Implementation of genomics in medical practice to deliver precision medicine for an Asian population

Whilst the underlying principles of precision medicine are comparable across the globe, genomic references, health practices, costs and discrimination policies differ in Asian settings compared to the reported initiatives involving European-derived populations. We have addressed these variables by developing an evolving reference base of genomic and phenotypic data and a framework to return medically significant variants to consenting research participants applicable for the Asian context. Targeting 10,000 participants, over 2000 Singaporeans, with no known pre-existing health conditions, have consented to an extensive clinical health screen, family health history collection, genome sequencing and ongoing follow-up. Genomic variants in a subset of genes associated with Mendelian disorders and drug responses are analysed using an in-house bioinformatics pipeline. A multidisciplinary team reviews the classification of variants and a research report is generated. Medically significant variants are returned to consenting participants through a bespoke return-of-result genomics clinic. Variant validation and subsequent clinical referral are advised as appropriate. The design and implementation of this flexible learning framework enables a cohort of detailed phenotyping and genotyping of healthy Singaporeans to be established and the frequency of disease-causing variants in this population to be determined. Our findings will contribute to international precision medicine initiatives, bridging gaps with ethnic-specific data and insights from this understudied population

Genetic studies of hypertrophic cardiomyopathy in Singaporeans identify variants in TNNI3 and TNNT2 that are common in Chinese patients

Background - To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry. Methods - We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3,634), compared findings with additional populations and Caucasian HCM cohorts (n=6,179) and performed in vitro functional studies. Results - Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (Pathogenic (P)/Likely Pathogenic (LP):18%, p<0.0001) but an excess of variants of unknown significance (exVUS: 24%, p<0.0001), as compared to Caucasians (P/LP: 31%, exVUS: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency (AF)=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Singaporean controls AF=0.0055, p=0.0057, gnomAD-East Asian (gnomAD-EA) AF=0.0062, p=0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017, p<0.0001, gnomAD-EA AF=0.0009, p<0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3:p.R79C, 0.7%; TNNT2:p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3:p.R79C carriers had significantly thicker left ventricular walls compared to non-carriers while its etiological fraction is limited (0.70, 95% CI: 0.35-0.86) and thus TNNI3:p.R79C is considered a VUS. Mutant TNNT2:p.R286H iPSC-CMs show hypercontractility, increased metabolic requirements and cellular hypertrophy and the etiological fraction (0.93, 95% CI: 0.83-0.97) support the likely pathogenicity of TNNT2:p.R286H. Conclusions - As compared to Caucasians, Chinese HCM patients commonly have low penetrance risk alleles in TNNT2 or TNNI3 but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-Caucasian populations

Genetic research: the role of citizens, public health and international stakeholders

Background: Genetic research has become an indispensable instrument for medical research, and the subjects involved have both divergent and convergent interests. Objective: The possibility of having more detailed genetic information undoubtedly offers benefits for the health of the subject, but could also pose risks and make the subject vulnerable to discrimination. Methods: The scientific community has viewed very favorably the public health utility of family history, in which data from a family whose members suffer from chronic pathologies is collected and filed, in order to develop a sort of “stratification of family risk.” Even though in the last decade the scientific and juridical literature has contributed greatly to the topic of biobanks, the perplexities that continue to surround this theme give the idea that current ethical protocols on research are inadequate. Results: Researchers, citizens, International stakeholders, mass media, Public Health and Governments play a key role in genetic research. It is obvious that the methods used for genetic research do not present intrinsic risks; they are much less dangerous than other activities of diagnosis and research. Before authorizing a research project, it is important to reflect on the responsibility and transparency of the studies to be conducted, and on the impact they may have on the interests of public health. Conclusion: We believe that the highest priority need is to develop a common language on the theme, as is the case in the sphere of clinical experimentation where rules of good clinical practice, albeit at times conflicting, have led to uniform convergences in the scientific world on the points to be actuated

Analysis of clinically relevant variants from ancestrally diverse Asian genomes

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population

A Model for Peer Experiential and Reciprocal Supervision (PEERS) for Genetic Counselors: Development and Preliminary Evaluation Within Clinical Practice

A model for practising genetic counselors to obtain clinical supervision via reciprocal peer observation and feedback was developed and trialled. The model was developed in response to a perceived lack of opportunity for immediate observational feedback for practising genetic counselors. The aims reached by consensus were to facilitate learning new approaches and skills, to revitalise current ways of practising, and to enhance supervision skills in a two-way process, where the observer learnt from the counselor, and vice-versa. The genetic counselors agreed on a process of paired reciprocal observation whereby the observer was present in the room during the counseling session, and a reflective feedback discussion was arranged within 24 h of the session. Four main themes emerged from analysis of the recorded discussions were (i) "I wasn't sure if I-": voicing of doubts or internal questions that occurred during session for the counselor conducting the session, (ii) "I really liked that": positive feedback and validation from the observer, (iii) "I wonder whether-": offering of alternative views, insights and strategies by the observer, and (iv) "That's a real thing for me to take away and think about": evidence of learning by both observers and counselors