Best Paper Award - Teaching and Learning Physical Examination in the Clinical Setting: Authentic Assessment of Multi-domain Competencies for Independent Professional Practice; 2019 World Federation for Medical Education World Conference
(shared with Dr Pamela Lee)
Sir Patrick Manson Gold Medal (2018) - Clinical application of whole-genome technologies on Paediatric-onset rare diseases
Audience Award, Free paper, Frontiers in Medical and Health Sciences Education (2018, shared with Dr Pamela Lee)
Award of Merit, Free paper, Frontiers in Medical and Health Sciences Education (2018, shared with Dr Pamela Lee)
Best Young Investigator Prize - Hong Kong College of Paediatricians (2017)
Knowledge Exchange Awards 2017 - Little People Care Alliance; Li Ka Shing Faculty of Medicine (2017, shared)
Long Service Awards, After 15 Years of Service; Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong (2016)
Outstanding Oral Presentation Award - Identifying genetic mutations in patients with RASopathies using a new generation sequencing diagnostic pipeline in Hong Kong; Annual Scientific Meeting 2013, Hong Kong College of Paediatricians (2013)
Outstanding Poster Presentation Award - Integration of chromosomal microarray into paediatric clinical care in Hong Kong; Annual Scientific Meeting 2013, Hong Kong College of Paediatricians (2013)
Certificate of Excellence - Master of Science in Genomics & Bioinformatics; Division of Genomics & Bioinformatics, CUHK-BGI Innovation Institute of Trans-omics (2013)
Outstanding Team award - The Hong Kong West Cluster (2012)
10-year Loyalty Award - Queen Mary Hospital (2010)
First Runner-up Best Poster Presentation - 7th Asia Pacific Medical Education Conference (APMEC) (2010)
One of the Top 4 submissions - 34th Annual Scientific Meeting, Canadian College of Medical Genetics (2010)
Best Basic Research - Annual Research Day, Paediatrics, Hospital for Sick Children, Toronto (2010)
Fellow Award - 30th Annual David W. Smith Workshop on Malformations and Morphogenesis (2009 & 2010)
Silver Medal in Best Original Research Contest - Clinical Markers Useful in Enhancing Diagnostic Yield for Children with Global Developmental Delay (GDD); HK Academy of Medicine (2005)
Most Outstanding Free Paper - (SMARD1) Spinal muscular atrophy with respiratory distress type 1 mutation in a Chinese boy; The 3rd Hong Kong Genetic Symposium 2005 (2005)
My research focuses in three main areas: (1) Medical application of whole genome technologies, (2) Clinical genetics & genetic counselling and (3) Multiomics & human diseases.
Medical application of whole-genome technologies
Genomic medicine is an emerging medical discipline that involves using genomic information about an individual as part of their clinical care and the health outcomes and policy implications of that clinical use. Its impact in clinical care depends significantly on the successful translation and integration of cutting-edge whole genome technologies from bench to bedside. My research interest is on the clinical application of whole genome technologies in the diagnosis of rare genetic diseases in children. My work includes a series of investigations using Chromosomal Microarray (CMA) in the genetic evaluation of congenital malformations, neurodevelopmental disorders, and congenital heart disease. I have also recruited over 1200 patients in the HKU paediatric exome sequencing project in various clinical contexts (see Figure).
As a clinical geneticist, I have contributed to the advancement of diagnosis, management, and genetic counselling. This is achieved by syndrome delineation, phenotype expansion, characterization of founder mutations and providing insights for improving the management and better understanding of molecular mechanisms. Through leading a consortium of researchers from 60 institutes across 11 countries, we characterized 23 cases and discovered a new syndrome named MN1 C-terminal truncation (MCTT) syndrome. We have also discovered a novel role of the CC2D1A gene in heterotaxy and ciliary dysfunction.
Multiomics is an approach to understand biological systems by a comprehensive, or global, assessment of a set of molecules simultaneously by high-throughput technologies. This includes genomics, epigenomics, transcriptomics, proteomics, metabolomics, which have given rise to the field of “integrative genetics” which integrates other technologies in the study of different molecular components in a biological system and how they contribute to human diseases across multiple ‘omics layers’.The use of multi-omics offers the opportunity to understand the flow of information and mechanism that underlies human disease , which can lead to an improvement in diagnosis, prevention and treatment strategies.
For example,Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence, and ‘epigenomics’ is the genome-wide study of such changes. Multiple studies have demonstrated the important role of epigenetics in interpreting genome data, especially in identifying regulatory elements that contain pathogenic non-coding mutations. My interest is in the study of epigenetics in rare (PIK3CA-Related Overgrowth Spectrum) and common (systemic lupus erythematosus (SLE)) diseases. I also described the first ever human case of paternal uniparental disomy for chromosome 19 using exome sequencing and DNA methylation array.
