Publications by authors named "Brian Hon-Yin Chung"

70 Publications

Elicitation of children's understanding of information in pediatric genetic counseling encounters: A discourse-oriented perspective.

J Genet Couns 2021 Nov 13. Epub 2021 Nov 13.

Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

Affirmation of children's understanding of information provided in genetic counseling encounters is crucial to obtaining children's informed consent/assent in pediatric genetic counseling encounters. It is also important for the proper management of a genetic condition. Currently, there is a relative scarcity of research on how understanding of complex genetic information by children is elicited in the process of pediatric genetic counseling. In this study, we apply theme-oriented discourse analysis to examine 23 video/audio-recorded genetic counseling encounters in Hong Kong. The encounters involve children aged between 3 and 17 years old who are suspected to have or diagnosed with Sudden Arrhythmic Death Syndrome (SADS). Specifically, we examine a range of communicative strategies that genetic professionals employ to elicit children's understanding of information in this genetic counseling setting. We also examine how children's epistemic status is negotiated between genetic professionals, parents, and children. The study reveals that genetic professionals typically use direct questioning (e.g., "do you understand?" or "do you have any questions?"). Less typical are examples where genetic professionals explore children's epistemic access and invite children to recall information after they deliver it. The study reveals two discourse strategies that genetic professionals and parents employ to justify a child's low epistemic status: (1) construction of "current ignorance" and "future competence" in children and (2) association with a child's character. In the examined counseling encounters, genetic professionals and parents tend to construct a low epistemic status in younger children and allocate the responsibility for understanding relevant information to the parents and the "future" competent children. The study highlights the impact of genetic professionals' and parents' assumptions on children's knowledge and comprehensibility at different ages, and the role that children themselves play in conforming or contesting these assumptions.
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http://dx.doi.org/10.1002/jgc4.1523DOI Listing
November 2021

Biallelic TMEM260 variants cause truncus arteriosus, with or without renal defects.

Clin Genet 2021 Oct 6. Epub 2021 Oct 6.

Department of Pediatric Cardiology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.

Only two families have been reported with biallelic TMEM260 variants segregating with structural heart defects and renal anomalies syndrome (SHDRA). With a combination of genome, exome sequencing and RNA studies, we identified eight individuals from five families with biallelic TMEM260 variants. Variants included one multi-exon deletion, four nonsense/frameshifts, two splicing changes and one missense change. Together with the published cases, analysis of clinical data revealed ventricular septal defects (12/12), mostly secondary to truncus arteriosus (10/12), elevated creatinine levels (6/12), horse-shoe kidneys (1/12) and renal cysts (1/12) in patients. Three pregnancies were terminated on detection of severe congenital anomalies. Six patients died between the ages of 6 weeks and 5 years. Using a range of stringencies, carrier frequency for SHDRA was estimated at 0.0007-0.007 across ancestries. In conclusion, this study confirms the genetic basis of SHDRA, expands its known mutational spectrum and clarifies its clinical features. We demonstrate that SHDRA is a severe condition associated with substantial mortality in early childhood and characterised by congenital cardiac malformations with a variable renal phenotype.
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http://dx.doi.org/10.1111/cge.14071DOI Listing
October 2021

A Fetus with Congenital Microcephaly, Microphthalmia and Cataract Was Detected with Biallelic Variants in the Gene: A Case Report.

Diagnostics (Basel) 2021 Aug 30;11(9). Epub 2021 Aug 30.

Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Hong Kong, China.

Microcephaly and microphthalmia are both rare congenital abnormalities, while concurrently, these two are even rarer. The underlying etiology would be complex interplaying between heterogeneous genetic background and the environmental pathogens, particularly during critical periods of early tissue development. Here, we reported a prenatal case with microcephaly, microphthalmia, and bilateral cataracts detected by ultrasonography and confirmed by autopsy. Various routine infection-related tests and invasive genetic testing were negative. Whole genome sequencing of fetus and parents revealed gene defects may be associated with these multiple congenital abnormalities.
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http://dx.doi.org/10.3390/diagnostics11091576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472215PMC
August 2021

CTNNB1-related neurodevelopmental disorder in a Chinese population: A case series.

Am J Med Genet A 2021 Sep 24. Epub 2021 Sep 24.

Clinical Genetic Service, Department of Health, Hong Kong, China.

