An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 ( GLIS3 )

Neonatal diabetes and hypothyroidism (NDH) syndrome was first described in 2003 in a consanguineous Saudi Arabian family where two out of four siblings were reported to have presented with proportionate IUGR, neonatal non-autoimmune diabetes mellitus, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterised by enlarged kidneys and multiple small cysts with deficient cortico-medullary junction differentiation and normal kidney function. There was minor facial dysmorphism (depressed nasal bridge, large anterior fontanelle, long philtrum) reported but no facial photographs were published. Mutations in the transcription factor GLI-similar 3 (GLIS3) gene in the original family and two other families were subsequently reported in 2006. All affected individuals had neonatal diabetes, congenital hypothyroidism but glaucoma and liver and kidney involvement were less consistent features. Detailed descriptions of the facial dysmorphism have not been reported previously. In this report, we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognisable facial gestalt in this group which evolves with age

Trend in CT utilisation and its impact on length of stay, readmission and hospital mortality in Western Australia tertiary hospitals: an analysis of linked administrative data 2003-2015

Objective: High use of CT scanning has raised concern due to the potential ionising radiation exposure. This study examined trends of CT during admission to tertiary hospitals and its associations with length of stay (LOS), readmission and mortality. Design Retrospective observational study from 2003 to 2015. Setting: West Australian linked administrative records at individual level. Participants: 2 375 787 episodes of tertiary hospital admission in adults aged 18+ years. Main outcome measures: LOS, 30-day readmissions and mortality stratified by CT use status (any, multiple (CTs to multiple areas during episode), and repeat (repeated CT to the same area)). Methods: Multivariable regression models were used to calculate adjusted rate of CT use status. The significance of changes since 2003 in the outcomes (LOS, 30-day readmission and mortality) was compared among patients with specific CT imaging status relative to those without. Results: Between 2003 and 2015, while the rate of CT increased 3.4% annually, the rate of repeat CTs significantly decreased −1.8% annually and multiple CT showed no change. Compared with 2003 while LOS had a greater decrease in those with any CT, 30- day readmissions had a greater increase among those with any CT, while the probability of mortality remained unchanged between the any CT/no CT groups. A similar result was observed in patients with multiple and repeat CT scanning, except for a significant increase in mortality in the recent years in the repeat CT group. Conclusion: The observed pattern of increase in CT utilisation is likely to be activity-based funding policydriven based on the discordance between LOS and readmissions. Meanwhile, the repeat CT reduction aligns with a more selective strategy of use based on clinical severity. Future research should incorporate in-hospital and out-of-hospital CT to better understand overall CT trends and potential shifts between settings over time.Thi Ninh Ha, Sviatlana Kamarova, David Youens, Cameron Wright, Donald McRobbie, Jenny Doust, John Slavotinek, Max K Bulsara, Rachael Moori

DNM1 encephalopathy: A new disease of vesicle fission.

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention

Array comparative genomic hybridisation-based identification of two imbalances of chromosome 1p in a 9-year-old girl with a monosomy 1p36 related phenotype and a family history of learning difficulties: a case report

<p>Abstract</p> <p>Introduction</p> <p>Monosomy 1p36 is one of the most common terminal deletion syndromes, with an approximate incidence of 1 in every 5000 live births. This syndrome is associated with several pronounced clinical features including characteristic facial features, cardiac abnormalities, seizures and mental retardation, all of which are believed to be due to haploinsufficiency of genes within the 1p36 region. The deletion size varies from approximately 1.5 Mb to 10 Mb with the most common breakpoints located at 1p36.13 to 1p36.33. Over 70% of 1p36 deletion patients have a true terminal deletion. A further 7% have interstitial deletions and a proportion have a derivative chromosome 1 where the 1p telomere is replaced by material from another chromosome, either as a result of a de-novo rearrangement or as a consequence of malsegregation of a balanced parental translocation at meiosis.</p> <p>Case presentation</p> <p>Array comparative genomic hybridisation analysis of a 9-year-old Caucasian girl presenting with dysmorphic facial features and learning difficulties, for whom previous routine karyotyping had been normal, identified two submicroscopic rearrangements within chromosome 1p. Detection of both an insertional duplication of a region of 1p32.3 into the subtelomeric region of the short arm of a chromosome 1 homologue and a deletion within 1p36.32 of the same chromosome instigated a search for candidate genes within these regions which could be responsible for the clinical phenotype of the patient. Several genes were identified by computer-based annotation, some of which have implications in neurological and physical development.</p> <p>Conclusion</p> <p>Array comparative genomic hybridisation is providing a robust method for pinpointing regions of candidate genes associated with clinical phenotypes that extend beyond the resolution of the light microscope. This case report provides an example of how this method of analysis and the subsequent reporting of findings have proven useful in collaborative efforts to elucidate multiple gene functions from a clinical perspective.</p

A systematic review of the literature on the effectiveness of exercise therapy for groin pain in athletes

