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  • A novel RUNX1 exon 3 - 7 deletion causing a familial platelet disorder

    Myers, Bethan (2022-02)
    Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM) is a rare inherited disorder confirmed with the presence of a pathogenic germline RUNX1 variant and is thought to be heavily underdiagnosed. RUNX1 has also been found to be mutated in up to 10% of adult AML cases and other cell malignancies. We performed targeted next-generation sequencing and subsequent MLPA analysis in a kindred with multiple affected individuals with low platelet counts and a bleeding history. We detected a novel heterozygous exon 3-7 large deletion in the RUNX1 gene in all affected family members which is predicted to remove all of the Runt-homology DNA-binding domain and a portion of the Activation domain. Our results show that the combination of targeted NGS and MLPA analysis is an effective way to detect copy number variants (CNVs) which would be missed by conventional sequencing methods. This precise diagnosis offers the possibility of accurate counseling and clinical management in such patients who could go onto develop other cell malignancies.
  • A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants

    Barwell, Julian; Vasudevan, Pradeep (2021-01)
    Objective: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. Methods: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing. Results: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits. Conclusions: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.
  • 'We have been in lockdown since he was born': a mixed methods exploration of the experiences of families caring for children with intellectual disability during the COVID-19 pandemic in the UK

    Barwell, Julian; Vasudevan, Pradeep (2021-09)
    Objectives: This study aimed to explore the experiences of parents caring for children with intellectual and developmental disabilities (IDD) during the UK national lockdown in spring 2020, resulting from the COVID-19 pandemic. Design: Participants were identified using opportunity sampling from the IMAGINE-ID national (UK) cohort and completed an online survey followed by a semistructured interview. Interviews were analysed using thematic analysis. Setting: Interviews were conducted over the telephone in July 2020 as the first UK lockdown was ending. Participants: 23 mothers of children with intellectual and developmental disabilities aged 5-15 years were recruited. Results: Themes reported by parents included: managing pre-existing challenges during a time of extreme change, having mixed emotions about the benefits and difficulties that arose during the lockdown and the need for appropriate, individualised support. Conclusions: Our findings confirm observations previously found in UK parents of children with IDD and provide new insights on the use of technology during the pandemic for schooling and healthcare, as well as the need for regular check-ins.
  • Childhood intellectual disability and parents' mental health: integrating social, psychological and genetic influences

    Barwell, Julian; Vasudevan, Pradeep (2021-06)
    Background: Intellectual disability has a complex effect on the well-being of affected individuals and their families. Previous research has identified multiple risk and protective factors for parental mental health, including socioeconomic circumstances and child behaviour. Aims: This study explored whether genetic cause of childhood intellectual disability contributes to parental well-being. Method: Children from across the UK with intellectual disability due to diverse genetic causes were recruited to the IMAGINE-ID study. Primary carers completed the Development and Well-being Assessment, including a measure of parental distress (Everyday Feeling Questionnaire). Genetic diagnoses were broadly categorised into aneuploidy, chromosomal rearrangements, copy number variants (CNVs) and single nucleotide variants. Results: Compared with the UK general population, IMAGINE-ID parents (n = 888) reported significantly elevated emotional distress (Cohen's d = 0.546). Within-sample variation was related to recent life events and the perceived impact of children's difficulties. Impact was predicted by child age, physical disability, autistic characteristics and other behavioural difficulties. Genetic diagnosis also predicted impact, indirectly influencing parental well-being. Specifically, CNVs were associated with higher impact, not explained by CNV inheritance, neighbourhood deprivation or family structure. Conclusions: The mental health of parents caring for a child with intellectual disability is influenced by child and family factors, converging on parental appraisal of impact. We found that genetic aetiologies, broadly categorised, also influence impact and thereby family risks. Recognition of these risk factors could improve access to support for parents, reduce their long-term mental health needs and improve well-being of individuals with intellectual disability.
  • Dissection of contiguous gene effects for deletions around ERF on chromosome 19

    Vasudevan, Pradeep (2021-07)
    Heterozygous intragenic loss-of-function mutations of ERF, encoding an ETS transcription factor, were previously reported to cause a novel craniosynostosis syndrome, suggesting that ERF is haploinsufficient. We describe six families harboring heterozygous deletions including, or near to, ERF, of which four were characterized by whole-genome sequencing and two by chromosomal microarray. Based on the severity of associated intellectual disability (ID), we identify three categories of ERF-associated deletions. The smallest (32 kb) and only inherited deletion included two additional centromeric genes and was not associated with ID. Three larger deletions (264-314 kb) that included at least five further centromeric genes were associated with moderate ID, suggesting that deletion of one or more of these five genes causes ID. The individual with the most severe ID had a more telomerically extending deletion, including CIC, a known ID gene. Children found to harbor ERF deletions should be referred for craniofacial assessment, to exclude occult raised intracranial pressure.
  • Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia

    Powell, Corinna; Vasudevan, Pradeep (2021-05)
    Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.
  • The contribution of X-linked coding variation to severe developmental disorders

    Vasudevan, Pradeep (2021-01)
    Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.
  • Impact of Diversity in Training Resources on Self-Confidence in Diagnosing Skin Conditions Across a Range of Skin Tones: An International Survey

    Roland, Damian (2022-02-25)
    Background: Medical images are invaluable in facilitating recognition of clinical signs. Recent studies highlight a lack of diversity of skin tone images used within medical education. However, there is a paucity of data on the impact of this on patient care. Aims: To investigate diversity in training resources used by users of an International online teaching platform and self-confidence in diagnosing skin conditions in all skin tones. Methods: Users of an online teaching platform ( were invited to participate in a survey evaluating key points including geographical location, ethnicity, profession, specialty, years of experience, training resources and confidence in diagnosing skin conditions. Data analyses were performed using SPSS. Categorical variables were presented as proportions. Chi-squared or Fisher's exact tests were used to compare the distribution between groups as appropriate. Results: Of 600 participants, 74% reported training resources featuring predominantly white skin. Participants were "generally uncertain" in 43% cases, "sometimes uncertain but clinically safe" (52%), and "confident across a range of skin tones" in a minority (5%). Self-confidence was associated with location [higher in Africa (29%) and Latin America (11%), (p < 0.001)]; diversity of training resources [higher with a mix (10%) or darker tones (20%) (p < 0.001)]; clinical experience [6-10 (5%) or >10 years of practice (11%) (p < 0.001)] and specialty [highest in dermatologists (53%, p < 0.001)]. Self-confidence was lowest among pediatricians, emergency medicine and pediatric emergency medicine specialists (<5%). Conclusions: These data provide preliminary evidence that training resources used by healthcare professionals on a global scale may lack enough diversity on representation of skin images, and a lack of self-confidence in diagnosing pediatric skin conditions. Further work is needed to understand the impact on knowledge and patient care to ensure equitable healthcare for all.
  • Verifying nomenclature of DNA variants in submitted manuscripts: guidance for journals

    Dorkins, Huw (2021-01)
    Documenting variation in our genomes is important for research and clinical care. Accuracy in the description of DNA variants is therefore essential. To address this issue, the Human Variome Project convened a committee to evaluate the feasibility of requiring authors to verify that all variants submitted for publication complied with a widely accepted standard for description. After a pilot study of two journals, the committee agreed that requiring authors to verify that variants complied with Human Genome Variation Society nomenclature is a reasonable step toward standardizing the worldwide inventory of human variation.
  • Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions

    Debiec, Radoslaw; Safwan, Kassem; Sosin, Michael; Hetherington, Simon; Elamin, Mohamed; Coolman, Sue; Skinner, Gregory; Samani, Nilesh; Bolger, Aidan (2022-03)
    Introduction: Bicuspid aortic valve (BAV) affects 1% of the general population. NOTCH1 was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to NOTCH1 mutations has not been estimated. Aim: The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to NOTCH1 mutations. Methods: The population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research-8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent NOTCH1 sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting NOTCH1 sequencing in context of congenital heart disease. Results: NOTCH1 sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic NOTCH1 variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting NOTCH1 sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic NOTCH1 variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic NOTCH1 mutations was observed in almost half of reported pedigrees. Conclusions: Pathogenic and likely pathogenic NOTCH1 genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart.
  • Mutation of the MYL3 gene in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy

