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A common polymorphism (R577X) in the ACTN3 gene results in complete deficiency of ⍺-actinin-3 protein in ~16% of humans worldwide. The presence of ⍺-actinin-3 protein is associated with improved sprint/power performance in athletes and the general population. Despite this, there is evidence that the null genotype XX has been acted on by recent positive selection, likely due to its emerging role in the regulation of muscle metabolism. ⍺-Actinin-3 deficiency reduces the activity of glycogen phosphorylase and results in a fundamental shift toward more oxidative pathways of energy utilization. [ABSTRACT FROM AUTHOR]

Background: Cutaneous neurofibromas (cNFs) are a major cause of disfigurement in patients with Neurofibromatosis Type 1 (NF1). However, clinical trials investigating cNF treatments lack standardised outcome measures to objectively evaluate changes in cNF size and appearance. 3D imaging has been proposed as an objective standardised outcome measure however various systems exist with different features that affect useability in clinical settings. The aim of this study was to compare the accuracy, precision, feasibility, reliability and accessibility of three imaging systems. Materials and methods: We compared the Vectra‐H1, LifeViz‐Micro and Cherry‐Imaging systems. A total of 58 cNFs from 13 participants with NF1 were selected for imaging and analysis. The primary endpoint was accuracy as measured by comparison of measurements between imaging systems. Secondary endpoints included reliability between two operators, precision as measured with the average coefficient of variation, feasibility as determined by time to capture and analyse an image and accessibility as determined by cost. Results: There was no significant difference in accuracy between the three devices for length or surface area measurements (p > 0.05), and reliability and precision were similar. Volume measurements demonstrated the most variability compared to other measurements; LifeViz‐Micro demonstrated the least measurement variability for surface area and image capture and analysis were fastest with LifeViz‐Micro. LifeViz‐Micro was better for imaging smaller number of cNFs (1–3), Vectra‐H1 better for larger areas and Cherry for uneven surfaces. Conclusions: All systems demonstrated excellent reliability but possess distinct advantages and limitations. Surface area is the most consistent and reliable parameter for measuring cNF size in clinical trials. [ABSTRACT FROM AUTHOR]

Background Cutaneous neurofibromas (cNF) are considered one of the highest burdens of neurofibromatosis type 1 (NF1). To date, no medical treatment can cure cNF or prevent their development. In that context, there is an urgent need to prepare and standardize the methodology of future trials targeting cNF. Objectives The objective was to develop a core outcome domain set suitable for all clinical trials targeting NF1-associated cNF. Methods The validated approach of this work consisted of a three-phase methodology: (i) generating the domains [systematic literature review (SLR) and qualitative studies]; (ii) agreeing (three-round international e-Delphi consensus process and working groups); and (iii) voting. Results (i) The SLR and the qualitative studies (three types of focus groups and a French e-survey with 234 participants) resulted in a preliminary list of 31 candidate items and their corresponding definitions. (ii) A total of 229 individuals from 29 countries participated in the first round of the e-Delphi process: 71 patients, relatives or representatives (31.0%), 130 healthcare professionals (HCPs, 56.8%) and 28 researchers, representatives of a drug regulatory authority, industry or pharmaceutical company representatives or journal editors (12.2%). The overall participation rate was 74%. After round 2, five candidate items were excluded. Between rounds 2 and 3, international workshops were held to better understand the disagreements among stakeholders. This phase led to the identification of 19 items as outcome subdomains. (iii) The items were fused to create four outcome domains ('clinical assessment', 'daily life impact', 'patient satisfaction' and 'perception of health') and prioritized. The seven items that did not reach consensus were marked for the research agenda. The final core outcome domain set reached 100% of the votes of the steering committee members. Conclusions Although numerous outcomes can be explored in studies related to cNF in NF1, the present study offers four outcome domains that should be reported in all trial studies, agreed on by international patients, relatives and representatives of patients; HCPs; researchers, representatives of drug regulatory authorities or pharmaceutical companies and journal editors. The next step will include the development of a set of core outcome measurement instruments to further standardize how these outcomes should be assessed. [ABSTRACT FROM AUTHOR]

