Immediate postpartum cessation of tenofovir did not increase risk of virological or clinical relapse in highly viremic pregnant mothers with chronic hepatitis B infection.

Background & Aims: Peripartum prophylaxis (PP) with tenofovir disoproxil fumarate (TDF) is the standard of care to prevent mother-to-child transmission of chronic hepatitis B (CHB) infection in mothers who are highly viremic. We investigated the maternal and infant outcomes in a large Chinese cohort of TDF-treated CHB pregnant participants. Methods: In this prospective study, treatment-naive mothers with CHB and highly viremic (HBV DNA ≥200,000 IU/ml) but without cirrhosis were treated with TDF at 24-28 weeks of pregnancy. In accordance with Chinese CHB guidelines, TDF was stopped at delivery or ≥4 weeks postpartum. Serum HBV DNA and alanine aminotransferase were monitored every 6-8 weeks to determine virological relapse (VR). Infants received standard neonatal immunization, and HBV serology was checked at 7-12 months of age. Results: Among 330 participants recruited (median age 30, 82.7% HBeAg+, median HBV DNA 7.82 log IU/ml), TDF was stopped at delivery in 66.4% and at ≥4 weeks in 33.6%. VR was observed in 98.3%, among which 11.6% were retreated with TDF. Timing of TDF cessation did not alter the risk of VR (99.0 vs. 96.9%), clinical relapse (19.5 vs. 14.3%), or retreatment (12.6 vs. 10.1%) (all p > 0.05). A similar proportion of patients developed alanine aminotransferase flare five times (1.1 vs. 2.1%; p = 0.464) and 10 times (0.5 vs. 0%; p = 0.669) above the upper limit of normal (ULN) in the early withdrawal and late withdrawal groups, respectively. No infants developed HBsAg-positivity. Conclusions: PP-TDF and neonatal immunization were highly effective in preventing mother-to-child transmission of HBV in mothers who are highly viremic. Timing of cessation of PP-TDF did not affect the risk of VR or retreatment. Impact and Implications: In pregnant mothers with chronic hepatitis B infection who are started on peripartum tenofovir to prevent mother-to-child-transmission (MTCT), the optimal timing for antiviral withdrawal during the postpartum period remains unknown. This prospective study demonstrates that stopping tenofovir immediately at delivery, compared with longer treatment duration of tenofovir, did not lead to an increased risk of virological relapse, retreatment, or transmission of the virus to the baby. Shortening the duration of peripartum antiviral prophylaxis from 12 weeks to immediately after delivery can be considered. The immediate withdrawal of peripartum tenofovir, combined with standard neonatal immunization schemes, is 100% effective in preventing MTCT among pregnant mothers with CHB who are highly viremic, with a high rate of vaccine response in infants.

Fetal Hyperthyroidism with Maternal Hypothyroidism: Two Cases of Intrauterine Therapy.

Fetal hyperthyroidism can occur secondary to maternal autoimmune hyperthyroidism. The thyroid-stimulating hormone receptor antibody (TRAb) transferred from the mother to the fetus stimulates the fetal thyroid and causes fetal thyrotoxicosis. Fetuses with this condition are difficult to detect, especially after maternal Graves disease therapy. Here, we present two cases of fetal hyperthyroidism with maternal hypothyroidism and review the assessment and intrauterine therapy for fetal hyperthyroidism. Both women were referred at 22+ and 23+ weeks of gestation with abnormal ultrasound findings, including fetal heart enlargement, pericardial effusion, and fetal tachycardia. Both women had a history of Graves disease while in a state of hypothyroidism with a high titer of TRAb. A sonographic examination showed a diffusely enlarged fetal thyroid with abundant blood flow. Invasive prenatal testing revealed no significant chromosomal aberration. Low fetal serum TSH and high TRAb levels were detected in the cord blood. Fetal hyperthyroidism was considered, and maternal oral methimazole (MMI) was administered as intrauterine therapy, with the slowing of fetal tachycardia, a reduction in fetal heart enlargement, and thyroid hyperemia. During therapy, maternal thyroid function was monitored, and the dosage of maternal levothyroxine was adjusted accordingly. Both women delivered spontaneously at 36+ weeks of gestation, and neonatal hyperthyroidism was confirmed in both newborns. After methimazole and propranolol drug treatment with levothyroxine for 8 and 12 months, both babies became euthyroid with normal growth and development.

20 years review of antenatal diagnosis of haemoglobin Bart's disease and treatment with intrauterine transfusion.

OBJECTIVE: To review prenatal diagnosis and outcome of alpha thalassaemia major through universal antenatal screening. METHOD: This was a retrospective study on ultrasound features, antenatal diagnosis, in-utero intervention and long term outcome of pregnancies at risk of Haemoglobin Bart's hydrops foetalis syndrome attending prenatal diagnosis from 2000 to 2019 at Tsan Yuk Hospital in Hong Kong. RESULTS: Among 390 foetuses from 373 at-risk pregnancies, 122 (31%) prenatal invasive procedures were performed and 65 affected foetuses were diagnosed antenatally. For foetuses with ultrasound features of anaemia, the diagnostic yield of BHFS was 73%. Cardiomegaly carried a positive predictive value of 65.2% while its absence had the highest negative predictive value (96.0%). Three women having affected foetuses continued pregnancy and received intrauterine transfusion beginning 20 weeks of gestation. All babies were born alive and non-hydropic. They were managed with regular transfusion and cured by haematopoietic stem cell transplantation. CONCLUSIONS: Absence of ultrasound features of anaemia had high negative predictive value for alpha thalassaemia major. Couple at risk of having affected foetus could be offered serial ultrasound surveillance. Invasive testing for pregnancies with features of foetal anaemia provided high diagnostic yield. Intrauterine transfusion corrected foetal anaemia and allowed long term transfusion free survival without significant neurological sequelae following postnatal transplant therapy.