I am an active member of the International Epigene Consortium led by Prof Rosanna Weksberg of SickKids, Toronto with ongoing work in epigenetics. Our collaborative work has demonstrated disease-specific DNA methylation signature can be used to classify variants of uncertain significance, which was demonstrated in multiple genetic syndromes including Weaver syndrome and Sotos syndrome.
Another area of multiomics is ‘transcriptomics’ which involves the use of RNA sequencing (RNA-seq) to reveal the functional impact of genetic variants, especially variants of the non-coding genome on transcriptional changes, which cannot be revealed by genome sequencing (GS). Multiple studies have conducted RNA-seq on blood, muscle or skin fibroblast from patients with rare muscle or mitochondrial diseases for genetic diagnosis and raised the diagnostic yield by 10%-36% above ES/GS. In addition to postnatal diagnosis, RNA-seq was great potential in prenatal diagnostics. Recently, my team has conducted a proof-of-concept study titled “Diagnostic potential of the amniotic fluid cell transcriptome in deciphering Mendelian disease: a proof-of-concept”. We showed that clinically significant genes are well-expressed in in amniotic fluid cells, known as amniocyte, and their expression patterns are comparable to other clinically accessible tissues commonly used in RNA-seq study. As a proof-of-concept, 3 prenatal cases have been used for amniocyte RNA-seq which was analysed by our bioinformatic pipeline. We demonstrated that amniocyte RNA-seq data could provide strong functional evidence to reclassify variants for making diagnoses in fetuses with congenital anomalies. This study was selected as the “Reviewers’ Choice”, which is in the top 10% of poster abstracts in the American Society of Human Genetics (ASHG) Annual Meeting 2022 and published in NPJ Genomic in 2022.
Beyond the epigenetics of rare diseases, my research team is also interested in studying DNA methylation in common diseases, particularly systemic lupus erythematosus (SLE) as it is common in Chinese
Pei SLC, Chung BHY. Editorial: Genetics and mechanism of ciliopathies. Front Genet. 2022 Oct 28; 13:1067168. Link
In this editorial, we explained the importance of the research topic “genetics and mechanism of ciliopathies” and how could it facilitate research with a deeper understanding on the genetic variations in ciliopathies. I am one of the topic editors for this research topic "Genetics and Mechanism of Ciliopathies".
Chau JFT, Lee M, Chui MMC, Yu MHC, Fung JLF, Mak CCY, Chau CS-K, Siu KK, Hung J, Yeung KS, Kwong AKY, O'Callaghan C, Lau YL, Lee C-WD, Chung BHY and Lee S-L (2022) Functional Evaluation and Genetic Landscape of Children and Young Adults Referred for Assessment of Bronchiectasis. Front Genet. 2022 Jul 19. (IF 4.772) Link
In this study, we performed exome sequencing (ES) on a total of 61 patients referred for assessment of bronchiectasis, including patients with suspected early-onset bronchiectasis, recurrent chest infections, and difficult-to-control asthma in Hong Kong. A back-to-back comparison between exome sequencing reanalysis (rES) and GS was performed on 30 initially negative exome cases. We show that the diagnostic yield is similar between rES and GS with the added advantage of improved coverage for a VUS. We also show that a molecular diagnosis can be obtained in 26% of patients classified with clinical suspicion of primary ciliary dyskinesia based on European Respiratory Society (ERS) guidelines.
Biesecker LG, Adam MP, Chung BHY, Kosaki K, Menke LA, White SM, Carey JC, Hennekam RCM. Elements of morphology: Standard terminology for the trunk and limbs. American Journal of Medical Genetics (Part A) 2022 Nov;188(11):3191-3228. (IF 2.578) Link
In this study we utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients and introduce the anatomy of the trunk and limbs and defined and illustrate the terms that describe the major characteristics of these body regions.
Chau JFT, Yu MHC, Chui MMC, Yeung CCW, Kwok AWC, Zhuang X, Lee R, Fung JLF, Lee M, Mak CCY, Ng NYT, Chung CCY, Chan MCY, Tsang MHY, Chan JCK, Chan KYK, Kan ASY, Chung PHY, Yang W, Lee SL, Chan GCF, Tam PKH, Lau YL, Yeung KS, Chung BHY, Tang CSM. Comprehensive analysis of recessive carrier status using exome and genome sequencing data in 1543 Southern Chinese. NPJ Genom Med. 2022 Mar 21. (IF 8.617) Link
In this study, we performed a secondary analysis on the spectrum and carrier status for 315 genes causing autosomal recessive disorders in 1543 Southern Chinese individuals with next-generation sequencing data, 1116 with exome sequencing and 427 with genome sequencing data. Our data revealed that 1 in 2 people (47.8% of the population) was a carrier for one or more recessive conditions, and 1 in 12 individuals (8.30% of the population) was a carrier for treatable inherited conditions. This comprehensive catalogue of the carrier spectrum and frequency in the Southern Chinese population is the first of such data in Hong Kong.
