HKG: an open genetic variant database of 205 Hong Kong cantonese exomes.

HKG is the first fully accessible variant database for Hong Kong Cantonese, constructed from 205 novel whole-exome sequencing data. There has long been a research gap in the understanding of the genetic architecture of southern Chinese subgroups, including Hong Kong Cantonese. HKG detected 196 325 high-quality variants with 5.93% being novel, and 25 472 variants were found to be unique in HKG compared to three Chinese populations sampled from 1000 Genomes (CHN). PCA illustrates the uniqueness of HKG in CHN, and the admixture study estimated the ancestral composition of HKG and CHN, with a gradient change from north to south, consistent with their geological distribution. ClinVar, CIViC and PharmGKB annotated 599 clinically significant variants and 360 putative loss-of-function variants, substantiating our understanding of population characteristics for future medical development. Among the novel variants, 96.57% were singleton and 6.85% were of high impact. With a good representation of Hong Kong Cantonese, we demonstrated better variant imputation using reference with the addition of HKG data, thus successfully filling the data gap in southern Chinese to facilitate the regional and global development of population genetics.

Genetic landscape of RASopathies in Chinese: Three decades' experience in Hong Kong.

RASopathies are a group of genetic disorders due to dysregulation of the RAS-MAPK signaling pathway, which is important in regulating cell growth, proliferation, and differentiation. These include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), cardiofaciocutaneous (CFC) syndrome, and Costello syndrome (CS), clinical manifestations include growth retardation, developmental delay, cardiac defects, and specific dysmorphic features. There were abundant publications describing the genotype and phenotype from the Western populations. However, detailed study of RASopathies in Chinese population is lacking. We present here the largest cohort of RASopathies ever reported in Chinese populations, detailing the mutation spectrum and clinical phenotypes of these patients. The Clinical Genetic Service, Department of Health, and Queen Mary Hospital are tertiary referral centers for genetic disorders in Hong Kong. We retrospectively reviewed all the genetically confirmed cases of RASopathies, including NS, NSML, CFC syndrome, and CS, over the past 29 years (from 1989 to 2017). Analyses of the mutation spectrum and clinical phenotypes were performed. One hundred and ninety-one ethnic Chinese patients with genetically confirmed RASopathies were identified, including 148 patients with NS, 23 NSML, 12 CFC syndrome, and eight CS. We found a lower incidence of hypertrophic cardiomyopathy in individuals with NSML (27.3%), and NS caused by RAF1 mutations (62.5%). Another significant finding was for those NS patients with myeloproliferative disorder, the mutations fall within Exon 3 of PTPN11 but not only restricted to the well-known hotspots, that is, p.Asp61 and p.Thr731, which suggested that re-evaluation of the current tumor surveillance recommendation maybe warranted.

Identification of a PTEN mutation with reduced protein stability, phosphatase activity, and nuclear localization in Hong Kong patients with autistic features, neurodevelopmental delays, and macrocephaly.

PTEN is a tumor suppressor gene inactivated in over 30% of human cancers. It encodes a lipid phosphatase that serves as a gatekeeper of the phosphoinositide 3-kinase signaling pathway. Germline mutation frequently occurs in this gene in patients diagnosed with PTEN Hamartoma Tumor Syndrome (PHTS). PHTS individuals are characterized by macrocephaly, benign growth of multiple tissues and increased tumor risk. In addition, autistic phenotypes are found in 10-20% of individuals carrying the germline PTEN mutation with macrocephaly. In this report, 13 suspected PHTS patients were screened for mutation in the PTEN gene. A missense variant (c. 302T > C) substituting the isoleucine at codon 101 to a threonine, a single nucleotide insertion (c. 327-328insC) causing a frame shift mutation and termination at codon 109, and a nonsense variant (c. 1003C > T) truncated the protein at codon 335 were identified. The I101T mutation significantly reduced PTEN protein expression levels by 2.5- to 4.0-fold. Mechanistically, I101T reduced the protein half-life of PTEN possibly due to enhanced polyubiquitination at Lysine 13. However, the I101T mutant retained almost 30% of the lipid phosphatase activity of the wild-type protein. Finally, the I101T mutant has reduced phosphorylation at a PTEN auto-dephosphorylation site at Threonine 366 and a lowered ratio of nuclear to cytosolic protein level. These partial losses of multiple PTEN biochemical functions may contribute to the tissue overgrowth and autistic features of this PHTS patient. Autism Res 2018, 11: 1098-1109. © 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: The genetics of autism spectrum disorders is highly complex with individual risk influenced by both genetic and environmental factors. Mutation in the human PTEN gene confers a high risk of developing autistic behavior. This report revealed that PTEN mutations occurred in 23% of a selected group of Hong Kong patients harboring autistic features with gross overgrowth symptoms. Detailed characterization of a PTEN mutation revealed reduced protein stability as one of the underlying mechanisms responsible for reduced PTEN activity.

