Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders

Bylstra, Yasmin; Kuan, Jyn Ling; Lim, Weng Khong; Bhalshankar, Jaydutt; Teo, Jing Xian; Dávila, Sonia; Teh, Bin an Te; Rozen, Steve; Tan, Eng Leong; Liew, Wendy; Yeo, Khung Keong; Tan, Patrick; Saw, Seang Mei; Cheng, Ching‐Yu; Cook, Stuart A.; Foo, Roger; Jamuar, Saumya Shekhar

doi:10.1038/s41436-018-0008-6

Cited by 19 publications

(17 citation statements)

References 26 publications

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“…We prospectively recruited unrelated Singaporean patients with HCM (n=224) and Singaporean controls (n=3634) 13 and performed targeted resequencing. 14 Variants of 15 genes 6 either robustly associated with HCM or well-validated pheno/genocopies ( ACTC1, CSRP3, FHL1, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, TNNC1, TNNI3, TNNT2 , and TPM1 ) were evaluated, 15 and we compared findings with reference population data sets, 9 , 16 – 18 White HCM cohorts (n=6179) 3 , 19 , 20 and performed functional studies using iPSC-CMs (induced pluripotent stem cells derived cardiomyocytes).…”

Section: Methodsmentioning

confidence: 99%

“… Overview of the study design outlining the major components of the study and the various disease and control populations used. ACGV indicates atlas of cardiac genetic variation 3 , 13 , 14 ; AF, allele frequency; CMR, cardiac magnetic resonance; EA, East Asian; exVUS, excess variant of uncertain significance; HCM, hypertrophic cardiomyopathy; LP, likely pathogenic; P, pathogenic; and SG, Singaporean. * https://www.cardioclassifier.org/15 …”

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confidence: 99%

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Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients

Pua

Tham

Chin

et al. 2020

Circ: Genomic and Precision Medicine

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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.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients

Pua

Tham

Chin

et al. 2020

Circ: Genomic and Precision Medicine

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“…Shen and colleagues cautioned that 94% of hypothetical East Asian fetuses affected by a genetic condition would be missed if screening only occurs for conditions in recommended guidelines . It was instructive to note that a carrier prevalence study of 104 genes for 80 treatable inherited disorders in Singapore showed 6% of a cohort of 831 were carriers of one of 13 treatable inherited disorders with citrin deficiency and Wilson disease having the highest carrier frequencies . This suggests that population‐specific genomics data are needed before targeted RCS can be implemented in Asia.…”

Section: Malaysia (And Other South East Asian Countries)mentioning

confidence: 99%

International perspectives on the implementation of reproductive carrier screening

et al. 2019

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Reproductive carrier screening started in some countries in the 1970s for hemoglobinopathies and Tay‐Sachs disease. Cystic fibrosis carrier screening became possible in the late 1980s and with technical advances, screening of an ever increasing number of genes has become possible. The goal of carrier screening is to inform people about their risk of having children with autosomal recessive and X‐linked recessive disorders, to allow for informed decision making about reproductive options. The consequence may be a decrease in the birth prevalence of these conditions, which has occurred in several countries for some conditions. Different programs target different groups (high school, premarital, couples before conception, couples attending fertility clinics, and pregnant women) as does the governance structure (public health initiative and user pays). Ancestry‐based offers of screening are being replaced by expanded carrier screening panels with multiple genes that is independent of ancestry. This review describes screening in Australia, Cyprus, Israel, Italy, Malaysia, the Netherlands, Saudi Arabia, the United Kingdom, and the United States. It provides an insight into the enormous variability in how reproductive carrier screening is offered across the globe. This largely relates to geographical variation in carrier frequencies of genetic conditions and local health care, financial, cultural, and religious factors.

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“…Additionally, our SEC local genomic database is analysed to understand carrier prevalence of genetic conditions that are more common in the local population, including diseases such as thalassaemia (1 in 25), citrin deficiency (1 in 41) and Wilson disease (1 in 103). 8,14–18 The ACMG framework was used as a guide for assessing the clinical actionability of genes in our panel. 19 Subsequently, the screening recommendations for each associated genetic condition were then reviewed to ensure that a management plan for ongoing follow-up could be offered in the Singapore context.…”

Section: Study Design Participants and Setting Overviewmentioning

confidence: 99%

“…We previously reported the development of an evolving aggregated genomic data set of Southeast Asians known as the Singapore Exome Consortium (SEC). 8 The SEC is derived from individuals from the multi-ethnic Singaporean population, comprising of Chinese, Malay, Indian and other minority Asian ethnic groups, who have been recruited as healthy controls for genomic-based research studies within Singapore. A subset of SEC genomic data was obtained from a research program called SPECTRA, a prospective cohort of consented volunteers without significant comorbidities who are extensively phenotyped and undergo whole genome sequencing, allowing for clinical and genomic correlations.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders

Cited by 19 publications

References 26 publications

Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients

Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients

International perspectives on the implementation of reproductive carrier screening

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

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