Yu MHC, Chan MCY, Chung CCY, Li AWT, Yip CYW, Mak CCY, Chau JFT, Lee M, Fung JLF, Tsang MHY, Chan JCK, Wong WHS, Yang J, Chui WCM, Chung PHY, Yang W, Lee SL, Chan GCF, Tam PKH, Lau YL, Tang CSM, Yeung KS, Chung BHY. Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population. PLoS Genet. 2021 Feb 18;17(2):e1009323. (IF 5.917) Link
In this study utilizing exome sequencing data of 1116 Hong Kong Chinese subjects, we studied the pharmacogenetics of the local population. We investigated the spectrum of 133 actionable pharmacogenetic variants and rare deleterious variants in 108 pharmacogenes. It was found that nearly all individuals carried at least one actionable pharmacogenetic variant and one rare, predicted deleterious pharmacogenetic variant. In addition, we projected the potential prescription impact of actionable pharmacogenetic variants using prescription data of Hong Kong's public healthcare system. We estimated that one-seventh of the Hong Kong population received at least one of the 36 drugs with clinical pharmacogenetics guideline recommendations. The findings demonstrated the potential of pharmacogenetic testing in improving patient care and resource allocation in Chinese. The study was quoted by the PHG foundation of the University of Cambridge: https://www.phgfoundation.org/blog/international-lessons-for-personalised-medicine
Chung BHY, Chau JFT, Wong GK. Rare versus common diseases: a false dichotomy in precision medicine. NPJ Genom Med. 2021;6(1):19. Published 2021 Feb 24. doi:10.1038/s41525-021-00176-x (IF 8.617) Link
In this article, we discuss the how technology and infrastructure on rare disease can be extended to common diseases, for example, by identifying drug targets for common diseases based on knockout models on rare diseases, so called Human Knockouts as Models of Drug action (HKMD).
Yu MHC, Chau JFT, Au SLK, Lo HM, Yeung KS, Fung JLF, Mak CCY, Chung CCY, Chan KYK, Chung BHY, Kan ASY. Evaluating the Clinical Utility of Genome Sequencing for Cytogenetically Balanced Chromosomal Abnormalities in Prenatal Diagnosis. Front Genet. 2021 Jan 27;11:620162. (IF 4.772) Link
In this pilot project, we looked at balanced chromosomal abnormalities (BCAs) which occur at a frequency of 1 in 500 newborns and are associated with an increased risk of multiple congenital anomalies and/or neurodevelopmental disorders. We used short read genome sequencing (GS) to retrospectively re-sequence ten prenatal subjects with de novo BCAs and compared the performance of GS with the original karyotyping. GS characterized all BCAs found by conventional karyotyping with the added benefit of precise sub-band delineation. We demonstrated that the additional information gained from GS can provide a more specific genetic diagnosis and change the interpretation of the BCAs and therefore using GS for the diagnosis of BCAs would have added clinical utility compared to karyotyping.
Ma ACH, Mak CCY, Yeung KS, Pei SLC, Ying D, Yu MHC, Hasan KMM, Chen X, Chow PC, Cheung YF, Chung BHY. Monoallelic Mutations in CC2D1A Suggest a Novel Role in Human Heterotaxy and Ciliary Dysfunction. Circulation: Precision and Genomic Medicine. 2020 Dec;13(6):e003000. (IF 7.465) Link
In this publication, a novel gene CC2D1A was found to be associated with human heterotaxy and ciliary defects. The novel finding provides insights into the complex genetic causes of congenital heart defects (left and right isomerism) and demonstrates the potential of the zebrafish animal model to validate novel candidate genes identified from next generation sequencing. By using whole exome sequencing and gene burden analysis, a significant enrichment of novel rare damaging mutations in the CC2D1A gene was identified. The CC2D1A gene is a transcription factor which has only previously been associated with intellectual disability and autism spectrum disorders but not heterotaxy. The function of this gene was further examined by use of a TALEN-mediated zebrafish knock-out model. Abnormalities of cardiovascular and gastrointestinal systems with relation to the left-right axis were identified in both somatic and germline mutants. By whole-mount immunostaining of acetylated α-tubulin, defective cilia were also identified in the mutants.