CTNNB1-related disorder is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment, microcephaly, truncal hypotonia, peripheral spasticity, visual defects, and dysmorphic features. In this case series, we report the clinical and molecular findings of nine Chinese patients affected by CTNNB1-related disorders. The facial features of these affected individuals appear to resemble what had been previously described, with thin upper lip (77.8%) and hypoplastic alae nasi (77.8%) being the most common. Frequently reported clinical characteristics in our cohort include developmental delay (100%), peripheral spasticity (88.9%), truncal hypotonia (66.7%), microcephaly (66.7%), and dystonia (44.4%). While various eye manifestations were reported, two affected individuals (22.2%) in our cohort had familial exudative vitreoretinopathy. One of the affected individuals had craniosynostosis, a feature not reported in the literature before. To our knowledge, this is the first reported Chinese case series of CTNNB1-related neurodevelopmental disorders. Further studies are required to look into whether ethnic differences play a role in phenotypic variations.
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http://dx.doi.org/10.1002/ajmg.a.62504DOI Listing
September 2021

Perception of personalized medicine, pharmacogenomics, and genetic testing among undergraduates in Hong Kong.

Hum Genomics 2021 08 18;15(1):54. Epub 2021 Aug 18.

Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.

Background: The global development and advancement of genomic medicine in the recent decade has accelerated the implementation of personalized medicine (PM) and pharmacogenomics (PGx) into clinical practice, while catalyzing the emergence of genetic testing (GT) with relevant ethical, legal, and social implications (ELSI).

Results: The perception of university undergraduates with regards to PM and PGx was investigated, and 80% of undergraduates valued PM as a promising healthcare model with 66% indicating awareness of personal genome testing companies. When asked about the curriculum design towards PM and PGx, compared to undergraduates in non-medically related curriculum, those studying in medically related curriculum had an adjusted 7.2 odds of perceiving that their curriculum was well-designed for learning PGx (95% CI 3.6-14.6) and a 3.7 odds of perceiving that PGx was important in their study (95% CI 2.0-6.8). Despite this, only 16% of medically related curriculum undergraduates would consider embarking on future education on PM. When asked about their perceptions on GT, 60% rated their genetic knowledge as "School Biology" level or below while 76% would consider undergoing a genetic test. As for ELSI, 75% of undergraduates perceived that they were aware of ethical issues of GT in general, particularly on "Patient Privacy" (80%) and "Data Confidentiality" (68%). Undergraduates were also asked about their perceived reaction upon receiving an unfavorable result from GT, and over half of the participants perceived that they would feel "helpless or pessimistic" (56%), "inadequate or different" (59%), and "disadvantaged at job seeking" (59%), while older undergraduates had an adjusted 2.0 odds of holding the latter opinion (95% CI 1.1-3.5), compared to younger undergraduates.

Conclusion: Hong Kong undergraduates showed a high awareness of PM but insufficient genetic knowledge and low interest in pursuing a career towards PM. They were generally aware of ethical issues of GT and especially concerned about patient privacy and data confidentiality. There was a predominance of pessimistic views towards unfavorable testing results. This study calls for the attention to evaluate education and talent development on genomics, and update existing legal frameworks on genetic testing in Hong Kong.
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http://dx.doi.org/10.1186/s40246-021-00353-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371796PMC
August 2021

Hospital mortality in patients with rare diseases during pandemics: lessons learnt from the COVID-19 and SARS pandemics.

Orphanet J Rare Dis 2021 08 12;16(1):361. Epub 2021 Aug 12.

Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, 1/F New Clinical Building, Queen Mary Hospital, 102 Pokfulam Road, Pok Fu Lam, Hong Kong SAR.

Background: The threat and experience of pandemics occur differently for different groups. The rare disease population is at particular risk of being further marginalised during pandemics. In this study, our objective was to assess the hospital mortality patterns in the rare disease and the general populations during the coronavirus disease of 2019 (COVID-19) and severe acute respiratory syndrome (SARS) pandemics in Hong Kong.

Methods: All admission records during the COVID-19 pandemic (January 23-August 23, 2020) and SARS pandemic (March 11-June 30, 2003) were extracted from the local public healthcare database. Patients with rare diseases were identified using one or more of the 1084 10th version International Classification of Diseases and Related Health Problems (ICD-10) codes cross-referenced with 467 ORPHAcodes. Hospital mortality patterns were compared in patients with and without COVID-19/SARS infection. Admission records during the same period in 2019 and 2002 were retrieved for comparison.

Results: During the COVID-19 pandemic, 407,219 patients were admitted to one or more of the 43 public hospitals in Hong Kong, of which, 13,894 were patients with rare diseases (3.4%). A total of 4381 and 77 patients from the general and rare disease populations were infected with COVID-19. Rare disease patients had an adjusted 3.4 times odds of COVID-19-related hospital mortality compared with that of the general population (95% C.I. 1.24-9.41). COVID-19-related mortality was almost exclusively seen in patients ≥ 60 years. While age-related increase in mortality was also observed for the general population during the SARS pandemic, the pattern observed in the rare disease population was significantly different, with a 12.5 times higher SARS-related mortality observed in rare disease patients ≤ 18 years than those in the general population (12.5% vs 1.0%). Patients admitted during the same pandemic periods without coronavirus infection had a significantly higher hospital mortality compared with those admitted one year before the pandemic (p < 0.001).

Conclusion: This population-based study demonstrated the differential impacts of the COVID-19 and SARS pandemics on the rare disease population. In the era of budget and resource scarcity, this study warrants cautious healthcare planning, with consideration of the rare disease population in healthcare prioritisation.
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http://dx.doi.org/10.1186/s13023-021-01994-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358899PMC
August 2021

High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.

J Hum Genet 2021 Oct 20;66(10):995-1008. Epub 2021 Apr 20.

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.

Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.
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http://dx.doi.org/10.1038/s10038-021-00925-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472897PMC
October 2021

Invasive cerebral phaeohyphomycosis in a Chinese boy with CARD9 deficiency and showing unique radiological features, managed with surgical excision and antifungal treatment.

Int J Infect Dis 2021 Jun 16;107:59-61. Epub 2021 Apr 16.

Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong; Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; Hong Kong Children's Hospital, Hong Kong. Electronic address:

We report this rare case of cerebral phaeohyphomycosis in a previously healthy Chinese boy, who was found to have caspase recruitment domain family member 9 (CARD9) deficiency. Initial radiological features suggested a neoplastic cerebral lesion, while histopathological examination supplemented by internal transcribed sequencing (ITS) of cerebral tissue confirmed the diagnosis of phaeohyphomycosis. He was treated with intravenous (IV) liposomal amphotericin B and voriconazole, guided by plasma and cerebrospinal fluid (CSF) level monitoring at drug initiation. At the 1 year follow-up, the patient demonstrated near complete neurological and radiological recovery.
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http://dx.doi.org/10.1016/j.ijid.2021.04.052DOI Listing
June 2021

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Am J Med Genet A 2021 06 30;185(6):1649-1665. Epub 2021 Mar 30.

Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.
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http://dx.doi.org/10.1002/ajmg.a.62124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631250PMC
June 2021

A thematic study: impact of COVID-19 pandemic on rare disease organisations and patients across ten jurisdictions in the Asia Pacific region.

Orphanet J Rare Dis 2021 03 5;16(1):119. Epub 2021 Mar 5.

Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR.

Background: This study assesses the areas and extent of impact of the Coronavirus Disease of 2019 (COVID-19) pandemic on rare disease (RD) organisations in the Asia Pacific region. There is no existing literature that focuses on such impact on RD organisations in any jurisdictions, nor RD populations across multiple jurisdictions in the Asia Pacific region. A cross-sectional survey was distributed to RD organisations between April and May 2020. Quantitative and qualitative data on the impact of COVID-19 on RD organisations and patients were collected from the organisation representative's perspective. Qualitative data was analysed using thematic analysis. A follow-up focus group meeting was conducted in August 2020 to validate the survey findings and to discuss specific needs, support and recommendations for sustainable healthcare systems during the pandemic.

Results: A total of 80 RD organisations from Australia, Hong Kong Special Administrative Region of China, India, Japan, mainland China, Malaysia, New Zealand, the Philippines, Singapore and Taiwan participated in the study. Of all, 89% were concerned about the impact of pandemic on their organisations. Results indicate that 63% of the organisations functioned at a reduced capacity and 42% stated a decrease in funding as their biggest challenge. Overall, 95% believed their patients were impacted, particularly in healthcare access, social lives, physical health, psychological health and financial impact. Specifically, 43% identified the reduced healthcare access as their top impact, followed by 26% about the impact on daily living and social life. Focus group meeting discussed differential impact across jurisdictions and point towards telemedicine and digitalisation as potential solutions.

Conclusions: This serves as the first study to assess the impact of COVID-19 on RD patients and organisations across multiple jurisdictions in the Asia Pacific region, identifying major themes on the impact on both RD patients and organisations. By including 80 organisations from ten jurisdictions, our study presents the most comprehensive assessment of the pandemic's impact to date. It highlights the need for mental health support and sheds light on moving towards telemedicine and digitalisation of organisation operation, which constitutes a sustainable model in times of pandemics and beyond.
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http://dx.doi.org/10.1186/s13023-021-01766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935006PMC
March 2021

Heterozygous NOTCH1 deletion associated with variable congenital heart defects.

Clin Genet 2021 06;99(6):836-841

The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Pathogenic heterozygous variants in the NOTCH1 gene are known to be associated with both left and right-sided congenital cardiac anomalies with strikingly incomplete penetrance and variable phenotypic expressivity. De novo NOTCH1 whole gene deletion has been reported rarely in the literature and its association with cardiac defects is less well established. Here, we report four cases of NOTCH1 gene deletion from two families associated with a spectrum of congenital heart defects from bicuspid aortic valve to complex cardiac anomalies. This is the first description of a familial NOTCH1 deletion, showing apparently high penetrance, which may be unique to this mechanism of disease. Immunohistochemical staining of cardiac tissue demonstrated reduced levels of NOTCH1 expression in both the left and right ventricular outflow tracts. These cases suggest that haploinsufficiency caused by NOTCH1 gene deletion is associated with both mild and severe cardiac defects, similar to those caused by pathogenic variants in the gene, but with apparently higher, if not complete, penetrance.
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http://dx.doi.org/10.1111/cge.13948DOI Listing
June 2021

Rare versus common diseases: a false dichotomy in precision medicine.

NPJ Genom Med 2021 Feb 24;6(1):19. Epub 2021 Feb 24.

Department of Medicine and Department of Biological Sciences, The University of Alberta, Edmonton, AB, Canada.

Precision medicine initiatives are being launched worldwide, each with the capacity to sequence many thousands to millions of human genomes. At the strategic planning level, all are debating the extent to which these resources will be directed towards rare diseases (and cancers) versus common diseases. However, these are not mutually exclusive choices. The organizational and governmental infrastructure created for rare diseases is extensible to common diseases. As we will explain, the underlying technology can also be used to identify drug targets for common diseases with a strategy focused on naturally occurring human knockouts. This flips on its head the prevailing modus operandi of studying people with diseases of interest, shifting the onus to defining traits worth emulating by pharmaceuticals, and searching phenotypically for people with these traits. This also shifts the question of what is rare or common from the many underlying causes to the possibility of a common final pathway.
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http://dx.doi.org/10.1038/s41525-021-00176-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904920PMC
February 2021

Actionable pharmacogenetic variants in Hong Kong Chinese exome sequencing data and projected prescription impact in the Hong Kong population.

PLoS Genet 2021 02 18;17(2):e1009323. Epub 2021 Feb 18.

Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

Preemptive pharmacogenetic testing has the potential to improve drug dosing by providing point-of-care patient genotype information. Nonetheless, its implementation in the Chinese population is limited by the lack of population-wide data. In this study, secondary analysis of exome sequencing data was conducted to study pharmacogenomics in 1116 Hong Kong Chinese. We aimed to identify the spectrum of actionable pharmacogenetic variants and rare, predicted deleterious variants that are potentially actionable in Hong Kong Chinese, and to estimate the proportion of dispensed drugs that may potentially benefit from genotype-guided prescription. The projected preemptive pharmacogenetic testing prescription impact was evaluated based on the patient prescription data of the public healthcare system in 2019, serving 7.5 million people. Twenty-nine actionable pharmacogenetic variants/ alleles were identified in our cohort. Nearly all (99.6%) subjects carried at least one actionable pharmacogenetic variant, whereas 93.5% of subjects harbored at least one rare deleterious pharmacogenetic variant. Based on the prescription data in 2019, 13.4% of the Hong Kong population was prescribed with drugs with pharmacogenetic clinical practice guideline recommendations. The total expenditure on actionable drugs was 33,520,000 USD, and it was estimated that 8,219,000 USD (24.5%) worth of drugs were prescribed to patients with an implicated actionable phenotype. Secondary use of exome sequencing data for pharmacogenetic analysis is feasible, and preemptive pharmacogenetic testing has the potential to support prescription decisions in the Hong Kong Chinese population.
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http://dx.doi.org/10.1371/journal.pgen.1009323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891783PMC
February 2021

Evaluating the Clinical Utility of Genome Sequencing for Cytogenetically Balanced Chromosomal Abnormalities in Prenatal Diagnosis.

Front Genet 2020 27;11:620162. Epub 2021 Jan 27.

Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong, China.

