Maternally inherited diabetes and deafness with a variable presentation across three generations within a pedigree, South Africa.

Introduction: Maternally inherited diabetes and deafness (MIDD) is caused by the m.3243A>G pathogenic variant in maternally inherited mitochondrial DNA. Diabetes is prevalent in our setting; however, MIDD is rarely diagnosed.

Chromosome 20p11.2 deletions cause congenital hyperinsulinism via the loss of FOXA2 or its regulatory elements.

Persistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI.

Mutation analysis and clinical profile of South African patients with Neurofibromatosis type 1 (NF1) phenotype.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition with complete age-dependent penetrance, variable expressivity and a global prevalence of ∼1/3,000. It is characteriszed by numerous café-au-lait macules, skin freckling in the inguinal or axillary regions, Lisch nodules of the iris, optic gliomas, neurofibromas, and tumour predisposition. The diagnostic testing strategy for NF1 includes testing for DNA single nucleotide variants (SNVs), copy number variants (CNVs) as well as RNA analysis for deep intronic and splice variants, which can cumulatively identify the causative variant in 95% of patients.

Mutation profiling in South African patients with Cornelia de Lange syndrome phenotype.

Background: Cornelia de Lange Syndrome (CdLS) presents with a variable multi-systemic phenotype and pathogenic variants have been identified in five main genes. This condition has been understudied in African populations with little phenotypic and molecular information available.

Methods And Results: We present a cohort of 14 patients with clinical features suggestive of CdLS.

A feasible molecular diagnostic strategy for rare genetic disorders within resource-constrained environments.

Timely and accurate diagnosis of rare genetic disorders is critical, as it enables improved patient management and prognosis. In a resource-constrained environment such as the South African State healthcare system, the challenge is to design appropriate and cost-effective assays that will enable accurate genetic diagnostic services in patients of African ancestry across a broad disease spectrum. Next-generation sequencing (NGS) has transformed testing approaches for many Mendelian disorders, but this technology is still relatively new in our setting and requires cost-effective ways to implement.

An observational study of individual child journeys through autism diagnostic pathways, and associated costs, in the UK National Health Service.

Background: Demand for diagnostic assessment in children with possible autism has recently increased significantly. Services are under pressure to deliver timely and high-quality diagnosis, following National Institute and Care Excellence multidisciplinary assessment guidelines. This UK National Health Service study aimed to answer: how many hours of health professional time are required to deliver autism diagnostic assessment, and how much does this cost?.

Parents' perspectives on the use of children's facial images for research and diagnosis: a survey.

Computer-aided facial diagnostic tools are valuable emerging technologies for the early detection and initial diagnosis of congenital disorders. These tools require large datasets of facial photographs, especially of infants and children, to identify these disorders and improve classification accuracies. Researchers need to balance this need for larger datasets with patients' privacy rights, needs and preferences.

A clinical and cost-effectiveness trial of a parent group intervention to manage challenging restricted and repetitive behaviours in young children with autism spectrum disorder: study protocol for a randomised controlled trial.

Background: Restricted and repetitive behaviours vary greatly across the autism spectrum, and although not all are problematic some can cause distress and interfere with learning and social opportunities. We have, alongside parents, developed a parent group based intervention for families of young children with autism, which aims to offer support to parents and carers; helping them to recognise, understand and learn how to respond to their child's challenging restricted repetitive behaviours.

Methods: The study is a clinical and cost-effectiveness, multi-site randomised controlled trial of the Managing Repetitive Behaviours (MRB) parent group intervention versus a psychoeducation parent group Learning About Autism (LAA) (n = 250; 125 intervention/125 psychoeducation; ~ 83/site) for parents of young children aged 3-9 years 11 months with a diagnosis of autism.

Comparison of Glycemic Excursion Using Flash Continuous Glucose Monitoring in Patients with Type 2 Diabetes Mellitus Before and After Treatment with Voglibose.

To determine the effect of Voglibose add-on therapy on daily glycemic excursions (using FreeStyle Libre Pro™, a Flash glucose monitoring system) in Indian patients with type 2 diabetes mellitus (T2DM) receiving a stable dose of metformin (Met) or metformin+sulfonylurea (Met+SU). T2DM patients with glycosylated hemoglobin (HbA1c) ≥7.0% and at least two postprandial excursions ≥140 mg/dL (within 2 h of meal) during the screening phase (visit 1/day -14 ± 2) were enrolled in this prospective, multicenter interventional study.

Response: Demand Avoidance Phenomena: a manifold issue? Intolerance of uncertainty and anxiety as explanatory frameworks for extreme demand avoidance in children and adolescents - a response to Woods (2020).

This paper is in response to the commentary written by Richard Woods in which he attempts to provide support for his Monotropism autism theory and the research indicating that Demand Avoidance Phenomena may not be developmentally persistent (Woods, 2019). We acknowledge the continuing controversy around the proposed construct of PDA and the clinical dilemma faced by professionals, within the United Kingdom, following increased demand from families seeking assessment and support. We appreciate that research on this topic is scarce and understanding of PDA behaviours remains limited and that methodological improvements are required.

Intolerance of uncertainty and anxiety as explanatory frameworks for extreme demand avoidance in children and adolescents.