NSW Health is implementing genomics as a mainstream component of clinical care. The strategic, holistic approach is considering infrastructure, data governance and management, workforce, education, service planning and delivery. This work is generating insights about how to realise the promise of genomics in healthcare, highlighting the need for strong foundations, real-world application, accessibility and a focus on people using genomic information in clinical care. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis 1 (NF1) is a common cancer predisposition syndrome. Affected individuals require lifelong surveillance and often suffer progressive disfigurement due to cutaneous neurofibromas. The aim of this research was to characterize health concerns and quality of life (QOL) in a population cohort. Methods: An online survey was completed by 68 adults and 32 parents of children with NF1, and 60 controls. The survey included the Skindex‐29 QOL scale, 5D‐itch scale, and additional health questions. Results: Frequency of itch was high in children (50%) and adults (69%), with most expressing interest in treatment for itch. The presence of itch and increased visibility of NF1 were predictors of poorer QoL. Many adults (53%) and parents (44%) desired access to treatment to improve cosmetic appearance. Muscle weakness/tiredness was also prevalent amongst (60–70%) adults and children with NF1. Two‐thirds of adults with NF1 reported limited awareness of NF1 services and poor knowledge of surveillance, particularly breast screening in young women. Conclusion: This study highlights the impact of NF1‐related itch and visibility in adults and children with a need for cosmetic and itch treatment. The findings emphasize a need for strategies to promote awareness, and access to management and treatment of NF1 in adults. [ABSTRACT FROM AUTHOR]

Purpose: To characterize the ophthalmic features and causes of visual loss in a cohort of Melanesians living in New Caledonia with nanophthalmos. Methods: In this observational study, axial length, visual acuity (VA), cycloplegic autorefraction were assessed and dilated fundus examination was performed. Visual impairment was defined as VA < 6/12 in the better eye, hypermetropia as >+1.0 dioptre (D), astigmatism as ≥1.0 D and anisometropia as ≥1.0 D difference between both eyes. Unilateral amblyopia was defined as at least a two-line difference in VA between both eyes and bilateral amblyopia as VA < 6/12 in both eyes which was not adequately explained by refractive error and macular folds. Results: Seventeen community-dwelling participants (aged 1.1–45.3 years) with short axial length (range from 16.1 to 21.6 mm) were identified. Of the 17 subjects, 14 were found to have crowded optic discs, three with papillomacular folds, three with a papillomacular band and three with macular radial folds. Further, all subjects demonstrated bilateral hypermetropia (range from +1.3 D to +15.1 D). A high proportion of subjects had astigmatism (12) and anisometropia (nine) in at least one eye. Visual impairment was found in nine subjects: five bilateral and four unilateral. Causes of visual impairment included amblyopia (seven), ametropia (seven) and macular folds (two). Amblyopia was attributed to several factors, including hypermetropia, anisometropia, astigmatism and esotropia. Conclusions: In this sample of Melanesians with nanophthalmos, a spectrum of ophthalmic features that was consistent with intraocular crowding was found. Over half of the subjects were visually impaired, mostly due to amblyopia and ametropia. Further characterization of the underlying genetic cause of nanophthalmos in this cohort will be the focus of future studies. [ABSTRACT FROM AUTHOR]

Monogenic rare disorders contribute significantly to paediatric morbidity and mortality, and elucidation of the underlying genetic cause may have benefits for patients, families and clinicians. Advances in genomic technology have enabled diagnostic yields of up to 50% in some paediatric cohorts. This has led to an increase in the uptake of genetic testing across paediatric disciplines. This can place an increased burden on paediatricians, who may now be responsible for interpreting and explaining test results to patients. However, genomic results can be complex, and sometimes inconclusive for the ordering paediatrician. Results may also cause uncertainty and anxiety for patients and their families. The paediatrician's genetic literacy and knowledge of genetic principles are therefore critical to inform discussions with families and guide ongoing patient care. Here, we present four hypothetical case vignettes where genomic testing is undertaken, and discuss possible results and their implications for paediatricians and families. We also provide a list of key terms for paediatricians. [ABSTRACT FROM AUTHOR]

