Validation and application of health utilities index in Chinese subjects with down syndrome

Objectives: The objectives of the study were (1) to validate the Chinese version of Health Utilities Index (HUI-Ch); (2) to examine the Health-related Quality of Life (HRQoL) of Chinese subjects with Down syndrome (DS); and (3) to study the impact of chronic health conditions on HRQoL of Chinese with DS. Methods: The multiple choice questionnaire for scoring Health Utilities Index Mark 2 (HUI2) and Health Utilities Index Mark 3 (HUI3) was translated and validated. In addition to the HRQoL scores from HUI2 and HUI3, proxy-data on socio-demographics, and 10 common chronic health conditions for people with DS were collected and analyzed. Data analysis involves multiple imputation and multiple regression analysis to predict variations in HRQoL in relation to different factors. Lastly, a gradient interval was constructed on the number of chronic health conditions in relation to HRQoL. Results: HUI-Ch was validated according to standard guidelines. People with DS were found to have a lower HRQoL as compared to the general population, with the majority categorized as moderate or severe on the scale. Behavioral and hearing problems on HUI2, and hearing problems on HUI3 were found to be statistically significant predictors of a lower HRQoL score. A significant gradient relationship existed showing when the number of health problems increased, the HRQoL scores decreased. Conclusions: HUI-Ch is a valid instrument to assess HRQoL. It can have broad application in Chinese subjects with DS including the study of the impact of different chronic health conditions on their quality of life. The quantifiable nature of HUI-Ch will facilitate longitudinal study on the well-being of subjects with DS and evaluation of effectiveness of intervention programs in the near future

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV

Physical measurements of Chinese children in Hong Kong

Background: Growth is defined as an increase in size over time. It is the essence of the developing organism. Growth of different parts of body follow a predictable schedule in normal development and any disturbance, genetic or environmental, will lead to disproportion of physical features. Most syndromes with dysmorphic features demonstrate recognizable patterns of disproportionate growth and thus physical measurement is important in the evaluation of children and adults with dysmorphic features and/or structural anomalies. In order to delineate if growth of a person is normal, a reference must be used for comparison. However the currently available reference data are mostly derived from children of restricted ethnic and geographic background which has been shown to be not equally applicable to all children due to substantial ethnic variability. Regional specific data for body parts is necessary to establish accurate reference for different ethnicities which is limited beyond the neonatal period. The aim of our pilot study is to obtain a set of region specific physical measurements of Chinese children from kindergartens in Hong Kong. Methods: In this cross-sectional study, we recruited children between 2 to 6 years old from kindergartens in Hong Kong. Consent for participation was obtained from school principal and informed consent was obtained from parents for each participant. Other than the 24 growth parameters included in the “Neonatal anthropometry for the Chinese” by Fok et al, we included 3 other parameters and followed the definition and instruction of measurements recommended by the same book as well as the “Handbook of Physical Measurements” by Hall et al. with minor modification. Measurement of penile length was not performed due to objections from schools and thus only 26 parameters were measured. Three measurers performed the measurements in kindergartens. They received training from a clinical geneticist and have achieved a satisfactory inter-rater reliability in a training cohort for each parameter before starting the study. The raw anthropometric data collected were then normalized and fitted into a model by LMS method. A growth curve was plotted for each of the 26 anthropometric measurements. Results and Discussion: For inter-rater reliability, an average Cronbach’s alpha of 0.927 (excellent internal consistency) were achieved. We recruited a total of 439 children between 3 to 6 years old from 5 participating kindergartens, 3 in Kwai Tsing District and one each in Kowloon City and Yuen Long Districts. Two year-olds were excluded due to small sample size. There are a total of 244 boys and 195 girls. Subjects were grouped according to their age. The number of subjects in each age group were: 3 years old: 112 (57.1% male); 4 years old: 160 (51.3% male); 5 years old: 131 (54.2% male); and 6 years old: 36 (75% male). Since no difference were observed between male and female in all of the measurements, therefore data were combined when plotting growth curves. The 3rd, 10th, 25th, 50th, 75th, 90th and 97th percentile lines were presented in the growth curves. Significant differences were identified compared to the Caucasian data in different important growth parameters including the outer canthal distance, the inner canthal distance, facial width, facial height and sternal length. Our current pilot study presents the first local and ethnicity specific data on physical measurements on children between the ages of 3 to 6 years old. And important differences are noted in the growth parameters between local Chinese children and their Caucasian counterparts. Of all the comparisons, the biggest differences existed in the measurement of facial width and facial height. For facial width, the -2 standard deviation of the Chinese coincided with the +2 standard deviation of the Caucasian data. Our findings highlighted the substantial ethnic variability in physical measurement and thus the need for an ethnic-specific reference for Chinese children. A more comprehensive study including more Chinese children and adults of different age groups is warranted to capture the full-spectrum ethnic-specific population reference in a longitudinal manner.published_or_final_versionObstetrics and GynaecologyMasterMaster of Medical Science

Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder—implications of a copy number variation involving DPP10

Abstract Background Array comparative genomic hybridization (aCGH) is recommended as a first-tier genetic test for children with autism spectrum disorder (ASD). However, interpretation of results can often be challenging partly due to the fact that copy number variants (CNVs) in non-European ASD patients are not well studied. To address this literature gap, we report the CNV findings in a cohort of Chinese children with ASD. Methods DNA samples were obtained from 258 Chinese ASD patients recruited from a child assessment center between January 2011 and August 2014. aCGH was performed using NimbleGen-CGX-135k or Agilent-CGX 60k oligonucleotide array. Results were classified based on existing guidelines and literature. Results Ten pathogenic CNVs and one likely pathogenic CNV were found in nine patients, with an overall diagnostic yield of 3.5%. A 138 kb duplication involving 3′ exons of DPP10 (arr[GRCh37] 2q14.1(116534689_116672358)x3), reported to be associated with ASD, was identified in one patient (0.39%). The same CNV was reported as variant of uncertain significance (VUS) in DECIPHER database. Multiple individuals of typical development carrying a similar duplication were identified among our ancestry-matched control with a frequency of 6/653 (0.92%) as well as from literature and genomic databases. Conclusions The DPP10 duplication is likely a benign CNV polymorphism enriched in Southern Chinese with a population frequency of ~1%. This highlights the importance of using ancestry-matched controls in interpretation of aCGH findings