Yu MHC, Mak CCY, Fung JLF, Lee M, Tsang MHY, Chau JFT, Chung PH, Yang W, Chan GCF, Lee SL, Lau YL, Tam PKH, Tang CSM, Yeung KS, Chung BHY. Actionable secondary findings in 1116 Hong Kong Chinese based on exome sequencing data. J Hum Genet. 2020 Nov 22:1-5. Link (IF 3.755)
In this project, primary data from whole exome sequencing was used to look for actionable secondary findings that offer medical benefit for patient care. In a cohort of 1116 Hong Kong Chinese individuals, we evaluated the secondary findings in the 59 genes recommended by the American College of Medical Genetics and Genomics. Fifteen unique pathogenic or likely pathogenic variants in 17 individuals were identified, representing a frequency of 1.52% in our cohort. Although 20 individuals harboured pathogenic or likely pathogenic variants in recessive conditions, none carried bi-allelic mutations in the same gene. Our finding was in accordance with the estimation from the American College of Medical Genetics and Genomics that about 1% individuals harbour secondary findings.
Chau JFT, Chung CCY, Yu MHC, Yeung KS, Chung BHY. “Rare” Monogenic Variants in Severe COVID-19 cases. Science. (e-Letter, 2020 Nov 19) Link (IF 47.728)
In this project, we performed an extensive population genomic analysis on potentially deleterious rare monogenic variants identified in Zhang et al (2020) associated with life-threatening COVID-19 infection. We found that amongst the 24 variants identified in the study, the autosomal dominant variants TICAM1 p.Ser60Cys and IFNAR1 p.Pro335del variants identified had a higher allelic frequency of 0.0041 and 0.0049, respectively in the East Asians (gnomAD_EAS) and 0.0100 and 0.0053, respectively in our Hong Kong Chinese Control database than other ethnicities. With the use of Hardy-Weinburg Equilibrium, this implied that 1.79% to 3.02% of the population would have a susceptibility to develop a severe life-threatening COVID-19 phenotype. Our findings emphasize that East Asian populations should be used for in-depth investigations of penetrance and expressivity of these variants, and their roles in developing life-threatening COVID-19 pneumonia.
Chung CCY, Leung GKC, Mak CCY, Fung JLF… Lau YL, Chan GCF, Lee SL, Yeung KS, Chung BHY. Rapid whole-exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs. The Lancet Regional Health-Western Pacific. 2020 Aug 1;1:100001. Link (IF 8.559)
This study is the largest prospectively ascertained cohort in using rWES for patients with suspected monogenic disorder that focused on the impact of clinical management and its actual costs-savings. Our study demonstrated rWES achieved a diagnostic yield of 31% with a median TAT of 11 days, comparable to international studies. Importantly, rWES aided clinical management in 88% of diagnosed patients in this cohort, which is higher than most of the published studies. We also demonstrated rWES reduced healthcare expenditure and achieved net healthcare cost-savings of HKD$5,325,187 in the clinical setting. This study has recently been published in the first issue of The Lancet Regional Health – Western Pacific, and was highlighted in the journal’s Editorial entitled “A new voice for the Western Pacific Region” (doi: 10.1016/j.lanwpc.2020.100015), and reported in the Cambridge Public Health Genomics webpage (https://www.phgfoundation.org/blog/rapid-exome-sequencing-for-paediatric-precision-medicine).