Genomic testing for a genetic diagnosis is becoming standard of care for many children, especially those with a syndromal intellectual disability. While previously this type of specialised testing was performed mainly by clinical genetics teams, it is increasingly being 'mainstreamed' into standard paediatric care. With the introduction of a new Medicare rebate for genomic testing in May 2020, this type of testing is now available for paediatricians to order, in consultation with clinical genetics. Children must be aged less than 10 years with facial dysmorphism and multiple congenital abnormalities or have global developmental delay or moderate to severe intellectual disability. This rebate should increase the likelihood of a genetic diagnosis, with accompanying benefits for patient management, reproductive planning and diagnostic certainty. Similar to the introduction of chromosomal microarray into mainstream paediatrics, this genomic testing will increase the number of genetic diagnoses, however, will also yield more variants of uncertain significance, incidental findings, and negative results. This paper aims to guide paediatricians through the process of genomic testing, and represents the combined expertise of educators, clinical geneticists, paediatricians and genomic pathologists around Australia. Its purpose is to help paediatricians navigate choosing the right genomic test, consenting patients and understanding the possible outcomes of testing. [ABSTRACT FROM AUTHOR]

Background: Whole genome sequencing (WGS) is a comprehensive genetic testing approach that reports most types of nucleotide variants.Objectives: This study sought to assess WGS for hypertrophic cardiomyopathy (HCM) in which prior genetic testing did not establish a molecular diagnosis, and as a first-line genetic test.Methods: WGS was performed on 58 unrelated patients with HCM, 14 affected family members, and 2 unaffected parents of a severely affected proband. The authors searched for nucleotide variants in coding regions of 184 candidate cardiac hypertrophy genes. They also searched for nucleotide variants in deep intronic regions that alter RNA splicing, large genomic rearrangements, and mitochondrial genome variants. RNA analysis was performed to validate splice-altering variants.Results: The authors found a pathogenic or likely pathogenic variant in 9 of 46 families (20%) for which prior genetic testing was inconclusive. Three families had variants in genes not included in prior genetic testing. One family had a pathogenic variant that was filtered out with prior exome sequencing. Five families had pathogenic variants in noncoding regions, including 4 with deep intronic variants that activate novel splicing, and 1 mitochondrial genome variant. As a first-line genetic test, WGS identified a pathogenic variant in 5 of 12 families (42%) that had never received prior genetic testing.Conclusions: WGS identified additional genetic causes of HCM over targeted gene sequencing approaches. Extending genetic screening to deep intronic regions identified pathogenic variants in 9% of gene-elusive HCM. These findings translate to more accurate diagnosis and management in HCM families. [ABSTRACT FROM AUTHOR]

Internationally, Tay- Sachs disease ( TSD) preconception screening of Ashkenazi Jewish ( AJ) individuals and couples has led to effective primary prevention of TSD. In Australia, adolescent preconception genetic screening programs operate mainly in Jewish community high schools. These existing programs offer an effective means of primary prevention of TSD, are cost effective and safe. However, in the broader Australian community TSD screening is not systematically performed and cases still occur in unscreened AJ individuals. In order to improve the effectiveness of Australian screening, there is a need for definitive guidelines for healthcare professionals to facilitate extension of the proven benefits of preconception TSD screening to all AJ individuals at risk. We performed a systematic review of the relevant literature relating to AJ pre-conception and antenatal screening for TSD. The evidence was assessed using an established National Health and Medical Research Council evidence grading system. Evaluations of efficacy of TSD screening programs design and execution, cost-benefit and cost-utility health economic evaluation, and population outcomes were undertaken. The results have been used to propose a model for universal AJ TSD preconception and antenatal screening for the primary care setting. [ABSTRACT FROM AUTHOR]

Abstract: Bone mineral density (BMD) is a complex trait that is the single best predictor of the risk of osteoporotic fractures. Candidate gene and genome-wide association studies have identified genetic variations in approximately 30 genetic loci associated with BMD variation in humans. α-Actinin-3 (ACTN3) is highly expressed in fast skeletal muscle fibres. There is a common null-polymorphism R577X in human ACTN3 that results in complete deficiency of the α-actinin-3 protein in approximately 20% of Eurasians. Absence of α-actinin-3 does not cause any disease phenotypes in muscle because of compensation by α-actinin-2. However, α-actinin-3 deficiency has been shown to be detrimental to athletic sprint/power performance. In this report we reveal additional functions for α-actinin-3 in bone. α-Actinin-3 but not α-actinin-2 is expressed in osteoblasts. The Actn3 −/− mouse displays significantly reduced bone mass, with reduced cortical bone volume (−14%) and trabecular number (−61%) seen by microCT. Dynamic histomorphometry indicated this was due to a reduction in bone formation. In a cohort of postmenopausal Australian women, ACTN3 577XX genotype was associated with lower BMD in an additive genetic model, with the R577X genotype contributing 1.1% of the variance in BMD. Microarray analysis of cultured osteoprogenitors from Actn3 −/− mice showed alterations in expression of several genes regulating bone mass and osteoblast/osteoclast activity, including Enpp1, Opg and Wnt7b. Our studies suggest that ACTN3 likely contributes to the regulation of bone mass through alterations in bone turnover. Given the high frequency of R577X in the general population, the potential role of ACTN3 R577X as a factor influencing variations in BMD in elderly humans warrants further study. [Copyright &y& Elsevier]