<p>Abstract</p> <p>Background</p> <p>Athletes competing in sports that require running, changes in direction, repetitive kicking and physical contact are at a relatively higher risk of experiencing episodes of athletic groin pain. To date, there has been no systematic review that aims to inform clinicians about the best available evidence on features of exercise interventions for groin pain in athletes. The primary aim of this systematic review was to evaluate the available evidence on the effectiveness of exercise therapy for groin pain in athletes. The secondary aim of this review was to identify the key features of exercise interventions used in the management of groin pain in an athletic population.</p> <p>Methods</p> <p>MEDLINE, CINAHL, PubMed, SPORTSDiscus, Embase, AMED, Ovid, PEDro, Cochrane Controlled Trials Register and Google Scholar databases were electronically searched. Data relating to research design, sample population, type of sport and exercise intervention was extracted. The methodological evaluation of included studies was conducted by using a modified quantitative critical appraisal tool.</p> <p>Results</p> <p>The search strategy identified 468 studies, 12 of which were potentially relevant. Ultimately five studies were included in this review. Overall the quality of primary research literature was moderate, with only one randomised controlled trial identified. All included studies provided evidence that an exercise intervention may lead to favourable outcomes in terms of return to sport. Four of the five studies reviewed included a strengthening component and most utilised functional, standing positions similar to those required by their sport. No study appropriately reported the intensity of their exercise interventions. Duration of intervention ranged from 3.8 weeks to 16 weeks. All five studies reported the use of one or more co-intervention.</p> <p>Conclusion</p> <p>Best available evidence to date, with its limitations, continues to support common clinical practice of exercise therapy as a key component of rehabilitation for groin pain in athletes. Overall, the available evidence suggests that exercise, particularly strengthening exercise of the hip and abdominal musculature could be an effective intervention for athletes with groin pain. Literature provides foundational evidence that this may need to be in the form of progressive exercises (static to functional) and performed through range. There is currently no clear evidence regarding the most effective intensity and frequency of exercise, because of a lack of reporting in the primary literature.</p

Patterns of computed tomography utilisation in injury management: latent classes approach using linked administrative data in Western Australia

Published online: 15 June 2023. OnlinePublPurpose: Whilst computed tomography (CT) imaging has been a vital component of injury management, its increasing use has raised concern regarding ionising radiation exposure. This study aims to identify latent classes (underlying patterns) of CT use over a 3-year period following the incidence of injury and factors predicting the observed patterns. Method: A retrospective observational cohort study was conducted in 21,544 individuals aged 18 + years presenting to emergency departments (ED) of four tertiary public hospitals with new injury in Western Australia. Mixture modelling approach was used to identify latent classes of CT use over a 3-year period post injury. Results: Amongst injured people with at least one CT scan, three latent classes of CT use were identified including a: temporarily high CT use (46.4%); consistently high CT use (2.6%); and low CT use class (51.1%). Being 65 + years or older, having 3 + comorbidities, history with 3 + hospitalisations and history of CT use before injury were associated with consistently high use of CT. Injury to the head, neck, thorax or abdomen, being admitted to hospital after the injury and arriving to ED by ambulance were predictors for the temporarily high use class. Living in areas of higher socio-economic disadvantage was a unique factor associated with the low CT use class. Conclusions: Instead of assuming a single pattern of CT use for all patients with injury, the advanced latent class modelling approach has provided more nuanced understanding of the underlying patterns of CT use that may be useful for developing targeted interventions.Ninh T. Ha, Mark Harris, Max Bulsara, Jenny Doust, Sviatlana Kamarova, Donald McRobbie, Peter O, Leary, Paul M. Parizel, John Slavotinek, Cameron Wright, David Youens, Rachael Moori

NAA10 polyadenylation signal variants cause syndromic microphthalmia

Background A single variant in NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia.Methods Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq.Results Genetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included NAA10. Exome sequencing identified a hemizygous NAA10 polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct NAA10 PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced NAA10 mRNA levels and abnormal 3′ UTRs in affected individuals. Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS.Conclusion These data show that PAS variants are the most common variant type in NAA10-associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yi

Targeted 'Next-Generation' sequencing in anophthalmia and microphthalmia patients confirms SOX2, OTX2 and FOXE3 mutations

<p>Abstract</p> <p>Background</p> <p>Anophthalmia/microphthalmia (A/M) is caused by mutations in several different transcription factors, but mutations in each causative gene are relatively rare, emphasizing the need for a testing approach that screens multiple genes simultaneously. We used next-generation sequencing to screen 15 A/M patients for mutations in 9 pathogenic genes to evaluate this technology for screening in A/M.</p> <p>Methods</p> <p>We used a pooled sequencing design, together with custom single nucleotide polymorphism (SNP) calling software. We verified predicted sequence alterations using Sanger sequencing.</p> <p>Results</p> <p>We verified three mutations - c.542delC in S<it>OX2</it>, resulting in p.Pro181Argfs*22, p.Glu105X in <it>OTX2 </it>and p.Cys240X in <it>FOXE3</it>. We found several novel sequence alterations and SNPs that were likely to be non-pathogenic - p.Glu42Lys in <it>CRYBA4</it>, p.Val201Met in <it>FOXE3 </it>and p.Asp291Asn in <it>VSX2</it>. Our analysis methodology gave one false positive result comprising a mutation in <it>PAX6 </it>(c.1268A > T, predicting p.X423LeuextX*15) that was not verified by Sanger sequencing. We also failed to detect one 20 base pair (bp) deletion and one 3 bp duplication in <it>SOX2</it>.</p> <p>Conclusions</p> <p>Our results demonstrated the power of next-generation sequencing with pooled sample groups for the rapid screening of candidate genes for A/M as we were correctly able to identify disease-causing mutations. However, next-generation sequencing was less useful for small, intragenic deletions and duplications. We did not find mutations in 10/15 patients and conclude that there is a need for further gene discovery in A/M.</p