Mak CCY, Doherty D, Lin AE, Vegas N, Cho MT, Viot G, Dimartino C, Weisfeld-Adams JD, Lessel D, Joss S, Li C, Gonzaga-Jauregui C, Zarate YA, Ehmke N, Horn D, Troyer C, Kant SG, Lee Y, Ishak GE, Leung G, Barone Pritchard A, Yang S, Bend EG, Filippini F, Roadhouse C, Lebrun N, Mehaffey MG, Martin PM, Apple B, Millan F, Puk O, Hoffer MJV, Henderson LB, McGowan R, Wentzensen IM, Pei S, Zahir FR, Yu M, Gibson WT, Seman A, Steeves M, Murrell JR, Luettgen S, Francisco E, Strom TM, Amlie-Wolf L, Kaindl AM, Wilson WG, Halbach S, Basel-Salmon L, Lev-El N, Denecke J, Vissers LELM, Radtke K, Chelly J, Zackai E, Friedman JM, Bamshad MJ, Nickerson DA; University of Washington Center for Mendelian Genomics, Reid RR, Devriendt K, Chae JH, Stolerman E, McDougall C, Powis Z, Bienvenu T, Tan TY, Orenstein N, Dobyns WB, Shieh JT, Choi M, Waggoner D, Gripp KW, Parker MJ, Stoler J, Lyonnet S, Cormier-Daire V, Viskochil D, Hoffman TL, Amiel J, Chung BHY*, Gordon CT*. MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis. Brain. 2020;143(1):55-68. Link (IF 15.255) *Co-corresponding Author
This study is an international collaboration co-led by HKU and Institut Imagine of France, involving genomic researchers from Asia, Europe and North America. Starting with a patient with an undiagnosed disease in the Duchess of Kent Children’s Hospital in Hong Kong, this journey has led to the discovery of a new neurodevelopmental syndrome caused by truncating mutations in the C-terminus of MN1 gene, a transcriptional regulator. We name this condition MN1 C-terminal truncation (MCTT) syndrome. We utilized state-of-the-art technologies including next generation sequencing, transcriptomics, and artificial intelligence neural network based facial recognition tool to characterize this new genetic disorder. This work also represents a breakthrough in our understanding of rhombencephalosynapsis (RES), a brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres. RES was first described in medical literature in 1914 with no known animal models or consistent genetic causes reported. Our work has for the first time identified a genetic cause for RES and opens the door to understanding the pathophysiological mechanisms underlying RES and normal development of the cerebellum.
Yu MHC, Tsang MHY, Lai S, Ho MSP, Tse DML, Wills B, Kwon gAKY, Chou YY, Lin SP, Quinzli CM, Hwu WL, Chien YH, Kuo PL, Chan VCM, Tsoi C,, Chong SC, Rodenburg RJT, Smeitink J, Mak CCY, Yeung KS, Fung JLF, Lam W, Hui J, Lee NC, Fung CW, Chung BHY. Primary coenzyme Q10 deficiency-7: expanded phenotypic spectrum and a founder mutation in southern Chinese. NPJ Genomic Medicine 2019; 4:18. Link (IF 8.617)
In this study, we performed detailed analysis on the largest case series worldwide harbouring mutations of primary coenzyme Q10 deficiency-7. We found that mutations in the COQ4 gene are the most common molecular diagnosis in mitochondrial disease in Hong Kong, and the predominance of Chinese subjects in this cohort led to the discovery of a founder mutation c.370G>A. Founder mutations are often responsible for the high prevalence of rare genetic disorders in specific populations but are also associated with more common monogenic disorders and complex traits. These founder mutations are ethnicity-specific and are typically not described or under-represented in genomic databases.
Zayts O, Shipman H, Fung JLF, Liu APY, Kwok SY, Tsai ACH, Yung TC, Chung BHY. The different facets of "culture" in genetic counseling: A situated analysis of genetic counseling in Hong Kong. Am J Med Genet C Semin Med Genet. 2019;181(2):187-195. Link (IF 3.359)
This research work was included in the issue “Clinical Genetics in Asia”, AJMG Part C in June 2019 where I was invited as a guest editor in-charge (https://onlinelibrary.wiley.com/toc/15524876/2019/181/2). This work is unique as it is a situated analysis on real life data in HK (HKU joint cardiac genetic clinic) and demonstrates the uniqueness of genetic counseling in HK with the cultural difference. This inter-disciplinary work on medicine and linguistics is one of the flagship projects of the newly established “Research and Impact Initiative on Communication in Healthcare in HKU”. This resulted from a long-term collaboration with the School of English which has been awarded a 2013 Faculty Knowledge Exchange award in HKU (http://arts.hku.hk/knowledge-exchange/faculty-ke-award/the-language-of-genetic-counselling). The unique research findings from our projects are extremely relevant to the practice of genetic counselling in HK, thus are applied into our teaching in the HKU Master of Medical Sciences curriculum for genetic counselling in which I serve as a programme director.
With my current role as the President Elect for the Asia Pacific Society of Human Genetics, this special issue facilitated collaborations between HK and the regions of China, Singapore, Japan, Taiwan, Thailand, the Philippines, Malaysia etc. The special issue included four papers from HK to strengthen connections of HK with the region. As I highlighted in the editorial introduction, the aim of this special issue is to show “Asia's readiness and willingness to be a part of more international conversations about genetics in future.”
