Recent Submissions

  • 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.
  • 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.
  • Leaders in Cardiovascular Research: Nilesh J. Samani

    Samani, Nilesh (2021)
    No abstract available.
  • 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.
  • Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

    Bown, Matthew; Samani, Nilesh (2022)
    Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
  • Throat and voice problems in Ehlers-Danlos syndromes and hypermobility spectrum disorders

    Lam, Chon Meng (2021)
    A small number of case reports and observational studies describe chronic nasal congestion, upper airway obstruction, dysphonia, vocal cord abnormalities, and swallowing abnormalities in the Ehlers-Danlos syndromes. Little is known of the causes and therefore treatments of these, yet they are not uncommon findings in persons with hypermobility-related conditions presenting in the healthcare setting. We have a specialist multidisciplinary ear, nose, and throat and speech therapy practice with accumulating observational and empirical experience of managing these conditions, which include altered voice, choking, high dysphagia and anterior and deep neck pains. Here, we present our experience, some illustrative cases, and suggestions for future work in this evolving field.
  • Gene and metabolite expression dependence on body mass index in human myocardium

    Roman, Marius; Zakkar, Mustafa; Joel-David, Lathishia; Kumar, Tracy; Murphy, Gavin (2022)
    We hypothesized that body mass index (BMI) dependent changes in myocardial gene expression and energy-related metabolites underlie the biphasic association between BMI and mortality (the obesity paradox) in cardiac surgery. We performed transcriptome profiling and measured a panel of 144 metabolites in 53 and 55, respectively, myocardial biopsies from a cohort of sixty-six adult patients undergoing coronary artery bypass grafting (registration: NCT02908009). The initial analysis identified 239 transcripts with biphasic BMI dependence. 120 displayed u-shape and 119 n-shape expression patterns. The identified local minima or maxima peaked at BMI 28-29. Based on these results and to best fit the WHO classification, we grouped the patients into three groups: BMI < 25, 25 ≤ BMI ≤ 32, and BMI > 32. The analysis indicated that protein translation-related pathways were downregulated in 25 ≤ BMI ≤ 32 compared with BMI < 25 patients. Muscle contraction transcripts were upregulated in 25 ≤ BMI ≤ 32 patients, and cholesterol synthesis and innate immunity transcripts were upregulated in the BMI > 32 group. Transcripts involved in translation, muscle contraction and lipid metabolism also formed distinct correlation networks with biphasic dependence on BMI. Metabolite analysis identified acylcarnitines and ribose-5-phosphate increasing in the BMI > 32 group and α-ketoglutarate increasing in the BMI < 25 group. Molecular differences in the myocardium mirror the biphasic relationship between BMI and mortality.
  • Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder

    Helbling, Ingrid; Barwell, Julian (2022)
    In the framework of the UK 100000 Genomes Project, we investigated the genetic origin of a previously undescribed recessive dermatological condition, which we named LIPHAK (LTV1-associated Inflammatory Poikiloderma with Hair abnormalities and Acral Keratoses), in four affected individuals from two UK families of Pakistani and Indian origins, respectively. Our analysis showed that only one gene, LTV1, carried rare biallelic variants that were shared in all affected individuals, and specifically they bore the NM_032860.5:c.503A > G, p.(Asn168Ser) change, found homozygously in all of them. In addition, high-resolution homozygosity mapping revealed the presence of a small 652-kb stretch on chromosome 6, encompassing LTV1, that was common to and haploidentical in all affected individuals. The c.503A > G variant was predicted by in silico tools to affect the correct splicing of LTV1's exon 5. Minigene-driven splicing assays in HEK293T cells and in a skin sample from one of the patients confirmed that this variant was indeed responsible for the creation of a new donor splice site, resulting in aberrant splicing and in a premature termination codon in exon 6 of this gene. LTV1 encodes one of the ribosome biogenesis factors that promote the assembly of the small (40S) ribosomal subunit. In yeast, defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm; however, the role of this gene in human pathology is unknown to date. Our data suggest that LIPHAK could be a previously unrecognised ribosomopathy.
  • The novel allele HLA-DQA1*05:05:10 was detected in a Nigerian who also lacks the DRB5 gene in the DRB1*16 haplotype

    Bradshaw, Robert; Dunn, Paul (2022)
    One synonymous nucleotide substitution in exon 2 of DQA1*05:05:01:13 results in a novel allele, HLA-DQA1*05:05:10.
  • Clinical genetics: past, present and future

    Tromans, Eva; Barwell, Julian (2022)
    No abstract available.
  • Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

    Vasudevan, Pradeep (2021)
    Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.
  • Variation in human herpesvirus 6B telomeric integration, excision, and transmission between tissues and individuals

    Romaine, Simon; Samani, Nilesh (2021)
    Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV-6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether, we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.

View more