Tsan Yuk Hospital

The Hong Kong Museum of Medical Sciences was honoured to receive the precious donation of a casebook from a senior midwife, Mrs Kai-ying Poon Yam, who underwent midwifery training during the 1940s in Hong Kong. Mrs Poon continued to serve as a midwife until her retirement in 1978. The

Traditional carrier screening has been utilized for the detection of carriers of genetic disorders. Since a comprehensive assessment of the carrier frequencies of recessive conditions in the Southern Chinese population is not yet available, 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. In alignment with current American College of Obstetricians and Gynecologists (ACOG) pan-ethnic carrier recommendations, 1 in 26 individuals were identified as carriers of cystic fibrosis, thalassemia, and spinal muscular atrophy in the Southern Chinese population. When the >1% expanded carrier screening rate recommendation by ACOG was used, 11 diseases were found to meet the criteria in the Southern Chinese population. Approximately 1 in 3 individuals (35.5% of the population) were carriers of these 11 conditions. If the 1 in 200 carrier frequency threshold is used, and additional seven genes would meet the criteria, and 2 in 5 individuals (38.7% of the population) would be detected as a carrier. This study provides a comprehensive catalogue of the carrier spectrum and frequency in the Southern Chinese population and can serve as a reference for careful evaluation of the conditions to be included in expanded carrier screening for Southern Chinese people.

BackgroundWe report here clinical, cytogenetic and molecular data for a pair of monochorionic diamniotic twins with paternal isodisomy for chromosome 19. Both twins presented with dysmorphic features and global developmental delay. This represents, to our knowledge, the first individual human case of paternal uniparental disomy for chromosome 19 (UPD19).MethodsWhole-exome sequencing, together with conventional karyotype and SNP array analysis were performed along with genome-wide DNA methylation array for delineation of the underlying molecular defects.ResultsConventional karyotyping on amniocytes and lymphocytes showed normal karyotypes for both twins. Whole-exome sequencing did not identify any pathogenic sequence variants but >5000 homozygous exonic variants on chromosome 19, suggestive of UPD19. SNP arrays on blood and buccal DNA both showed paternal isodisomy for chromosome 19. Losses of imprinting for known imprinted genes on chromosome 19 were identified, including ZNF331, PEG3, ZIM2 and MIMT1. In addition, imprinting defects were also identified in genes located on other chromosomes, including GPR1-AS, JAKMP1 and NHP2L1.ConclusionImprinting defects are the most likely cause for the dysmorphism and developmental delay in this first report of monozygotic twins with UPD19. However, epigenotype-phenotype correlation will require identification of additional individuals with UPD19 and further molecular analysis.

According to the published work, pregnancy termination rates due to prenatal diagnosis of fetal sex chromosome aneuploidies (SCA) vary widely. Some potentially modifiable and non-modifiable factors have been reported to be associated with parental decision. This study aimed to evaluate the rate of pregnancy termination for fetal SCA and the factors influencing parents' decisions in Hong Kong. This was a 21-year retrospective cohort study of parents' decisions following prenatal diagnosis of SCA. Univariate and multivariate analyses for the association between demographic factors, prenatal factors, or counseling provided and decision-making were conducted. The study included 399 pregnancies with prenatal diagnosis of SCA and the overall termination rate was 55.6% (91.7%, 48.0%, 23.4%, 4.8%, and 22.7% for 45,X, 47,XXY, 47,XXX, 47,XYY, and mosaicism, respectively). Pregnancies with ultrasound abnormalities were associated with higher termination rates than pregnancies with normal ultrasound findings (91.3% vs 28.3%, P < 0.0001). From multivariate regression analysis on 226 pregnancies with normal ultrasound examination, a higher likelihood to terminate was found in pregnancies affected by 45,X and 47,XXY (adjusted odds ratio, 4.72, P < 0.0001). Increased maternal age and history of infertility were associated with lower likelihood to terminate (adjusted odds ratio, 0.9, P = 0.012; and 5.12, P = 0.038, respectively). The pregnancy termination rate declined over time. A significant correlation was found between the termination of SCA-affected pregnancy and the presence of fetal sonographic abnormalities, type of SCA, maternal age, and presence of infertility.

Hydrops fetalis is commonly due to Hb Bart’s (γ4) disease in South East Asia. Here, we report an unusual case of hydrops fetalis due to congenital dyserythropoietic anemia (CDA) associated with compound heterozygosity for Krüppel-like factor 1 (KLF1) gene mutations. Fetal cardiomegaly was first detected on routine mid-trimester scan in a pregnant woman with normal mean corpuscular volume (MCV) and Rhesus positive status. The fetus subsequently developed hydrops fetalis, and cordocentesis showed severe fetal anemia with a hemoglobin (Hb) level of 3.4 g/dL. Common causes of fetal anemia including Hb Bart’s disease, parvovirus infection, and red cell antibodies were excluded. In view of the marked increase in erythroblasts at various stages of erythropoiesis, the diagnosis of CDA was suspected. We screened the couple for previously reported KLF1 gene mutations, showing that the mother was heterozygous for the c.525_526insCGGCGCC, p.Gly176Argfs*179 mutation, and her husband heterozygous for c.1012C>A, p.Pro338Thr mutation. The fetus was a compound heterozygote for these two KLF1 mutations. After counseling, repeated intrauterine transfusions were given at 27, 29, and 34 weeks’ gestation; the hydrops fetalis was resolved. The baby was delivered at 34 weeks’ gestation and required monthly blood transfusions but was otherwise thriving. Bone marrow aspiration at 10 months of age showed the features of ineffective erythropoiesis, compatible with CDA. In conclusion, hydrops fetalis can rarely be due to CDA associated with a compound heterozygous mutation for KLF1 gene mutations, and be managed by repeated intrauterine transfusions. Our present report adds to the wide clinical spectrum of KLF1 mutations.

