VAMP2 Gene-Related Neurodevelopmental Disorder: A Differential Diagnosis for Rett/Angelman-Type Spectrum of Disorders.

Introduction: VAMP2 is an instrumental protein in neuronal synaptic transmission in the brain, facilitating neurotransmitter release. It is encoded by the VAMP2 gene, and pathogenic variants in this gene cause neurodevelopmental features including early onset axial hypotonia, intellectual disability, and features of autism spectrum disorder. To date, only three types of allelic variants (loss of function, in-frame deletions, and missense variants) in the VAMP2 gene have been previously reported in 11 patients with learning difficulties. Here, we describe a patient in whom a novel de novo pathogenic variant in the VAMP2 gene was identified. Case Presentation: A 15-month-old girl presented with early onset hypotonia, global developmental delay, learning difficulties, microcephaly, nystagmus, strabismus, and stereotypies. Later, she developed a sleep disorder, challenging behaviour with self-injury, and scoliosis. Gene agnostic analysis of whole genome sequencing data identified a novel de novo heterozygous missense variant c.197G>C (p.Arg66Pro) in the VAMP2 gene SNARE motif region. Discussion: This is the fourth report describing VAMP2 gene-related neurodevelopmental disorder. This report adds to the genotype-phenotype correlation and highlights this condition as an important differential diagnosis of Rett/Angelman-type spectrum of disorders. Patients presenting with features of either Rett syndrome or Angelman syndrome, in whom genetic testing is not suggestive, should be evaluated for variants in the VAMP2 gene, given the significant overlap in clinical presentation of these disorders.

Risk-conferring HLA variants in an epilepsy cohort: benefits of multifaceted use of whole genome sequencing in clinical practice.

BACKGROUND: Whole genome sequencing is increasingly used in healthcare, particularly for diagnostics. However, its clinically multifaceted potential for individually customised diagnostic and therapeutic care remains largely unexploited. We used existing whole genome sequencing data to screen for pharmacogenomic risk factors related to antiseizure medication-induced cutaneous adverse drug reactions (cADRs), such as human leucocyte antigen HLA-B*15:02, HLA-A*31:01 variants. METHODS: Genotyping results, generated from the Genomics England UK 100 000 Genomes Project primarily for identification of disease-causing variants, were used to additionally screen for relevant HLA variants and other pharmacogenomic variants. Medical records were retrospectively reviewed for clinical and cADR phenotypes for HLA variant carriers. Descriptive statistics and the χ2 test were used to analyse phenotype/genotype data for HLA carriers and compare frequencies of additional pharmacogenomic variants between HLA carriers with and without cADRs, respectively. RESULTS: 1043 people with epilepsy were included. Four HLA-B*15:02 and 86 HLA-A*31:01 carriers were identified. One out of the four identified HLA-B*15:02 carriers had suffered antiseizure medication-induced cADRs; the point prevalence of cADRs was 16.9% for HLA-A*31:01 carriers of European origin (n=46) and 14.4% for HLA-A*31:01 carriers irrespective of ancestry (n=83). CONCLUSIONS: Comprehensive utilisation of genetic data spreads beyond the search for causal variants alone and can be extended to additional clinical benefits such as identifying pharmacogenomic biomarkers, which can guide pharmacotherapy for genetically-susceptible individuals.

SARS-CoV-2 Susceptibility and ACE2 Gene Variations Within Diverse Ethnic Backgrounds.