Chiu ATG, Chung CCY, Wong WHS, Lee SL, Chung BHY. Healthcare burden of rare diseases in Hong Kong–adopting ORPHAcodes in ICD-10 based healthcare administrative datasets. Orphanet Journal of Rare Diseases. 2018 Dec 1;13(1):147. Link (IF 4.303)
In this study, we have set out to cross reference ORPHA codes and ICD-10 to identify rare diseases-related admissions in health administrative datasets in Hong Kong. In the 7-million populations, the prevalence of rare diseases was found to be 1 in 67, representing 1.5% of the whole population. This placed the estimated total inpatient cost for rare disease population at HKD$1,594,339,530 i.e. 4.3% of total inpatient cost in 2015-2016. The disparity reflects the importance of rare diseases in healthcare policies. This study for the first time provides information on healthcare burden of rare diseases in Hong Kong.
Yeung KS, Ho MSP, Lee SL, Kan ASY, Chan KYK, Tang MHY, Mak CCY, Leung GKC, So PL, Pfundt R, Marshall CR, Scherer SW, Choufani S, Weksberg R, Chung BHY. Paternal uniparental disomy of chromosome 19 in a pair of monochorionic diamniotic twins with dysmorphic features and developmental delay. Journal of Medical Genetics 2018;55(12):847-852 Link (IF 5.941)
Uniparental disomy (UPD) occurs when a person obtains both copies of the homologous chromosome from one parent. UPD can be associated with human diseases caused by disruption of genomic imprinting or homozygosity for a recessive trait. In this report, we describe the first human case of paternal UPD for chromosome 19 in monozygotic twins showing dysmorphic features and global developmental delay. Comprehensive genetics and DNA methylation analysis suggested that imprinting defects were considered a potentially important mechanism to explain the clinical features of the twins.
Mak CCY, Leung GKC, Mok GTK, Yeung KS, Yang W, Fung CW, Chan SHS, Lee SL, Lee NC, Pfundt R, Lau YL, Chung BHY. Exome sequencing for paediatric-onset diseases: impact of the extensive involvement of medical geneticists in the diagnostic odyssey. NPJ Genom Med. 2018;3:19. Link (IF 8.617)
As described by the journal’s editorial summary titled “Pediatrics: Extra Review of exome data boosts diagnostic yield”: In-depth reviews by clinical geneticists can improve the diagnostic accuracy of exome sequencing data for children with unexplained genetic disorders, especially in non-Western populations that are under-represented in genomic databases. Working with children predominantly of Han Chinese origin, Brian Chung from the University of Hong Kong and coworkers sequenced the entire protein-coding portion of the genome for 104 patients with pediatric-onset genetic disease. Specially trained geneticists analyzed the DNA data to resolve any ambiguous interpretations, link the molecular findings with clinical records, identify ethnic-specific differences and, when necessary, request additional assays. This extra review process was sometimes laborious, taking several hours of the physician’s
time, but ultimately led to a more comprehensive assessment in 16 of the 43 diagnoses successfully made. This overall diagnostic yield—41%—was comparable to previous studies in other populations.
Our team has finished “A three-year follow-up study evaluating the clinical utility of exome sequencing and diagnostic potential of exome reanalysis” on the same cohort of patients. In collaboration with Yale School of Medicine, we performed exome reanalysis in 46 undiagnosed individuals and achieved 12 new diagnoses. The additional yield compared with the initial analysis was at least 12% (increased from 41% to at least 53%). After a median follow-up period of 3.4 years, change in clinical management was observed in 72.2% of the individuals (26/36), leading to positive change in clinical outcome in four individuals (11%). There was a minimum healthcare cost saving of HKD$152,078 (USD$19,497; €17,282) annually for these four individuals. This three-year follow-up study demonstrated the long-term clinical utility of ES at individual, familial and health system level, and the promising diagnostic potential of subsequent reanalysis. This work has just been accepted in the npj Genomic Medicine for publication.
Yeung KS, Tso WWY, Ip JJK, Mak CCY, Leung GKC, Tsang MHY, Ying D, Pei SLC, Lee SL, Yang W, Chung BHY. Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism. Molecular Autism 2017; 8:66.Link (IF 6.476)
This study illustrated that in patients with autism and/or developmental delay who also have macrocephaly, mutations in the PI3K-AKT-mTOR signalling pathway can be identified in nearly half of them. Both germline and somatic mosaicism can be the cause. This study showed that genetic testing should not be limited to PTEN, but also other genes in the PI3K-AKT-mTOR signalling pathway. In addition, sequencing should be performed with higher sequencing depth and in other tissues in order to detect low level of mosaicism. In a meta-analysis by Srivastava S et al. (Genetics in Medicine 2019; 21:2413-2421), our study was included as one of the 30 studies (from 973 articles) selected, and the review demonstrates that ES consistently outperforms chromosome microarray for the evaluation of unexplained neurodevelopmental disorders (NDDs). This results in a consensus statement suggesting ES as the first-tier clinical diagnostic test for individuals with NDDs.
