Deciphering the molecular landscape of microcephaly in 87 Indian families by exome sequencing

Microcephaly is a frequent feature of neurodevelopmental disorders (NDDs). Our study presents the heterogeneous spectrum of genetic disorders in patients with microcephaly either in isolated form or in association with other neurological and extra-neural abnormalities. We present data of 91 patients from 87 unrelated families referred to our clinic during 2016–2020 and provide a comprehensive clinical and genetic landscape in the studied cohort. Molecular diagnosis using exome sequencing was made in 45 families giving a yield of 51.7%. In 9 additional families probable causative variants were detected. We identified disease causing variations in 49 genes that are involved in different functional pathways Among these, 36 had an autosomal recessive pattern, 8 had an autosomal dominant pattern (all inherited de novo), and 5 had an X-linked pattern. In 41 probands where sequence variations in autosomal recessive genes were identified 31 were homozygotes (including 16 from non-consanguineous families). The study added 28 novel pathogenic/likely pathogenic variations. The study also calls attention to phenotypic variability and expansion in spectrum as well as uncovers genes where microcephaly is not reported previously or is a rare finding. We here report phenotypes associated with the genes for ultra-rare NDDs with microcephaly namely ATRIP, MINPP1, PNPLA8, AIMP2, ANKLE2, NCAPD2 and TRIT1.     

Physiotherapeutic methods of treatment of mandibular distal occlusion and the progress of therapy: A case report

BackgroundStudies have demonstrated a relationship between dental malocclusion and posture defects. The aims of the study were to present (1) the effect of a physiotherapeutic approach to a patient with a distal occlusion defect with the use of a set of exercises to strengthen the muscles responsible for mandibular protrusion, and (2) a non-invasive and easy-to-use method to monitor the effects of therapy.MethodsFive year old girl with a distal occlusion and with a low basic postural tone was referred to physiotherapy. A therapeutic program i.a. concerning a strengthening of the temporomandibular joint muscles with the use of a flexible tape was proposed. To assess the functional changes of the masticatory apparatus a photoanthropometric method was used. In side-face photos, proportions of 2 linear measurements and values of two angles on the first day of therapy, after 2 and after 4 months of exercises, with the mandible located freely and in the maximum protrusion were compared.ResultsA comparison of indices and angles showed a marked improvement in mandibular mobility already after two and four months of the exercises. Using the elastic resistance tape in addition to general developmental exercises allowed for increasing the mobility in the temporomandibular joint.ConclusionMalocclusion should not be considered separately, without taking into account the body posture. The work of the physiotherapist can benefit the orthodontist, correcting postural defects and consequently affecting malocclusion. A comparison of linear measurements and angles can be used to assess the progress of the therapy.     

On the possibility of photodynamic inactivation of tracheobronchial tree pathogenic microbiota using methylene blue (in vitro study)

BackgroundThe treatment of patients after mechanical ventilation of lungs suffering from a multi-species infection of the tracheobronchial tree can be complicated.. The situation is aggravated in patients with post-intubation tracheal stenosis, where infection plays a leading pathogenetic role in damage to the tracheal wall. As a result of such a pathological process, cicatricial stenosis of the trachea of purulent-inflammatory infectious genesis or infected tracheal stenosis (ITS) may occur.MethodsIn this work, we studied the possibility of photodynamic inactivation of pathogenic microbiota typical for patients with ITS using methylene blue (MB) as a photosensitizer.Results13 clinical isolates of 8 species of bacteria from 9 patients were susceptible to photodynamic inactivation with MB. 30 μM of MB at a light irradiation dose of 25 J/cm² and incubation with MB for 15 min allows to completely inactivate bacteria found in the tracheobronchial secretions of patients with ITS.ConclusionsMB retains its optico-physical properties in the range of 3–30 μM and provides effective inactivation of isolated Gram-positive and Gram-negative bacteria, including multi- and pan-resistant to antibiotics.     

Left ventricular noncompaction associated with a pathogenic mutation in the MYH7 gene: Known mutation,different phenotype

Left ventricular noncompaction (LVNC) is a genetically heterogeneous cardiomyopathy, with familial and sporadic forms, but genetic testing only identifies a pathogenic mutation in a minority of cases. The main complications are heart failure, embolism and dysrhythmias. Herein we report a familial case of LVNC associated with a mutation in the MYH7 gene and review the literature regarding controversies in LVNC. A 50-year-old woman was referred to the cardiology clinic for palpitations. She underwent echocardiography and cardiac magnetic resonance imaging that revealed mild left ventricular systolic dysfunction and LVNC criteria. She had several episodes of non-sustained ventricular tachycardia and received an implantable cardioverter-defibrillator (ICD). Genetic testing revealed the c.1003G>C (p.Ala335Pro) mutation in the MYH7 gene. Familial screening showed clear genotype-phenotype cosegregation, which provided strong evidence for the pathogenic role of this mutation. To the best of our knowledge, this is the first report of LVNC associated with the p.Ala335Pro mutation in the MYH7 gene. This mutation has been described in hypertrophic cardiomyopathy, suggesting that the same pathogenic sarcomere mutation may be associated with different cardiomyopathies. This case also highlights the current difficulties regarding decisions on ICD implantation for primary prevention of sudden cardiac death in LVNC.     

A systematic review of the methodological quality of economic evaluations in genetic screening and testing for monogenic disorders

PurposeUnderstanding the value of genetic screening and testing for monogenic disorders requires high-quality, methodologically robust economic evaluations. This systematic review sought to assess the methodological quality among such studies and examined opportunities for improvement.MethodsWe searched PubMed, Cochrane, Embase, and Web of Science for economic evaluations of genetic screening/testing (2013-2019). Methodological rigor and adherence to best practices were systematically assessed using the British Medical Journal checklist.ResultsAcross the 47 identified studies, there were substantial variations in modeling approaches, reporting detail, and sophistication. Models ranged from simple decision trees to individual-level microsimulations that compared between 2 and >20 alternative interventions. Many studies failed to report sufficient detail to enable replication or did not justify modeling assumptions, especially for costing methods and utility values. Meta-analyses, systematic reviews, or calibration were rarely used to derive parameter estimates. Nearly all studies conducted some sensitivity analysis, and more sophisticated studies implemented probabilistic sensitivity/uncertainty analysis, threshold analysis, and value of information analysis.ConclusionWe describe a heterogeneous body of work and present recommendations and exemplar studies across the methodological domains of (1) perspective, scope, and parameter selection; (2) use of uncertainty/sensitivity analyses; and (3) reporting transparency for improvement in the economic evaluation of genetic screening/testing.