Balanced chromosomal abnormalities (BCAs) are changes in the localization or orientation of a chromosomal segment without visible gain or loss of genetic material. BCAs occur at a frequency of 1 in 500 newborns and are associated with an increased risk of multiple congenital anomalies and/or neurodevelopmental disorders, especially if it is a mutation. In this pilot project, we used short read genome sequencing (GS) to retrospectively re-sequence ten prenatal subjects with 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. By identifying BCA breakpoints at the nucleotide level using GS, we found disruption of OMIM genes in three cases and identified cryptic gain/loss at the breakpoints in two cases. Of these five cases, four cases reached a definitive genetic diagnosis while the other one case had a BCA interpreted as unknown clinical significance. The additional information gained from GS can change the interpretation of the BCAs and has the potential to improve the genetic counseling and perinatal management by providing a more specific genetic diagnosis. This demonstrates the added clinical utility of using GS for the diagnosis of BCAs.
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http://dx.doi.org/10.3389/fgene.2020.620162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873444PMC
January 2021

Exome sequencing in paediatric patients with movement disorders.

Orphanet J Rare Dis 2021 01 15;16(1):32. Epub 2021 Jan 15.

Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.

Background: Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis.

Results: We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation.

Conclusions: A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.
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http://dx.doi.org/10.1186/s13023-021-01688-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809769PMC
January 2021

Further expanding the clinical phenotype in Bainbridge-Ropers syndrome and dissecting genotype-phenotype correlation in the ASXL3 mutational cluster regions.

Eur J Med Genet 2021 Jan 23;64(1):104107. Epub 2020 Nov 23.

Clinical Genetic Service, Department of Health, University of Hong Kong, HKSAR, Hong Kong.

Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, intellectual disability with poor or absent speech, feeding difficulties, growth failure, specific craniofacial and minor skeletal features. It was firstly reported in 2013 by Bainbridge et al., who observed a group of individuals sharing overlapping features with Bohring-Opitz syndrome which were caused by pathogenic variant in ASXL1, who indeed carried truncating mutations in ASXL3. To date, 33 cases were described in the literature. BRPS is caused by loss-of-function mutations in ASXL3 which are mostly located in two mutational cluster regions (MCR). The exact molecular mechanism of these mutations resulting in the disease phenotype is still uncertain due to the observation of LOF mutations in healthy population. Here, we report four individuals with BRPS carrying de novo LOF mutations in ASXL3, comparing and summarizing the clinical phenotype of all BRPS reported so far. Furthermore, we try to dissect the genotype-phenotype correlation among the two well reported MCRs in all BRPS from the literature.
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http://dx.doi.org/10.1016/j.ejmg.2020.104107DOI Listing
January 2021

Headache in a Child with Pseudohypoparathyroidism: An Alarming Symptom Not to Miss.

Case Rep Endocrinol 2020 10;2020:8840082. Epub 2020 Nov 10.

Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.

Background: While the endocrine manifestations of pseudohypoparathyroidism are well known, less is known about the associated brain and spine abnormalities. These abnormalities may present with nonspecific symptoms in the paediatric population, and lack of awareness to these uncommon manifestations of the disease may result in a delay in necessary intervention. . We herein present a case of known pseudohypoparathyroidism type 1a who presented initially with minor head injury. She later developed progressive worsening headache, increased irritability, and vomiting. Repeated imaging showed hydrocephalus and Chiari malformation type 1 necessitating emergency craniectomy.

Conclusion: Growth hormone deficiency, a common manifestation of pseudohypoparathyroidism type 1a, results in underdevelopment of the posterior cranial fossa and may account for the higher incidence of Chiari malformation in this group of patients. Other associated neurological features reported in pseudohypoparathyroidism type 1a include spinal stenosis, syringomyelia, and craniosynostosis. While less commonly seen, awareness to these associations is important in order to optimize the multidisciplinary care to this group of patients.
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http://dx.doi.org/10.1155/2020/8840082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673925PMC
November 2020

Actionable secondary findings in 1116 Hong Kong Chinese based on exome sequencing data.

J Hum Genet 2021 Jun 22;66(6):637-641. Epub 2020 Nov 22.

Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

The use of exome and genome sequencing has increased rapidly nowadays. After primary analysis, further analysis can be performed to identify secondary findings that offer medical benefit for patient care. Multiple studies have been performed to evaluate secondary findings in different ethnicities. However, relevant data are limited in Chinese. Here, with the use of a cohort consisted of 1116 Hong Kong Chinese exome sequencing data, 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.
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http://dx.doi.org/10.1038/s10038-020-00875-wDOI Listing
June 2021

Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.

Neuron 2021 01 20;109(2):241-256.e9. Epub 2020 Nov 20.

Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds LS9 7TF, UK.

Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.
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http://dx.doi.org/10.1016/j.neuron.2020.10.035DOI Listing
January 2021

Monoallelic Mutations in Suggest a Novel Role in Human Heterotaxy and Ciliary Dysfunction.