    Mavilakandy, Akash (2022-03)
    In this study, we discuss a female patient referred to cardiology with left ventricular hypertrophy at mid-ventricular segments resulting in a mid-cavitary obstruction and a left ventricular apical aneurysm. The patient had normal epicardial coronary arteries, but presented with recurrent cerebrovascular events. The patient had a positive family history for sudden cardiac death. Cardiac MRI detected positive features of left ventricular mid-cavity obstruction, left ventricular apical aneurysm and delayed gadolinium enhancement, with Holter monitoring assessment displaying segments of non-sustained ventricular tachycardia. Genetic analysis detected an myosin light chain 3 (MYL3) gene mutation. The patient will be referred to receive an implantable cardioverter defibrillator.The MYL3 gene mutation is a rare variant in patients with familial hypertrophic cardiomyopathy. To our knowledge, the presence of a left ventricular apical aneurysm has not been previously reported in literature concerning the MYL3 gene mutation. The presence of this abnormality further increases the risk of sudden cardiac death.
  • Making sense of the paediatric ECG: rate and rhythm

    Oakley, Chris (2022)
    No abstract available.
  • Making sense of the paediatric ECG

    Oakley, Chris (2022)
    No abstract available.
  • Leaders in Cardiovascular Research: Nilesh J. Samani

    Samani, Nilesh (2021)
    No abstract available.
  • Effect of endometrial scratching on unassisted conception for unexplained infertility: a randomized controlled trial.

    Jayaprakasan, Kanna
    OBJECTIVE: To investigate whether endometrial scratching increases the chance of live birth in women with unexplained infertility attempting to conceive without assisted reproductive technology. DESIGN: Randomized, placebo-controlled, participant-blind, multicenter international trial. SETTING: Fertility clinics. PATIENT(S): Women with a diagnosis of unexplained infertility trying to conceive without assistance. INTERVENTION(S): Participants were randomly assigned to receive an endometrial biopsy or a placebo procedure (placement of a biopsy catheter in the posterior fornix, without inserting it into the external cervical os). Both groups performed regular unprotected intercourse with the intention of conceiving over three consecutive study cycles. MAIN OUTCOME MEASURE(S): The primary outcome was live birth. RESULT(S): A total of 220 women underwent randomization. The live birth rate was 9% (10 of 113 women) in the endometrial-scratch group and 7% (7 of 107 women) in the control group (adjusted OR, 1.39; 95% CI, 0.50-4.03). There were no differences between the groups in the secondary outcomes of clinical pregnancy, viable pregnancy, ongoing pregnancy, and miscarriage. Endometrial scratching was associated with a higher pain score on a 10-point scale (adjusted mean difference, 3.07; 95% CI, 2.53-3.60). CONCLUSION(S): This trial did not find evidence that endometrial scratching improves the live birth rate in women with unexplained infertility trying to conceive without assistance. CLINICAL TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ACTRN12614000656639.
  • Paediatric and adult congenital cardiology education and training in Europe

    Bu'Lock, Frances (2022)
    Background: Limited data exist on training of European paediatric and adult congenital cardiologists. Methods: A structured and approved questionnaire was circulated to national delegates of Association for European Paediatric and Congenital Cardiology in 33 European countries. Results: Delegates from 30 countries (91%) responded. Paediatric cardiology was not recognised as a distinct speciality by the respective ministry of Health in seven countries (23%). Twenty countries (67%) have formally accredited paediatric cardiology training programmes, seven (23%) have substantial informal (not accredited or certified) training, and three (10%) have very limited or no programme. Twenty-two countries have a curriculum. Twelve countries have a national training director. There was one paediatric cardiology centre per 2.66 million population (range 0.87-9.64 million), one cardiac surgical centre per 4.73 million population (range 1.63-10.72 million), and one training centre per 4.29 million population (range 1.63-10.72 million population). The median number of paediatric cardiology fellows per training programme was 4 (range 1-17), and duration of training was 3 years (range 2-5 years). An exit examination in paediatric cardiology was conducted in 16 countries (53%) and certification provided by 20 countries (67%). Paediatric cardiologist number is affected by gross domestic product (R2 = 0.41). Conclusion: Training varies markedly across European countries. Although formal fellowship programmes exist in many countries, several countries have informal training or no training. Only a minority of countries provide both exit examination and certification. Harmonisation of training and standardisation of exit examination and certification could reduce variation in training thereby promoting high-quality care by European congenital cardiologists.
  • A case series review of patients with Thrombocytopenia and Absent-Radii syndrome (TARS) and their management during pregnancy

    Halperin, Daniel; Myers, Bethan (2021)
    Bleeding diatheses due to platelet-related disorders can present challenges to treating clinicians, especially in the context of peri- and post-partum patients in the obstetric setting. Thrombocytopenia and Absent-Radii syndrome (TARS) is an inherited disorder characterized by reduced bone marrow platelet production, skeletal deformities affecting radii and other limbs; cardiac, renal, and other heterogeneous anomalies may occur. It is caused by the co-inheritance of a microdeletion and a nucleotide polymorphism in the RBM8A gene on chromosome 1. Bleeding phenotype is more severe than platelet numbers which might predict especially in infants but improves with age. There is minimal literature regarding the impact of pregnancy and puerperium. We describe the management of three pregnancies in the hematology-obstetrics clinic. As platelet counts normally decrease through pregnancy, close monitoring is required in TARS. No major bleeding was seen antenatally but two required platelet transfusions during labor. No other treatment definitely improves bleeding, although case reports of steroids claim variable success. Tranexamic acid may be helpful, and thrombopoietin agonists represent a potential future option.
  • Inguinal endometriosis: a systematic review

    Salta, Styliani (2022)
    Inguinal endometriosis is a very rare entity with uncertain pathophysiology, that poses several diagnostic and therapeutic challenges. This study aimed to summarize published literature on the diagnosis and treatment of this condition. Thus, a systematic literature search was conducted in PubMed/MEDLINE, Scopus and the Cochrane Library. An effort was made to numerically analyze all parameters included in case reports and retrospective analyses, as well. The typical and atypical features of this condition, investigations used, type of treatment and histopathology were recorded. More specifications about the surgical treatment, such as operations previously performed, type of surgery and treatment after surgery have been acknowledged. Other sites of endometriosis, the presence of pelvic endometriosis and the follow-up and recurrence have been also documented. Overall, the search yielded 61 eligible studies including 133 cases of inguinal endometriosis. The typical clinical presentation includes a unilateral inguinal mass, with or without catamenial pain. Transabdominal or transvaginal ultrasound was typically used as the first line method of diagnosis. Groin incision and exploratory surgery was the treatment indicated by the majority of the authors, while excision of part of the round ligament was reported in about half of the cases. Chemotherapy and radiotherapy were initiated in cases of coexisting endometriosis-related neoplasia. Inguinal recurrence or malignant transformation was rarely reported. The treatment of inguinal endometriosis is surgical and a long-term follow-up is needed. More research is needed on the effectiveness of suppressive hormonal therapy, recurrence rate and its relationship with endometriosis-associated malignancies.
  • Evaluation of tumour surveillance protocols and outcomes in von Hippel-Lindau disease in a national health service

    Barwell, Julian; Harrison, Rachel (2022)
    Background: Von Hippel-Lindau (VHL) disease is an inherited tumour predisposition syndrome and a paradigm for the importance of early diagnosis and surveillance. However, there is limited information on the "real world" management of VHL disease. Methods: A national audit of VHL disease in the United Kingdom. Results: VHL disease was managed mostly via specialist clinics coordinated through regional clinical genetics services (but frequently involving additional specialties). Over the study period, 19 genetic centres saw 842 individuals (393 males, 449 females) with a clinical and/or molecular diagnosis of VHL disease and 74 individuals (35 male, 39 female) with a prior risk of 50% (affected parent). All centres offered retinal, central nervous system and abdominal surveillance to affected individuals and at-risk relatives though surveillance details differed between centres (but complied with international recommendations). Renal lesions detected on the first surveillance scan were, on average, larger than those detected during subsequent scans and the larger the diameter at detection the greater the likelihood of early intervention. Conclusions: In a state-funded health care system individuals with a rare inherited cancer predisposition syndrome are generally able to access appropriate surveillance and patient management is improved compared to historical data. The "real world" data from this study will inform the future development of VHL management protocols.
  • Guideline for the first-line management of Classical Hodgkin Lymphoma - A British Society for Haematology guideline

    Bhuller, Kaljit (2022)
    This guideline was compiled according to the British Society for Haematology (BSH) process at BSH Guidelines Process 2016 ( The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at Recommendations are based on a review of the literature using Medline, PubMed/Medline and Cochrane searches beginning from 2013 up to January 2021. The following search terms were used: [Hodgkin lymphoma OR Hodgkin disease] NOT non-Hodgkin; AND [chemotherapy OR radiotherapy]; AND [elderly]; AND [teenage OR adolescent OR young adult]; AND [pregnancy]. Filters were applied to include only publications written in English, studies carried out in humans, clinical conferences, congresses, clinical trials, clinical studies, meta-analyses, multicentre studies and randomised controlled trials. References pre-2013 were taken from the previous version of this guideline.1 Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haematology Oncology Taskforce, the BSH Guidelines Committee and the Haematology Oncology sounding board of BSH.

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