Mak ASL, Chiu ATG, Leung GKC, Mak CCY, Chu YWY, Mok GTK, Tang WF, Chan KYK, Tang MHY, Lau ETK, So KW, Tao VQ, Fung CW, Wong VCN, Uddin M, Lee SL, Marshall CR, Scherer SW, Kan ASY, Chung BHY. Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder-implications of a copy number variation involving DPP10. Molecular Autism. 2017;8:31. Link (IF 6.476)
To our knowledge this is the 3rd study on CNVs in Chinese with ASD, and the largest series reporting on DPP10-related CNV in normal individuals. The results have not only substantiated the genetic heterogeneity inherent to ASD, but also allowed for the reclassification of DPP10-related CNVs as a Chinese specific copy number polymorphism. Our findings illustrated the importance of using ancestry-matched controls and keeping a local genomic database when characterizing the clinical relevance of rare genetic variants in a population. I was awarded the Best Young Investigator Prize by the Hong Kong College of Paediatricians in 2017.
Choufani, S, Cytrynbaum C, Chung BHY, Turinsky A, Grafodatskaya D, Chen YA, Cohen A, Dupuis L, Butcher D, Siu MT, Luk HM, Lo I, Lam S, Caluseriu O, Stavropoulos D, Reardon W, Mendoza-Londono R, Brudno M, Gibson W, Chitayat D, Weksberg R. NSD1 mutations generate a genome-wide DNA methylation signature. Nature Communications 2015;6:10207. Link(IF 17.694)
After successfully identifying a germline DNA methylation signature in patient with mutation in KDM5C (*Grafodatskaya D, *Chung BHY et al. BMC Medical Genomics 2013;6:1-18), we herewith identified a NSD1-specific DNA methylation signature in Sotos Syndrome and that loss of function NSD1 mutation can deregulate the transcriptional balance of key developmental genes. My role is to recruit and analyze a Chinese-specific cohort of patients with Soto Syndrome for validation of finding in the primary cohort. This work opens a new field of research in evaluating the diagnostic utility of genome-wide DNA methylation in individuals with unsolved genetic syndromes. *Co-First Authors
Editorship or editorial board membership of scholarly journals
President-Elect, Asia Pacific Society of Human Genetics
Dr Chung has served as the Education Committee Chairman of the Department 2017 - 2021 (co-chairman: Dr Pamela Lee).
He has served as the secretary of the Subspecialty Board of Genetics Genomics of the Hong Kong College of Paediatricians from 2018 - 2020. Now he is a member of the Subspecialty Board.
Dr Chung has achieved the status of Fellow (FHEA) in recognition of attainment against the UK Professional Standards Framework for teaching and learning support in higher education.
I believe great teachers provide the environment and insights for the students to learn proactively and independently. I believe that clinical educators shall go beyond content knowledge and foster critical thinking and problem-solving skills (clinical reasoning). It is also particularly important to be clear about the relevance of the learning process to clinical practice. I take every opportunity to make use of real-life scenarios e.g. use of real patients or personal experience to enhance the student learning process. I strongly believe that learning should be patient-centered, as we are training future doctors to manage patients not only professionally but also humanely.
1) The learning process begins by identifying the gaps in the student's mindset, knowledge, and skills such that the student recognizes areas for development. Through effective feedback and techniques of self-reflection, our future doctors are equipped for their journey of self-long learning.
2) The learner must understand the relevance of the information in the clinical care of the patients. The use of real-life experiences in clinical practice is a powerful tool to engrave the relevance of the knowledge to their future practice as a doctor.
3) The ultimate aim of learning is not to be a good student but a good doctor, someone that can be entrusted with the important responsibilities of the health of Hong Kong citizens.
As a student (1995-1999) and teacher (2000-present) growing up in HKU, I embrace HKU’s vision to provide a “total learning experience”. The key institutional educational aims (https://tl.hku.hk/tl/) matches a lot of my core values in teaching: critical intellectual inquiry, life-long learning, critical self-reflection, collaboration, global citizenship and advocacy for the improvement of human conditions. In recognition of my contribution to teaching and curriculum development, I was awarded the Faculty Teaching Award in 2018-2019.