Circ Genom Precis Med 2020 12 16;13(6):e003000. Epub 2020 Nov 16.

Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Kong Kong, Hong Kong Special Administrate Region, China (C.C.Y.M., K.S.Y., S.L.C.P., D.Y., M.H.C.Y., P.C.C., Y.F.C., B.H.Y.C.).

Background: Human heterotaxy is a group of congenital disorders characterized by misplacement of one or more organs according to the left-right axis. The genetic causes of human heterotaxy are highly heterogeneous.

Methods: We performed exome sequencing in a cohort of 26 probands with heterotaxy followed by gene burden analysis for the enrichment of novel rare damaging mutations. Transcription activator-like effector nuclease was used to generate somatic loss-of-function mutants in a zebrafish model. Ciliary defects were examined by whole-mount immunostaining of acetylated α-tubulin.

Results: We identified a significant enrichment of novel rare damaging mutations in the gene. Seven occurrences of mutations were found to affect 4 highly conserved amino acid residues of the protein. Functional analyses in the transcription activator-like effector nuclease-mediated zebrafish knockout models were performed, and heterotaxy phenotypes of the cardiovascular and gastrointestinal systems in both somatic and germline mutants were observed. Defective cilia were demonstrated by whole-mount immunostaining of acetylated α-tubulin. These abnormalities were rescued by wild-type mRNA but not mutant mRNA, strongly suggesting a loss-of-function mechanism. On the other hand, overexpression of orthologous mutations P559L and G808V (orthologous to human P532L and G781V) did not affect embryonic development.

Conclusions: Using a zebrafish model, we were able to establish a novel association of with heterotaxy and ciliary dysfunction in the F2 generation via a loss-of-function mechanism. Future mechanistic studies are needed for a better understanding of the role of in left-right patterning and ciliary dysfunction.
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http://dx.doi.org/10.1161/CIRCGEN.120.003000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748040PMC
December 2020

Prenatal and postnatal diagnosis of Schuurs-Hoeijmakers syndrome: Case series and review of the literature.

Am J Med Genet A 2021 02 9;185(2):384-389. Epub 2020 Nov 9.

Department of Obstetrics and Gynecology, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong.

Schuurs-Hoeijmakers syndrome (SHS) is a rare syndrome involving a de novo variant in the PACS1 gene on chromosome 11q13. There are 36 individuals published in the literature so far, mostly diagnosed postnatally (34/36) after recognizing the typical facial features co-occurring with developmental delay, intellectual disability, and multiple malformations. Herein, we present one prenatal and 15 postnatal cases with the recurrent heterozygous pathogenic variant NM_018026.3:c.607C>T p.(Arg203Trp) in the PACS1 gene detected by exome sequencing. These 16 cases were identified by mining Centogene and the Hong Kong clinical genetic service databases. Collectively, the 49 postnatally diagnosed individuals present with typical facial features and developmental delay, while the three prenatally diagnosed individuals present with multiple congenital anomalies. In the current study, the use of exome sequencing as an unbiased diagnostic tool aided the diagnosis of SHS (pre- and postnatally). The identification of additional cases with SHS add to the current understanding of the clinical phenotype associated with pathogenic PACS1 variants. Databases combining clinical and genetic information are helpful for the study of rare diseases.
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http://dx.doi.org/10.1002/ajmg.a.61964DOI Listing
February 2021

Rubinstein-Taybi syndrome in diverse populations.

Am J Med Genet A 2020 12 27;182(12):2939-2950. Epub 2020 Sep 27.

Kapi'olani Medical Center and University of Hawai'i, Honolulu, Hawaii, USA.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.
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http://dx.doi.org/10.1002/ajmg.a.61888DOI Listing
December 2020

CHARGE syndrome patient with novel CHD7 mutation presenting with severe laryngomalacia and feeding difficulty.

BMJ Case Rep 2020 Jul 22;13(7). Epub 2020 Jul 22.

Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, China.

We report a case of CHARGE syndrome with atypical phenotype and a novel mutation in the CHD7 gene. Laryngomalacia and swallowing difficulties are prominent features in this case. These are commonly found in patients with CHARGE syndrome and are well described in previous studies. However, with the traditional diagnostic criteria, diagnosis is difficult without the presence of coloboma or choanal atresia. Early diagnosis is possible with the aid of clinical genetics. The current diagnostic criteria would need to be broadened with the inclusion of pathogenic CHD7 variant status as a major criterion. Further research on the function of CHD7 gene may also give us more insight on the pathogenic mechanism of various clinical features of CHARGE syndrome.
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http://dx.doi.org/10.1136/bcr-2019-233037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380955PMC
July 2020

Coexistence of paternally-inherited mutation and mosaic paternal uniparental disomy 11p hyperinsulinism.