Background: Pathological demand avoidance (PDA) is a proposed subtype of autism spectrum disorder (ASD), characterised by extreme avoidance of demands. Demand avoidant behaviour has been proposed to be driven by an anxious need to be in control, although has never been explicitly studied. Emerging evidence suggests intolerance of uncertainty (IU) and anxiety may explain the behaviours seen in ASD.

Response: Anxiety and behaviour in and beyond ASD; does the idea of 'PDA' really help? - a response to Green (2020).

We acknowledge Green's viewpoint and agree that currently the literature does not support the validity of PDA as an independent syndrome. However, the controversy is real and exists for a reason. We therefore argue that it is important to move beyond labelling and the potentially unhelpful implications of discussion around whether or not it is a condition, diagnosis or a co-morbid condition, to a point of recognition of the phenomenon.

A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report.

Background: Application of whole genome sequencing (WGS) enables identification of non-coding variants that play a phenotype-modifying role and are undetectable by exome sequencing. Recently, non-coding regulatory single nucleotide variants (SNVs) have been reported in patients with lethal lung developmental disorders (LLDDs) or congenital scoliosis with recurrent copy-number variant (CNV) deletions at 17q23.1q23.

Holoprosencephaly with Clefts: Data of 85 Patients, Treatment and Outcome: Part 1: History, Subdivisions, and Data on 85 Holoprosencephalic Cleft Patients.

Context: Cleft patients with Holoprosencephaly (HPE) constitute a controversy due to a variable facial appearance. HPE appearance varies from only a columella to a prolabium-premaxilla complex agenesis up to a common unilateral or bilateral cleft lip and palate with a single central incisor, various brain deformities, and/or even normal brain development. It is challenging to designate such various appearances, to understand their etiopathogenesis, and to choose the most appropriate management.

Teachers' perceptions of Restricted and Repetitive Behaviours (RRBs) in children with ASD: Attributions, confidence and emotional response.

Background: Restricted and Repetitive Behaviours (RRBs) are some of the most difficult behaviours to manage in children with Autism Spectrum Disorders (ASD). Although RRBs frequently occur in educational settings, we know little about the way in which teachers understand these behaviours.

Aims: The study aimed to explore the attributions, emotional response and feelings of confidence held by teachers working in different educational settings when faced with RRBs.

A Randomised Controlled Feasibility Trial of Immersive Virtual Reality Treatment with Cognitive Behaviour Therapy for Specific Phobias in Young People with Autism Spectrum Disorder.

We examined the feasibility and acceptability of using an immersive virtual reality environment (VRE) alongside cognitive behaviour therapy (CBT) for young people with autism experiencing specific phobia. Thirty-two participants were randomised to treatment or control. Treatment involved one session introducing CBT techniques and four VRE sessions, delivered by local clinical therapists.

Cornelia de Lange syndrome in diverse populations.

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies.

Pena-Shokeir syndrome: current management strategies and palliative care.

Pena-Shokeir syndrome (PSS) type 1, also known as fetal akinesia deformation sequence, is a rare genetic syndrome that almost always results in intrauterine or early neonatal death. It is characterized by markedly decreased fetal movements, intrauterine growth restriction, joint contractures, short umbilical cord, and features of pulmonary hypoplasia. Antenatal diagnosis can be difficult.

Williams-Beuren syndrome in diverse populations.

Williams-Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23.

Towards a Treatment for Intolerance of Uncertainty for Autistic Adults: A Single Case Experimental Design Study.

Intolerance of uncertainty (IU) is indicated as an important transdiagnostic process variable in a range of anxiety disorders. Anxiety is very common in autistic adults. This study evaluates a manualised treatment programme for autistic adults, which focused on IU.

A novel mutation in ETFDH manifesting as severe neonatal-onset multiple acyl-CoA dehydrogenase deficiency.

Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD type I) is an autosomal recessive disorder of the electron transfer flavoprotein function characterized by a severe clinical and biochemical phenotype, including congenital abnormalities with unresponsiveness to riboflavin treatment as distinguishing features. From a retrospective study, relying mainly on metabolic data, we have identified a novel mutation, c.1067G>A (p.

Mental Wellbeing of Family Members of Autistic Adults.

Family members are often the primary caregiver for autistic adults and this responsibility may impact on the carer's wellbeing and quality of life. 109 family members of autistic adults completed an online survey assessing their wellbeing relating to their caring role for their autistic relative. Family members who were supporting an autistic relative with co-occurring mental health difficulties and who they reported as unprepared for the future, self-reported higher levels of worry, depression, anxiety and stress, and poorer quality of life.

Brief Report: What Happens When I Can No Longer Support My Autistic Relative? Worries About the Future for Family Members of Autistic Adults.

Very little is known about autism and adulthood. Family members are often the primary support for autistic adults and frequently express concerns about what the future will hold and what support will be available for their relative. 120 family members of autistic adults completed an online survey exploring concerns about the future for their relative.

Noonan syndrome in diverse populations.

Noonan syndrome (NS) is a common genetic syndrome associated with gain of function variants in genes in the Ras/MAPK pathway. The phenotype of NS has been well characterized in populations of European descent with less attention given to other groups. In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology.