Pre-implantation genetic diagnosis in Hong Kong

This paper presents the first two successful cases of pre-implantation genetic diagnosis in Hong Kong and discusses the indications and the advantages over prenatal diagnosis. Patients should be informed about the procedure and extensively counselled about the possibility of misdiagnosis and the need for conventional prenatal diagnosis during pregnancy.published_or_final_versio

Prenatal Diagnosis of Agenesis of the Corpus Callosum and Cerebellar Vermian Hypoplasia Associated with a Microdeletion on Chromosome 1p32

We present the prenatal detection of a 1p32.1p31.3 microdeletion (3.46 Mb) by array comparative genomic hybridization (CGH) associated with fetal agenesis of the corpus callosum (ACC) and cerebellar vermian hypoplasia. Analysis of cultured amniocytes showed a normal karyotype. Our observations strengthen the association between this locus and central nervous system development. In addition, the fetus reported herein underscores the importance of array CGH analysis when ACC is detected prenatally, especially when there are additional central nervous system anomalies, to search for submicroscopic imbalances which can facilitate further management and parental counselling. Moreover, the presence of urinary tract anomalies should alert the clinician to the possibility of a 1p interstitial deletion, although the absence of such does not exclude it. Further reports will help to provide more information on the long-term outcomes of individuals with such microdeletion as there are only limited data.published_or_final_versio

Rapid aneuploidy testing (knowing less) versus traditional karyotyping (knowing more) for advanced maternal age: What would be missed, who should decide?

Objectives The application of rapid aneuploidy testing as a stand-alone approach in prenatal diagnosis is much debated. The major criticism of this targeted approach is that it will not detect other chromosomal abnormalities that will be picked up by traditional karyotyping. This study aimed to study the nature of such chromosomal abnormalities and whether parents would choose to terminate affected pregnancies. Design Retrospective study on a cytogenetic database. Setting Eight public hospitals in Hong Kong. Participants The karyotype results of 19 517 amniotic fluid cultures performed for advanced maternal age (≥35 years) from 1997 to 2002 were classified according to whether they were detectable by rapid aneuploidy testing. The outcomes of pregnancies with abnormal karyotypes were reviewed from patient records. Results In all, 333 (1.7%) amniotic fluid cultures yielded abnormal karyotypes; 175 (52.6%) of these were detected by rapid aneuploidy testing, and included trisomy 21 (n=94, 28.2%), trisomy 18 or 13 (n=21, 6.3%), and sex chromosome abnormalities (n=60, 18.0%). The other 158 (47.4%) chromosomal abnormalities were not detectable by rapid aneuploidy testing, of which 63 (18.9%) were regarded to be of potential clinical significance and 95 (28.5%) of no clinical significance. Pregnancy outcomes in 327/333 (98.2%) of these patients were retrieved. In total, 143 (42.9%) of these pregnancies were terminated: 93/94 (98.9%) for trisomy 21, 20/21 (95.2%) for trisomy 18 or 13, 19/60 (31.7%) for sex chromosome abnormalities, and 11/63 (17.5%) for other chromosomal abnormalities with potential clinical significance. There were no terminations in the 95 pregnancies in which karyotyping results were regarded to be of no clinical significance. Conclusions 'Knowing less' by the rapid aneuploidy stand-alone testing could miss about half of all chromosomal abnormalities detectable by amniocentesis performed for advanced maternal age. Findings from two fifths of the latter were of potential clinical significance, and the parents chose to terminate one out of six of the corresponding pregnancies. If both techniques are available, parents could have enhanced autonomy to choose.published_or_final_versio

The clinical impact of chromosomal microarray on paediatric care in Hong Kong

Objective To evaluate the clinical impact of chromosomal microarray (CMA) on the management of paediatric patients in Hong Kong. Methods We performed NimbleGen 135k oligonucleotide array on 327 children with intellectual disability (ID)/developmental delay (DD), autism spectrum disorders (ASD), and/or multiple congenital anomalies (MCAs) in a university-affiliated paediatric unit from January 2011 to May 2013. The medical records of patients were reviewed in September 2013, focusing on the pathogenic/likely pathogenic CMA findings and their “clinical actionability” based on established criteria. Results Thirty-seven patients were reported to have pathogenic/likely pathogenic results, while 40 had findings of unknown significance. This gives a detection rate of 11% for clinically significant (pathogenic/likely pathogenic) findings. The significant findings have prompted clinical actions in 28 out of 37 patients (75.7%), while the findings with unknown significance have led to further management recommendation in only 1 patient (p<0.001). Nineteen out of the 28 management recommendations are “evidence-based” on either practice guidelines endorsed by a professional society (n = 9, Level 1) or peer-reviewed publications making medical management recommendation (n = 10, Level 2). CMA results impact medical management by precipitating referral to a specialist (n = 24); diagnostic testing (n = 25), surveillance of complications (n = 19), interventional procedure (n = 7), medication (n = 15) or lifestyle modification (n = 12). Conclusion The application of CMA in children with ID/DD, ASD, and/or MCAs in Hong Kong results in a diagnostic yield of ∼11% for pathogenic/likely pathogenic results. Importantly the yield for clinically actionable results is 8.6%. We advocate using diagnostic yield of clinically actionable results to evaluate CMA as it provides information of both clinical validity and clinical utility. Furthermore, it incorporates evidence-based medicine into the practice of genomic medicine. The same framework can be applied to other genomic testing strategies enabled by next-generation sequencing.published_or_final_versio

Whole-Genome Array CGH Evaluation for Replacing Prenatal Karyotyping in Hong Kong

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Diagnostic yield of array CGH in patients with autism spectrum disorder in Hong Kong

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

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Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study.