Int J Pediatr Endocrinol 2020 10;2020:13. Epub 2020 Jul 10.

Prenatal Diagnostic Laboratory, Department of Obstetrics and Gynaecology, Tsan Yuk Hospital, Room 314, 3/F, 30 Hospital Road, Sai Ying Pun, Hong Kong.

Background: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome with variable clinical phenotype and complex molecular aetiology. It is mainly caused by dysregulation of the chromosome 11p15 imprinted region, which results in overgrowth in multiple tissues, often in a mosaic manner.

Case Presentation: A large-for-gestational-age infant without any other somatic features of BWS presented with medically refractory hyperinsulinism (HI) requiring 80% pancreatectomy. Next generation sequencing with congenital HI sequencing panel identified a pathogenic :c.1792C > T (p.Arg598Ter) variant of paternal origin, suggestive of focal HI. However, pancreatic histology revealed atypical findings of coalescing nests and trabeculae of adenomatosis scattered with islets with isolated enlarged, hyperchromatic nuclei scattered throughout the pancreas. Methylation analysis, SNP-based chromosomal microarray and short tandem repeat markers analysis revealed mosaic segmental paternal uniparental disomy (UPD) 11p15.5-p15.1 in the pancreatic tissue, but not the peripheral blood, suggestive of BWS/BW-spectrum HI.

Conclusions: This case highlights the importance of integrating the clinical presentation and subsequent clinical course, together with radiological, genetic and histological findings in the definitive diagnosis of this rare yet clinically important entity. In addition, this is the first report that demonstrated the level of paternal inherited c.1792 T pathogenic variant in the pancreatic tissue being directly correlated to the mosaic level of pUPD.
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http://dx.doi.org/10.1186/s13633-020-00083-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350603PMC
July 2020

Mowat-Wilson syndrome in a Chinese population: A case series.

Am J Med Genet A 2020 06 20;182(6):1336-1341. Epub 2020 Mar 20.

Clinical Genetic Service, Department of Health, HKSAR, Hong Kong.

Mowat-Wilson syndrome (MWS) is characterized clinically by a distinctive facial gestalt, intellectual disability, microcephaly, epilepsy, and nonobligatory congenital malformations such as Hirschsprung disease, urogenital anomalies, congenital heart disease, eye malformations. This article summarized the clinical features and molecular findings of 15 Chinese MWS patients. The results revealed a higher incidence of congenital heart disease in Chinese MWS patients compared to that previously reported in Caucasian cohorts, while the incidence of Hirschsprung disease and genitourinary malformation appeared to be lower. This suggests possible ethnicity-related modifying effects in the MWS phenotype.
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http://dx.doi.org/10.1002/ajmg.a.61557DOI Listing
June 2020

Cost-effectiveness analysis of chromosomal microarray as a primary test for prenatal diagnosis in Hong Kong.

BMC Pregnancy Childbirth 2020 Feb 14;20(1):109. Epub 2020 Feb 14.

Department of Obstetrics and Gynaecology, Queen Mary Hospital, Hong Kong, Special Administrative Region, China.

Background: Chromosomal microarray (CMA) has been shown to be cost-effective over karyotyping in invasive prenatal diagnosis for pregnancies with fetal ultrasound anomalies. Yet, information regarding preceding and subsequent tests must be considered as a whole before the true cost-effectiveness can emerge. Currently in Hong Kong, karyotyping is offered free as the standard prenatal test while genome-wide array comparative genome hybridization (aCGH), a form of CMA, is self-financed. A new algorithm was proposed to use aCGH following quantitative fluorescent polymerase chain reaction (QF-PCR) as primary test instead of karyotyping. This study aims to evaluate the cost-effectiveness of the proposed algorithm versus the current algorithm for prenatal diagnosis in Hong Kong.

Methods: Between November 2014 and February 2016, 129 pregnant women who required invasive prenatal diagnosis at two public hospitals in Hong Kong were prospectively recruited. The proposed algorithm was performed for all participants in this demonstration study. For the cost-effectiveness analysis, cost and outcome (diagnostic rate) data were compared with that of a hypothetical scenario representing the current algorithm. Further analysis was performed to incorporate women's willingness-to-pay for the aCGH test. Impact of government subsidies on the aCGH test was explored as a sensitivity analysis.