A database linking Chinese patents to China's census firms.

To meet researchers' increasing interest in the fast growing innovation activities taking place in China, we match patents filed with China's State Intellectual Property Office to firms covered in China's Census. China has experienced a strong growth in patent filings over the past two decades, and has since 2011 become the world's top patent filing country. China's Census database covers about one million unique manufacturing firms from 1998-2009, representing the broad Chinese economy. We design data parsing and pre-processing routines to clean and stem firm and assignee names, create a matching algorithm that fits with our data and maintains a balance between matching accuracy and workload of manual check, and implement a systematic manual check process to filter out false positives generated from computerized matching. Our project generates 1,113,588 matches for the Census firms, among which 849,647 patents are uniquely matched. By creating the patent-firm linked dataset, we hope to reduce duplicative effort and encourage more research to better understand China's fast changing innovation landscape.

A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia.

BACKGROUND: Spinocerebellar ataxias (SCAs) are a group of clinically and genetically diverse and autosomal-dominant disorders characterised by neurological deficits in the cerebellum. At present, there is no cure for SCAs. Of the different distinct subtypes of autosomal-dominant SCAs identified to date, causative genes for only a fraction of them are currently known. In this study, we investigated the cause of an autosomal-dominant SCA phenotype in a family that exhibits cerebellar ataxia and pontocerebellar atrophy along with a global reduction in brain volume. METHODS AND RESULTS: Whole-exome analysis revealed a missense mutation c.G1391A (p.R464H) in the coding region of the coiled-coil domain containing 88C (CCDC88C) gene in all affected individuals. Functional studies showed that the mutant form of CCDC88C activates the c-Jun N-terminal kinase (JNK) pathway, induces caspase 3 cleavage and triggers apoptosis. CONCLUSIONS: This study expands our understanding of the cause of autosomal-dominant SCAs, a group of heterogeneous congenital neurological conditions in humans, and unveils a link between the JNK stress pathway and cerebellar atrophy.

Oculopharyngeal muscular dystrophy: underdiagnosed disease in Hong Kong.

Despite the advances in the understanding of the molecular basis for oculopharyngeal muscular dystrophy in the last decade, it remains an underdiagnosed disease, especially among the Chinese. In the presence of a positive family history and late-onset ptosis, dysphagia, and proximal muscle weakness (its cardinal features), we suggest that PABPN1 gene analysis should be the first-line investigation to rule out this condition. Muscle biopsy can be reserved for atypical cases. Non-specific mitochondrial changes in the muscle specimens of these patients should be appreciated, so as to avoid diagnostic confusion. It is hoped that greater awareness among medical professionals and judicious use of PABPN1 gene analysis will lead to earlier diagnosis, better management, and avoidance of unnecessary invasive investigations of affected patients.

Congenital fibrosis of extraocular muscle type 1A due to KIF21A mutation: first case report from Hong Kong.

With the advancement of ophthalmological genetics, the molecular basis for more and more eye diseases can be elucidated. Congenital fibrosis of extraocular muscle (CFEOM) is an example. It is characterised by a congenital non-progressive restrictive ophthalmoplegia and ptosis. It is an autosomal dominant disease, caused by mutations of the KIF21A gene. With positive family history and typical ophthalmological findings, mutational analysis of KIF21A gene should be performed, not only to confirming the diagnosis, but also to offer a prognosis, for genetic counselling, and the possibility of prenatal diagnosis. Here we report the first KIF21A mutation associated with CFEOM1A in Hong Kong.