Dr Yeung Kit San
Postdoctoral Fellow, The University of Hong Kong, 2020-2021
PhD, The University of Hong Kong, 2017
Current Position: Scientific Officer (Medical), Department of Pathology, Hong Kong Children's Hospital
Dr Leung KC Gordon
PhD, The University of Hong Kong, 2018
Current Position: Scientific Officer (Medical), Department of Pathology, Hong Kong Children's Hospital
Dr Steven LC Pei
Postdoctoral Fellow, The University of Hong Kong, 2016-2018
PhD, The University of Hong Kong, 2016
Current: Post Doctoral Fellow, Department of Internal Medicine, Yale University
Dr Marcus CY Chan
MRes (Med), The University of Hong Kong, 2020 (With Mr & Mrs SH Wong Foundation Scholarship)
MBBS, The University of Hong Kong, 2021
Current: Resident, Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital
Research Assistant and Genetic Counsellor, The University of Hong Kong, 2017-2021
Current: Genetic Counsellor, Hong Kong Genome Institute
Dr Mullin Yu
PhD, The University of Hong Kong, 2022
Current: Head of Operation (Bioinformatics), Hong Kong Genome Institute
Dr Mandy HY Tsang
PhD, The University of Hong Kong, 2016 - 2022 (Part Time)
Current: Scientific Officer (Medical), Department of Pathology, Hong Kong Children's Hospital
Dr Claudia Chung
PhD, The University of Hong Kong, 2022
Current: Research Officer, Hong Kong Genome Institute
Bachelor of Biomedical Science (BBMS Final Year Project) Students
Lam Kit Yan Melissa 2017 Grade A
Fung Lee Fong Jasmine 2017 Grade A
Kwong Ming Hong Bernard 2018 Grade A
Chau Fong Ting Jeffrey 2019 Grade A+
Lee Da Kyung 2020 Grade A
Lee Ryan 2020
Significant Achievement of Team Members
"Every tree is known by its own fruit"
Award for Poster Presentation - Reviewers’ Choice Abstracts, 2022, American Society of Human Genetics, Ms Mianne Lee
Award for Poster Presentation - 1st Prize, 2021, Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Dr Anna Ka Yee Kwong Link
Award for Oral Presentation - 2nd Runner-Up, 2021, Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Dr Christopher Chun Yu Mak Link
Award for Oral Presentation - 1st Runner-Up, 2020, Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Miss Claudia Chung Link
Award for Poster Presentation - 1st Runner-Up, 2020, Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Miss Claudia Chung Link
Award for Oral Presentation - 1st Runner-Up, 2020, Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Mr Jeffrey Chau Link
Award for Poster Presentation - 1st Runner-Up, 2020, Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Miss Constance Lui Link
Best paediatric abstract award, 2020, Twenty-eighth Annual Congress (Virtual) for Hong Kong College of Cardiology, Dr Julia Shi
Chen Travel Award, 2019, Asia Pacific Conference on Human Genetics, Miss Claudia Chung
Best Poster Award, 2019, Asia Pacific Conference on Human Genetics, Miss Jasmine Fung
Award for Oral Presentation - 1st Runner-Up, 2019, Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Miss Jasmine Fung
Award for Oral Presentation - 1st Runner-Up, 2018, Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Mr Mullin Yu
Young Investigator Award , 2017, Asia Society of Pediatric Research, Dr Winnie Tso
Young Investigator Award , 2017, Asia Society of Pediatric Research, Mr Steven Pei
Award for Oral Presentation - 1st Prize, 2017, Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Mr Christopher Mak
Best Fellow Dissertation Award, 2016, HK College of Paediatricians, Dr Victoria Tao
Outstanding Oral Presentation, 2016, 4th Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Mr Gary Mok
Outstanding Oral Presentation, 2016, 4th Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Ms Mandy Tsang
Outstanding Oral Presentation, 2015, 3rd Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Dr Annisa Mak
First Runner-up, 2014, Golden Jubilee Scientific Meeting, Department of Paediatrics & Adolescent Medicine, HKU, Mr Gordon Leung
Outstanding Oral Presentation, 2014, 2nd Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Mr Kit-San Yeung
Outstanding Oral Presentation, 2014, 2nd Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Mr Christopher Mak
Outstanding Oral Presentation, 2014, 2nd Joint Annual Research & Scientific Meeting, Hong Kong College of Paediatricians and Hong Kong Paediatric Society, Mr Gordon Leung
Dr. Winnie Tso, Assistant Professor (left), and
Dr. Steven Pei, Post-doctoral Fellow (right)
were both awarded the Young Investigator Award in The 13th Congress of Asian Society for Paediatric Research (ASPR) in 2017 under my supervision.
Miss Claudia Chung, PhD student, was awarded the Chen Travel Award at The 13th Asia Pacific Conference on Human Genetics (APCHG) in 2019 under my supervision. This was awarded to the best 10 students and young scientists in recognition of their outstanding research work at the conference.
Miss Jasmine Fung was awarded the Best Poster Award in the 13th Asia Pacific Conference on Human Genetics (APCHG) in 2019 under my supervision.