Objective: To investigate the outcome of fetuses with cystic hygroma (CH) diagnosed at the first trimester from a general population in Hong Kong.Method: This was a prospective study of 30 fetal cystic hygroma detected at 11 to 13 + 6 weeks’ gestation in 8835 sequential unselected pregnancies. Fetal cystic hygroma was categorized as isolated cystic hygroma (ICH) or associated cystic hygroma (ACH) according to the presence of associated multiple congenital structural abnormalities (MCA).Results: There were 10 cases of ICH and 20 cases of ACH. The karyotypes were obtained in 29 cases. In the ICH, 30% (3/10) were associated with chromosomal abnormalities. In the ACH, 65% (13/20) were associated with major chromosomal abnormalities.Conclusion: This study suggests that the prognosis of cystic hygroma detected in the first trimester is guarded, with high incidence of MCA (66.7%, 20/30) and chromosomal abnormalities (53.3%, 16/30). The findings support detailed ultrasound examination and invasive prenatal diagnosis for cystic hygroma.

Gene expression profiling aimed at classifying and prognosing breast cancer has yielded signatures with little, if any, concordance. However, expression arrays used in these studies do not discriminate alternate RNA splice isoforms that vary widely in cancer and may resolve this problem. In this study, we profiled splice isoforms in a panel of tamoxifen-sensitive and -resistant cell lines, defining a novel variant (BQ323636.1) of the nuclear receptor corepressor 2 (NCOR2) that was associated with tamoxifen resistance. Overexpression of this variant in a tamoxifen-sensitive cell line induced its resistance to tamoxifen. We confirmed our initial findings from cell lines in 77 breast tumors from a Chinese cohort, where BQ323636.1 expression was higher in tamoxifen-resistant patients than tamoxifen-sensitive patients. For patients who were estrogen receptor (ER)-positive and had received tamoxifen treatment, higher BQ323636.1 expression level correlated with distant metastasis. High expression level of BQ323636.1 was found to be associated with poorer overall and disease-free survival for patients who had received tamoxifen treatment. Notably, higher BQ323636.1 versus NCOR2 wild-type ratio was also associated with negative ER and progesterone receptor (PR) status, and triple-negative status (ER-/PR-/HER2- receptor status). Mechanistic investigations showed that under conditions of tamoxifen exposure, BQ323636.1 suppressed the transcriptional activity of ERα, exhibiting promoter-regulating functions. Our findings highlight a novel splice variant of the ERα corepressor NCOR2 as a candidate biomarker in breast cancer that not only predicts tamoxifen response but may be targeted to overcome tamoxifen resistance.

Introduction: Epidemiologic studies suggest that multiple cardiovascular (CVD) protection-factors (i.e., non-smoking, physically active, normal blood pressure, normal blood glucose, normal total cholesterol, non-obese, and healthy diet) are associated with significantly reduced risk of cardiovascular disease incidence and mortality. Hypothesis: We assessed the hypothesis that the increased number of CVD protection-factors is associated with reduced risk for all-cause and CVD mortality and adherence to low CVD risk profile could result in significant lower rates of all-cause and CVD mortality. Methods: We used the Third National Health and Nutrition Examination Survey (NHANES III 1988-1994) Linked Mortality File (through 2006), a prospective cohort study of a nationally representative sample of 12,861 U.S. adults to examine the prevalence, associations, and population attributable fraction (PAF) of seven CVD protection-factors in relation to risk of all-cause and CVD mortality. Results: Only 3.1% of U.S. adults had all seven CVD protection-factors. The average follow-up was 14.5 years. After multivariable adjustment for potential confounders, hazard ratios (HR) were: 0.30 (95% CI 0.22-0.40), 0.21 (0.12-0.34), and 0.17 (0.09-0.32), comparing individuals with ≥six protection-factors to those with ≤one protection-factors for all-cause, CVD, and IHD mortality respectively. Elevated blood pressure was responsible for the largest number of all-cause and CVD death followed by smoking and poor diet. Overall, 59% (95% CI 27-78) of total deaths and 66% (95% CI 22-88) CVD death would have been avoided during the average of 14.5 years follow-up if the population were changed to the high CVD protection-factors status (with ≥six protection-factors). Conclusions: Few adults in this U.S.-based study population had all seven desirable CVD protection-factors. The presence of an increasing number of CVD protection-factors was associated with a progressively lower risk of total and CVD mortality. Comprehensive population-based initiatives are needed to improve modifiable CVD risk factors, resulting in substantial reductions of all-cause and CVD mortality in the U.S. population.