Risk factors associated with linezolid-nonsusceptible enterococcal infections.

Linezolid is one of few treatment options available for vancomycin-resistant enterococci. The present study investigated risk factors for linezolid-nonsusceptible enterococci using a case-control study of 15 cases and 60 control patients. Previous hospitalization, admission to a medical service, comorbidity, and linezolid and sulfonamide therapy were identified as risk factors.

Singleton birth after preimplantation genetic diagnosis for Huntington disease using whole genome amplification.

OBJECTIVE: To report a successful case of preimplantation genetic diagnosis (PGD) for Huntington disease using whole genome amplification. DESIGN: Case report. SETTING: University assisted reproduction unit. PATIENT(S): A couple with family history of Huntington disease: The husband was carrying the expanded allele of the IT15 gene, and the wife had the normal allele. INTERVENTION(S): Preimplantation genetic diagnosis with whole genome amplification for identification of genetically normal embryos. MAIN OUTCOME MEASURE(S): Live birth. RESULT(S): In an IVF cycle, 15 oocytes were retrieved, of which 13 were mature and 11 were fertilized. On day 3, embryo biopsy and PGD were performed on ten good-quality embryos. Multiple displacement amplification was conducted, followed by polymerase chain reaction with fluorescence primers. Three pairs of primers were used for the amplification of the IT15 gene at the: 1) trinucleotide expansion site; 2) trinucleotide expansion site plus the polymorphic site situated on its 3'-end; and 3) polymorphic marker located downstream of the trinucleotide repeats. Two normal blastocysts were replaced on day 5 and another two good-quality blastocysts were cryopreserved. The woman gave birth to a normal baby girl whose normal genetic status was confirmed by prenatal diagnosis. CONCLUSION(S): Whole genome amplification by multiple displacement amplification can be used for PGD of Huntington disease.

Identification of novel FBN1 and TGFBR2 mutations in 65 probands with Marfan syndrome or Marfan-like phenotypes.

Marfan syndrome is an autosomal dominant connective tissue disorder, and mutations in the FBN1 and TGFBR2 genes have been identified in probands with MFS and related phenotypes. Using DHPLC and sequencing, we studied the mutation spectrum in 65 probands with Marfan syndrome and related phenotypes. A total of 24 mutations in FBN1 were identified, of which 19 (nine missense, six frameshift, two nonsense and two affecting splice junctions) were novel. In the remaining 41 probands, six were identified to have novel TGFBR2 mutations (one frameshift and five missense mutations). All novel mutations found in this study were confirmed to be absent in 50 unrelated normal individuals of the same ethnic background. In probands who fulfilled the Ghent criteria (n = 16), mutations in FBN1 were found in 81% of cases. None of those with TGFBR2 mutations fulfilled the Ghent criteria. Novel missense mutations of unknown significance were classified according to the latest ACMG guidelines and their likelihood to be causative was evaluated.

Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003.