Abstract: Deficiency of the fast-twitch muscle protein α-actinin-3 due to homozygosity for a nonsense polymorphism (R577X) in the ACTN3 gene is common in humans. α-Actinin-3 deficiency (XX) is associated with reduced muscle strength/power and enhanced endurance performance in elite athletes and in the general population. The association between R577X and loss in muscle mass and function (sarcopenia) has previously been investigated in a number of studies in elderly humans. The majority of studies report loss of ACTN3 genotype association with muscle traits in the elderly, however, there is some indication that the XX genotype may be associated with faster muscle function decline. To further explore these potential age-related effects and the underlying mechanisms, we examined the effect of α-actinin-3 deficiency in aging male and female Actn3 knockout (KO) mice (2, 6, 12, and 18months). Our findings support previous reports of a diminished influence of ACTN3 genotype on muscle performance in the elderly: genotype differences in intrinsic exercise performance, fast muscle force generation and male muscle mass were lost in aged mice, but were maintained for other muscle function traits such as grip strength. The loss of genotype difference in exercise performance occurred despite the maintenance of some “slower” muscle characteristics in KO muscles, such as increased oxidative metabolism and greater force recovery after fatigue. Interestingly, muscle mass decline in aged 18month old male KO mice was greater compared to wild-type controls (WT) (−12.2% in KO; −6.5% in WT). These results provide further support that α-actinin-3 deficient individuals may experience faster decline in muscle function with increasing age. [Copyright &y& Elsevier]

More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein α-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that α-actinin-3 deficiency influences the function of fast muscle fibers. Here we show that loss of α-actinin-3 expression in a knockout mouse model results in a shift in muscle metabolism toward the more efficient aerobic pathway and an increase in intrinsic endurance performance. In addition, we demonstrate that the genomic region surrounding the 577X null allele shows low levels of genetic variation and recombination in individuals of European and East Asian descent, consistent with strong, recent positive selection. We propose that the 577X allele has been positively selected in some human populations owing to its effect on skeletal muscle metabolism. [ABSTRACT FROM AUTHOR]

Introduction: Loss of function variants in plakophilin-2 (PKP2) are a well-established cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). Sustained ventricular arrhythmias have been shown only to occur in variant carriers with clear structural disease on cardiac imaging. Here we describe the yield and characteristics of PKP2 loss-of-function variants in probands who present with sudden cardiac death (SCD) events in the absence of ARVC features. Methods: Patients or family members attending a specialised inherited heart disease clinic in Sydney, Australia, where the proband suffered an unexplained SCD event (SCD or resuscitated cardiac arrest) and comprehensive genetic testing were included. Information was collected from the medical record. Results: Four of 173 (2%) were found to have pathogenic or likely pathogenic loss-of-function variants in PKP2. All had SCD events <30 years of age, with no diagnosis of ARVC, and no family history of any cardiac disease. Patient 1 had a SCD event aged 29 years while playing sport, with no structural disease. Genetic testing demonstrated a pathogenic variant c.2489+1G>A. Patient 2 suffered SCD event at 23 years playing football, with no cardiac disease. Genetic testing identified a novel, likely pathogenic variant, p.Leu744Serfs*3. Patient 3 had a SCD aged 21 years during a physical altercation, and postmortem examination revealed no abnormalities macroscopically or on histology, and carried a likely pathogenic 2 base pair deletion, p.Glu85Metfs*26. Patient 4 had a SCD during sleep aged 30 years and postmortem examination showed some isolated areas of fibrosis and fat infiltration on histology, and a likely pathogenic nonsense variant, p.Tyr797Ter. Conclusions: The yield of PKP2 causative variants in sudden unexplained death events is 2%. We demonstrate multiple cases of severe arrhythmia in the absence of structural disease, suggesting a concealed phase of ARVC and highlighting the need for greater understanding of the full PKP2 phenotype spectrum. [ABSTRACT FROM AUTHOR]