To validate the clinical efficacy and practical feasibility of massively parallel maternal plasma DNA sequencing to screen for fetal trisomy 21 among high risk pregnancies clinically indicated for amniocentesis or chorionic villus sampling. Diagnostic accuracy validated against full karyotyping, using prospectively collected or archived maternal plasma samples. Prenatal diagnostic units in Hong Kong, United Kingdom, and the Netherlands. 753 pregnant women at high risk for fetal trisomy 21 who underwent definitive diagnosis by full karyotyping, of whom 86 had a fetus with trisomy 21. Intervention Multiplexed massively parallel sequencing of DNA molecules in maternal plasma according to two protocols with different levels of sample throughput: 2-plex and 8-plex sequencing. Proportion of DNA molecules that originated from chromosome 21. A trisomy 21 fetus was diagnosed when the z score for the proportion of chromosome 21 DNA molecules was >3. Diagnostic sensitivity, specificity, positive predictive value, and negative predictive value were calculated for trisomy 21 detection. Results were available from 753 pregnancies with the 8-plex sequencing protocol and from 314 pregnancies with the 2-plex protocol. The performance of the 2-plex protocol was superior to that of the 8-plex protocol. With the 2-plex protocol, trisomy 21 fetuses were detected at 100% sensitivity and 97.9% specificity, which resulted in a positive predictive value of 96.6% and negative predictive value of 100%. The 8-plex protocol detected 79.1% of the trisomy 21 fetuses and 98.9% specificity, giving a positive predictive value of 91.9% and negative predictive value of 96.9%. Multiplexed maternal plasma DNA sequencing analysis could be used to rule out fetal trisomy 21 among high risk pregnancies. If referrals for amniocentesis or chorionic villus sampling were based on the sequencing test results, about 98% of the invasive diagnostic procedures could be avoided.published_or_final_versio

Array CGH testing in prenatal diagnosis: a promising new service with improved diagnostic yield and shortened reporting time

Eletronic Presentation: abstract no. 904Conference Theme: Enhancing Health - 協作同心‧醫澤社群INTRODUCTION: Array Comparative Genomic Hybridization (aCGH) with genome-wide coverage has proved to be valuable for postnatal and prenatal studies. Traditionally, prenatal diagnosis of chromosomal abnormalities has relied on conventional cytogenetics which required cell culture and chromosome analysis under micro…postprin

Copy number variation in Hong Kong patients with autism spectrum disorder

Oral Free Paper Session: Oral Presentation 6 [best oral presentation]BACKGROUND AND AIMS: When offering chromosomal microarray for patients with autism spectrum disorder (ASD), as according to international standards, copy number variations of uncertain significance (CNV VUS) are frequently identified, which leads to challenges in genetic counselling. We aim to study the CNV findings in children with ASD in Hong Kong, and to gather information for reclassification of recurrent CNV VUS. METHODS: ASD patients from the Department of Paediatrics and Adolescent Medicine QMH/HKU were recruited if their Array Comparative Genomic Hybridization (aCGH) were done anytime from January 2011 to August 2014 in Prenatal Diagnostic Laboratory, Tsan Yuk Hospital. Diagnosis of ASD was made by developmental paediatricians and clinical psychologists using the criteria from Diagnostic and Statistical Manual of Mental Disorders, Fourth or Fifth Edition. NimbleGen CGX-135k oligonucleotide array and Agilent CGX 60k oligonucleotide array were used. Information was summarised from the literature and existing databases to re-classify CNV VUS occurring in our ASD cohort. RESULTS: Among 288 patients with ASD in our cohort, we identified 5 patients with pathogenic CNV (1.74%) and 5 patients with likely pathogenic CNV (1.74%). Among all the CNV VUS, one variant overlapping DPP10 (hg[19] chr2:116,534,689-116,672,358) was recurrently found in Chinese individuals. The frequency of this variant in our ASD cohort was 0.35% (1 in 288), and 0.96% (9 in 935) in our controls. (P=0.467, two-tailed Fisher’s exact test). Similar CNVs were suggested to be ASD-related in previous studies recruiting mainly Caucasians. However, there were Chinese individuals with typical development possessing similar CNVs identified in independent sources (9 from our internal database, 1 from Singapore Genome Variation Project, 24 from The Singapore Prospective Study Program). CONCLUSIONS: Our study explored the CNV findings in Hong Kong paediatric ASD patients. The CNV overlapping DPP10 may be a Chinese-related copy-number variation in Hong Kong Chinese, and we reclassified it to be likely benign in our locality. Our result emphasized the need to account for ethnicity to give the most precise interpretation of aCGH data.published_or_final_versio