BACKGROUND: Persons who are HIV-infected may be at higher risk for certain types of cancer than the general population. OBJECTIVE: To compare cancer incidence among HIV-infected persons with incidence in the general population from 1992 to 2003. DESIGN: Prospective observational cohort studies. SETTING: United States. PATIENTS: 54,780 HIV-infected persons in the Adult and Adolescent Spectrum of HIV Disease Project (47,832 patients) and the HIV Outpatient Study (6948 patients), who contributed 157,819 person-years of follow-up from 1992 to 2003, and 334,802,121 records from the Surveillance, Epidemiology, and End Results program of 13 geographically defined, population-based, central cancer registries. MEASUREMENTS: Standardized rate ratios (SRRs) to compare cancer incidence in the HIV-infected population with standardized cancer incidence in the general population. RESULTS: The incidence of the following types of non-AIDS-defining cancer was significantly higher in the HIV-infected population than in the general population: anal (SRR, 42.9 [95% CI, 34.1 to 53.3]), vaginal (21.0 [CI, 11.2 to 35.9]), Hodgkin lymphoma (14.7 [CI, 11.6 to 18.2]), liver (7.7 [CI, 5.7 to 10.1]), lung (3.3 [CI, 2.8 to 3.9]), melanoma (2.6 [CI, 1.9 to 3.6]), oropharyngeal (2.6 [CI, 1.9 to 3.4]), leukemia (2.5 [CI, 1.6 to 3.8]), colorectal (2.3 [CI, 1.8 to 2.9]), and renal (1.8 [CI, 1.1 to 2.7]). The incidence of prostate cancer was significantly lower among HIV-infected persons than the general population (SRR, 0.6 [CI, 0.4 to 0.8]). Only the relative incidence of anal cancer increased over time. LIMITATIONS: Lower ascertainment of cancer in the HIV cohorts may result in a potential bias to underestimate rate disparities. Tobacco use as a risk factor and the effect of changes in cancer screening practices could not be evaluated. CONCLUSION: The incidence of many types of non-AIDS-defining cancer was higher among HIV-infected persons than among the general population from 1992 to 2003.

Clinical toxicity of highly active antiretroviral therapy in a home-based AIDS care program in rural Uganda.

BACKGROUND: We evaluated clinical toxicity in HIV-infected persons receiving antiretroviral therapy (ART) in Uganda. METHODS: From May 2003 through December 2004, adults with a CD4 cell count < or =250 cells/microL or World Health Organization stage 3/4 HIV disease were prescribed ART. We calculated probabilities for time to toxicity and single-drug substitution as well as multivariate-adjusted hazard ratios for development of toxicity. RESULTS: ART (stavudine plus lamivudine with nevirapine [96%] or efavirenz [4%]) was prescribed for 1029 adults, contributing 11,268 person-months of observation. Toxicities developed in 543 instances in 411 (40%) patients (incidence rate = 4.47/100 person-months): 36% peripheral neuropathy (9% severe); 6% rash (2% severe); 2% hypersensitivity reaction; < or =0.5% acute hepatitis, anemia, acute pancreatitis, or lactic acidosis; and 13% other. Probabilities of remaining free from any toxicity at 6, 12, and 18 months were 0.76, 0.59, and 0.47 and from any severe toxicity at 6, 12, and 18 months were 0.92, 0.86, and 0.85, respectively. For 217 patients (21%), 222 single-drug substitutions were made, mostly because of peripheral neuropathy or rash. CONCLUSIONS: Clinical toxicities were common, but no patients discontinued ART because of toxicity. The most common toxicities, peripheral neuropathy and rash, were managed with single-drug substitutions. In resource-limited settings, toxicity from ART regimens containing stavudine or nevirapine is manageable but more tolerable regimens are needed.

A study of pH-responsive microgel dispersions: from fluid-to-gel transitions to mechanical property restoration for load-bearing tissue.

An interesting, and potentially important, challenge for colloid scientists is to design injectable dispersions that enable repair of damaged and degenerated tissue. This work presents a study of the ability of pH-responsive microgel particles to restore the mechanical properties of load-bearing soft tissue. Microgel particles are cross-linked polymer colloid particles that are swollen with solvent. The first part of the study consists of an investigation of the pH-triggered swelling of poly(EA/MAA/BDDA) (ethylacrylate, methacrylic acid and 1,4-butanediol diacrylate) microgel particles using photon correlation spectroscopy (PCS) measurements. The concentrated dispersions exhibit a strong fluid-to-gel transition when the pH is increased to above 6.0, i.e., above this pH they form gelled microgel dispersions. The swelling data are used to aid interpretation of the pH-triggered changes in the gel modulus, as probed using dynamic rheology. The second part of the study involves an investigation of the mechanical properties of artificially degenerated, model intervertebral discs (IVDs) containing gelled microgel dispersions. High concentration microgel dispersions were injected as fluids into the interior of degenerated IVDs and the pH increased by subsequent alkaline solution injection to cause particle swelling and dispersion gelation. Uniaxial compression data measured for the IVDs containing injected microgel dispersions indicate that the pH-induced particle swelling of the microgel restores the mechanical properties of degenerated IVDs to values similar to those measured for normal, non-degenerated, IVDs.