Results: The proposed algorithm dominated the current algorithm for prenatal diagnosis. Both algorithms were equally effective but the proposed algorithm was significantly cheaper (p ≤ 0.05). Taking into account women's willingness-to-pay for an aCGH test, the proposed algorithm was more effective and less costly than the current algorithm. When the government subsidy reaches 100%, the maximum number of diagnoses could be made.

Conclusion: By switching to the proposed algorithm, cost saving can be achieved whilst maximizing the diagnostic rate for invasive prenatal diagnosis. It is recommended to implement aCGH as a primary test following QF-PCR to replace the majority of karyotyping for prenatal diagnosis in Hong Kong.
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http://dx.doi.org/10.1186/s12884-020-2772-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023733PMC
February 2020

Primary coenzyme Q10 deficiency-7: expanded phenotypic spectrum and a founder mutation in southern Chinese.

NPJ Genom Med 2019 5;4:18. Epub 2019 Aug 5.

1Department of Paediatrics & Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Primary coenzyme Q10 deficiency-7 (COQ10D7) is a rare mitochondrial disease caused by biallelic mutations in . Here we report the largest cohort of COQ10D7 to date, with 11 southern Chinese patients confirmed with biallelic mutations. Five of them have the classical neonatal-onset encephalo-cardiomyopathy, while the others have infantile onset with more heterogeneous clinical presentations. We also identify a founder mutation (NM_016035.5): c.370G>A, p.(Gly124Ser) for COQ10D7, suggesting a higher chance of occurrence in the southern Chinese. This study helps improve understanding of the clinical spectrum of this disorder.
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http://dx.doi.org/10.1038/s41525-019-0091-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683205PMC
August 2019

Training in clinical genetics and genetic counseling in Asia.

Am J Med Genet C Semin Med Genet 2019 06 29;181(2):177-186. Epub 2019 Apr 29.

Department of Pediatrics, College of Medicine, University of the Philippines Manila, Manila, Philippines.

The status of training in clinical genetics and genetic counseling in Asia is at diverse stages of development and maturity. Most of the training programs are in academic training centers where exposure to patients in the clinics or in the hospital is a major component. This setting provides trainees with knowledge and skills to be competent geneticists and genetic counselors in a variety of patient care interactions. Majority of the training programs combine clinical and research training which provide trainees a broad and integrated approach in the diagnosis and management of patients while providing opportunities for research discoveries that can be translated to better patient care. The background on how the training programs in clinical genetics and genetic counseling in Asia evolved to their current status are described. Each of these countries can learn from each other through sharing of best practices and resources.
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http://dx.doi.org/10.1002/ajmg.c.31703DOI Listing
June 2019

Myhre syndrome: a report of six Chinese patients and literature review.

Clin Dysmorphol 2019 Jul;28(3):145-150

Clinical Genetic Service, Department of Health.

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http://dx.doi.org/10.1097/MCD.0000000000000271DOI Listing
July 2019

Exome sequencing identifies molecular diagnosis in children with drug-resistant epilepsy.

Epilepsia Open 2019 Mar 6;4(1):63-72. Epub 2018 Dec 6.

Department of Paediatrics & Adolescent Medicine LKS Faculty of Medicine The University of Hong Kong Hong Kong SAR China.

Objective: Early onset drug-resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure-free status of the patient. Heterogeneous clinical presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug-resistant epilepsy and evaluate whether the findings can provide information on patient management.

Methods: We include patients with drug-resistant epilepsy onset before 18 years of age. Singleton clinical chromosomal microarray (CMA) followed by whole exome sequencing (WES) was performed using genomic DNA. In the first-tier analysis of the exome data, we aimed to identify disease-causing mutations in 546 genes known to cause, or to be associated with, epilepsy. For negative cases, we proceeded to exome-wide analysis. Rare coding variants were interrogated for pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guidelines.

Results: We recruited 50 patients. We identified 6 pathogenic or likely pathogenic mutations, giving a diagnostic yield of 12%. Mutations were found in 6 different genes: , , , , , and . The variant was found to be mosaic. One variant of unknown significance (VUS) in was found in a patient with compatible clinical features. Of note, a reported pathogenic mutation known to contribute to Brugada syndrome, was also found in the patient with an mutation.

Significance: Our study suggests that singleton WES is an effective diagnostic tool for drug-resistant epilepsy. Genetic diagnosis can help to consolidate the clinical diagnosis, to facilitate phenotypic expansion, and to influence treatment and management options for seizure control in our patients. In our study, a significant portion of the genetic findings are known to be associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). These findings could assist with more appropriate management in patients with epilepsy.
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http://dx.doi.org/10.1002/epi4.12282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398105PMC
March 2019
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