesis for intrauterine growth retardation was considered normal. Mosaic trisomy 7 was diagnosed after birth, on fibroblasts karyotype performed for blaschkolinear pigmentary skin anomalies and failure to thrive. Maternal uniparental disomy of chromosome 7 was observed in blood sample. Retrospectively, trisomic 7 cells were identified in one prenatal long‐term flask culture revealing a prenatal diagnosis failure. This report emphasizes the difficulty of assessing fetal mosaicism and distinguishing it from pseudomosaicism in cultured amniocytes. It is important to search for uniparental disomy as an indirect clue of trisomy 7 mosaicism and a major prognosis element. Although there are only few prenatal informative cases, detection of trisomy 7 in amniocentesis appears to be associated with a relatively good outcome when maternal uniparental disomy has been ruled out.
Bilateral periventricular nodular heterotopia (BPNH) is the most common form of periventricular heterotopia. Mutations in FLNA, encoding filamin A, are responsible for the X linked dominant form of ...BPNH (FLNA-BPNH). Recently, atypical phenotypes including BPNH with Ehlers-Danlos syndrome (BPNH-EDS) have been recognised. A total of 44 FLNA mutations have so far been reported in this phenotype. Most of these mutations lead to a truncated protein, but few missense mutations have also been described. Here, the results of a mutation screening conducted in a series of 32 BPNH patients with the identification of 12 novel point mutations in 15 patients are reported. Nine mutations were truncating, while three were missense. Three additional patients with BPNH-EDS and a mutation in FLNA are described. No phenotype-genotype correlations could be established, but these clinical data sustain the importance of cardiovascular monitoring in FLNA-BPNH patients.
With the development of next generation sequencing technologies in France, exome sequencing (ES) has recently emerged as an opportunity to improve the diagnosis rate of patients presenting an ...intellectual disability (ID). To help French policy makers determine an adequate tariff for ES, we aimed to assess the unit cost per ES diagnostic test for ID from the preparation of the pre-analytical step until the report writing step and to identify its main cost drivers.
A micro-costing bottom-up approach was conducted for the year 2018 in a French setting as part of the DISSEQ study, a cost-effectiveness study funded by the Ministry of Health and performed in collaboration with the GAD (Génétique des Anomalies du Développement), a genetic team from the Dijon University Hospital, and a public sequencing platform, the Centre National de Recherche en Génomique Humaine (CNRGH). The analysis was conducted from the point of view of these two ES stakeholders. All of the resources (labor, equipment, disposables and reagents, reusable material) required to analyze blood samples were identified, collected and valued. Several sensitivity analyses were performed.
The unit nominal cost per ES diagnostic test for ID was estimated to be €2,019.39. Labor represented 50.7% of the total cost. The analytical step (from the preparation of libraries to the analysis of sequences) represented 88% of the total cost. Sensitivity analyses suggested that a simultaneous price decrease of 20% for the capture kit and 50% for the sequencing support kit led to an estimation of €1,769 per ES diagnostic test for ID.
This is the first estimation of ES cost to be done in the French setting of ID diagnosis. The estimation is especially influenced by the price of equipment kits, but more generally by the organization of the centers involved in the different steps of the analysis and the time period in which the study was conducted. This information can now be used to define an adequate tariff and assess the efficiency of ES.
ClinicalTrials.gov identifier NCT03287206 on September 19, 2017.
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