Poly(DEAEMa-co-PEGMa): a new pH-responsive comb copolymer stabilizer for emulsions and dispersions.

Stimulus responsive copolymers are an important class of surfactants that are attracting growing attention in the literature. When used to stabilize colloids, they confer responsiveness to an otherwise nonresponsive system. In this work, a new pH-responsive comb copolymer surfactant, poly(DEAEMa-co-PEGMa), where DEAEMa and PEGMa are diethylaminoethyl methacrylate and poly(ethylene glycol) methacrylate, is introduced and used to stabilize emulsions and particulate dispersions. The copolymer contained 70 mol % of DEAEMa. Turbidity versus pH measurements and photon correlation spectroscopy of the copolymer solutions revealed pH-triggered collapse of the chains above the pK(a). The surface activity of the copolymer increased with pH. The minimum surface tension measured was 33.6 mN/m at pH = 10. These data enabled identification of the pK(a) for poly(DEAEMa-co-PEGMa) as 6.8. The emulsions consisted of tetradecane-in-water and had a droplet size in the range 5-11 mum. They were slightly flocculated when the pH value was close to the isoelectric point. The emulsions phase separated at low pH values. The particulate dispersions were based on carbendazim, which is a fungacide, and had an average size of 1.8 mum. The data for the emulsions and carbendazim dispersions show that the extent of flocculation decreases with decreasing size of the dispersed phase. Analysis of the data suggest that optimum emulsion stability occurs in the pH region of 5.3-6.8 as judged by turbidity measurements. Electrophoretic mobility measurements as a function of pH for the emulsions and carbendazim dispersions reveal a similar isoelectric point in the range of 8.5-9.0, which is about two pH units higher than the pK(a) of the copolymer. A mechanism that explains the pH-responsive stability of the emulsions and dispersions is presented and discussed.

Metaphyseal chondrodysplasia McKusick type in a Chinese fetus, caused by novel compound heterozygosity 64T> A and 79G >T in RMRPgene.

We present the first confirmed case by molecular analysis of a metaphyseal chondrodysplasia, McKusick type, in a 22-week fetus. Two novel compound heterozygous mutations, 64T> A and 79G > T, were found in the highly conserved regions of the RMRP gene. Twenty-two heterozygous g.1018 T> C mutations, two homozygous g.1018 T> C mutations, two heterozygous insertion mutations g.799_g.800insC and one heterozygous insertion mutation g.849_g.850insT were found among 100 normal controls. Careful radiological examination of the fetus for skeletal dysplasia allowed definitive diagnosis, proper genetic counselling and future prenatal diagnosis.

A different spectrum of DMD gene mutations in local Chinese patients with Duchenne/Becker muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive, allelic disorders. This study was conducted to look into the spectrum of DMD gene mutations in Hong Kong Chinese patients with Duchenne or Becker muscular dystrophy (DMD/BMD), and to study genotype-phenotype correlation. METHODS: A retrospective review of 67 patients. RESULTS: Twenty-three (34.3%) patients had exon deletions; whereas 5 (7.5%) patients had exon duplications. Twenty-three (34.3%) patients had small mutations, including 17 point mutations and 6 small insertions or deletions. No correlation was found between the type of mutation and the muscle phenotype or mental retardation. Significantly fewer maternal carriers were found in patients with exon deletions, and a positive family history was more common in those with small mutations. DMD phenotype was significantly less common in patients with exon deletions/duplications at the 5' hotspot, whereas all 4 small mutations associated with mental retardation were located in the 3' end of the gene. CONCLUSIONS: The percentage of DMD exon deletions in local Chinese patients was significantly lower than the commonly quoted 60%. This indicated an ethnic or regional difference in predisposition to DMD exon deletions.