There is considerable variability in the susceptibility and progression for COVID-19 and it appears to be strongly correlated with age, gender, ethnicity and pre-existing health conditions. However, to our knowledge, cohort studies of COVID-19 in clinically vulnerable groups are lacking. Host genetics has also emerged as a major risk factor for COVID-19, and variation in the ACE2 receptor, which facilitates entry of the SARS-CoV-2 virus into the cell, has become a major focus of attention. Thus, we interrogated an ethnically diverse cohort of National Health Service (NHS) patients in the United Kingdom (United Kingdom) to assess the association between variants in the ACE2 locus and COVID-19 risk. We analysed whole-genome sequencing (WGS) data of 1,837 cases who were tested positive for SARS-CoV-2, and 37,207 controls who were not tested, from the UK's 100,000 Genomes Project (100KGP) for the presence of ACE2 coding variants and extract expression quantitative trait loci (eQTLs). We identified a splice site variant (rs2285666) associated with increased ACE2 expression with an overrepresentation in SARS-CoV-2 positive patients relative to 100KGP controls (p = 0.015), and in hospitalised European patients relative to outpatients in intra-ethnic comparisons (p = 0.029). We also compared the prevalence of 288 eQTLs, of which 23 were enriched in SARS-CoV-2 positive patients. The eQTL rs12006793 had the largest effect size (d = 0.91), which decreases ACE2 expression and is more prevalent in controls, thus potentially reducing the risk of COVID-19. We identified three novel nonsynonymous variants predicted to alter ACE2 function, and showed that three variants (p.K26R, p. H378R, p. Y515N) alter receptor affinity for the viral Spike (S) protein. Variant p. N720D, more prevalent in the European population (p < 0.001), potentially increases viral entry by affecting the ACE2-TMPRSS2 complex. The spectrum of genetic variants in ACE2 may inform risk stratification of COVID-19 patients and could partially explain the differences in disease susceptibility and severity among different ethnic groups.

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases.

Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes, but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic and likely pathogenic (P/LP) germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Whole-genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100 000 Genomes Project, a nationwide multicentre study, was analyzed to identify rare P/LP short variants (single nucleotide variants and insertions/deletions ranging from 1 to 50 base pairs) and structural variants in 121 CSGs. Among 1336 RCC participants [mean: 61.3 years (±12 SD), range: 13-88 years; 64% male], 85 participants [6.4%; 95% CI (5.1, 7.8)] had one or more P/LP germline variant in a wider range of CSGs than previously recognized. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 'hot VUSs') and were considered to be of potential clinical relevance as further evaluation might results in their reclassification. Most patients with P variants in well-established CSGs known to predispose to renal cell carcinoma (RCC-CSGs) were aged <50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants in European RCC participants compared with the healthy European controls (P = 0.0019). Approximately, 6% of the patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield, we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing.

Phenotype-driven approaches to enhance variant prioritization and diagnosis of rare disease.

Rare disease diagnostics and disease gene discovery have been revolutionized by whole-exome and genome sequencing but identifying the causative variant(s) from the millions in each individual remains challenging. The use of deep phenotyping of patients and reference genotype-phenotype knowledge, alongside variant data such as allele frequency, segregation, and predicted pathogenicity, has proved an effective strategy to tackle this issue. Here we review the numerous tools that have been developed to automate this approach and demonstrate the power of such an approach on several thousand diagnosed cases from the 100,000 Genomes Project. Finally, we discuss the challenges that need to be overcome if we are going to improve detection rates and help the majority of patients that still remain without a molecular diagnosis after state-of-the-art genomic interpretation.

Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants.

Structural eye disorders are increasingly recognised as having a genetic basis, although current genetic testing is limited in its success. De novo missense variants in WDR37 are a recently described cause of a multisystemic syndromic disorder featuring ocular coloboma. This study characterises the phenotypic spectrum of this disorder and reports 2 de novo heterozygous variants (p.Thr115Ile, p.Ser119Tyr) in three unrelated Caucasian individuals. All had a clinical phenotype consisting of bilateral iris and retinal coloboma, developmental delay and additional, variable multisystem features. The variants fall within a highly conserved region upstream of the WD-repeat domains, within an apparent mutation cluster. Consistent with the literature, intellectual disability, structural eye disorders, epilepsy, congenital heart disease, genitorenal anomalies and dysmorphic facial features were observed. In addition, a broader developmental profile is reported with a more specific musculoskeletal phenotype described in association with the novel variant (p.Thr115Ile). We further expand the phenotypic spectrum of WDR37-related disorders to include those with milder developmental delay and strengthen the association of ocular coloboma and musculoskeletal features. We promote the inclusion of WDR37 on gene panels for intellectual disability, epilepsy and structural eye disorders.