Expanded Carrier Screening in Chinese Population - A Survey on Views and Acceptance of Pregnant and Non-Pregnant Women.

OBJECTIVE: Recessive genetic diseases impose physical and psychological impacts to both newborns and parents who may not be aware of being carriers. Expanded carrier screening (ECS) allows screening for multiple genetic conditions at the same time. Whether or not such non-targeted panethnic approach of genetic carrier screening should replace the conventional targeted approach remains controversial. There is limited data on view and acceptance of ECS in general population, as well as the optimal timing of offering ECS to women. This study assesses views and acceptance of ECS in both pregnant women and non-pregnant women seeking fertility counseling or checkup and their reasons for accepting or declining ECS. MATERIALS AND METHODS: This is a questionnaire survey with ECS information in the form of pamphlets distributed from December 2016 to end of 2018. Women were recruited from the antenatal clinics and the assisted reproductive unit at the Department of Obstetrics and Gynaecology, Queen Mary Hospital and the prepregnancy counseling clinic at the Family Planning Association of Hong Kong. RESULTS: A total of 923 women were recruited: 623 pregnant women and 300 non-pregnant women. There were significantly more non-pregnant women accepting ECS compared to pregnant women (70.7% vs. 61.2%). Eight hundred and sixty-eight (94%) women perceived ECS as at least as effective as or superior to traditional targeted screening. Significantly more pregnant women have heard about ECS compared with non-pregnant women (42.4% vs. 32.3%, P = 0.0197). Majority of women showed lack of understanding about ECS despite reading pamphlets that were given to them prior to filling in the questionnaires. Cost of ECS was a major reason for declining ECS, 28% (n = 256). Significantly more pregnant women worried about anxiety caused by ECS compared with the non-pregnant group (21.1% vs. 7.4%, P = 0.0006). CONCLUSION: Our study demonstrates that expanded carrier screening was perceived as a better screening by most women. Prepregnancy ECS maybe a better approach than ECS during pregnancy, as it allows more reproductive options and may cause less anxiety. Nevertheless, implementation of universal panethnic ECS will need more patient education, ways to reduce anxiety, and consensus on optimal timing in offering ECS.

Prenatal diagnosis and long-term follow-up of a Chinese patient with mosaic variegated aneuploidy and its molecular analysis.

Mosaic variegated aneuploidy (MVA) is a rare genetic disorder caused by mutations in BUB1B, CEP57, or TRIP13. We describe the prenatal diagnosis, molecular characterization, and clinical management of a long-lived patient with BUB1B-related MVA.

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

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.

Fetomaternal hemorrhage syndrome in a single fetus in dichorionic diamniotic twin pregnancy: a case report / 中华围产医学杂志

Fetomaternal hemorrhage (FMH) syndrome refers to a group of symptoms, including fetal anemia and maternal hemolytic transfusion reaction caused by fetal blood entering the maternal circulation through intervillous space. Diagnosis of FMH can be easily missed due to its non-specific symptoms and may lead to high perinatal mortality. The degree of fetal anemia and the volume of blood loss can be clinically evaluated by ultrasound measurement of middle cerebral artery peak systolic velocity and Kleihauer-Betke test. Clinical management is based on the degree of fetal anemia and gestational age. Intrauterine blood transfusion and termination are standard management. Fetal-maternal transfusion over 20 ml/kg is associated with fetal/neonatal morbidity or mortality. The incidence of FMH in twin pregnancy is rarely reported. We here report a case of dichorionic diamniotic twin pregnancy. Intrauterine death occurred to one of the twins because of FMH, and the other fetus was delivered at term with good outcome based on close monitoring.

Prenatal diagnosis of 5p deletion syndrome: Report of five cases.

It is difficult to prenatally identify 5p deletion (-) syndrome. Here, we report five cases of 5p- syndrome diagnosed by invasive prenatal diagnosis. Of them, three had a small cerebellum in the second trimester. In one case, a prominent renal pelvis and an absent nasal bone were also found in the first trimester. However, there were no abnormal ultrasound findings in the other two cases. Two cases had noninvasive prenatal testing and one showed a '5p- syndrome positive result' because of reduced amount of cell-free DNA in 5p. Two had combined first-trimester screening performed where one had a high-risk result for trisomy 18 and a low pregnancy-associated plasma protein-A level. Two cases of 5p- syndrome resulted from a parental balanced translocation. Prenatal diagnosis will only be made on invasive prenatal diagnosis for abnormal ultrasound findings with small cerebellum, abnormal prenatal screening or a parental reciprocal translocation involving 5p.

Experience of chromosomal microarray applied in prenatal and postnatal settings in Hong Kong.

Chromosomal microarray (CMA) is recommended as a first tier investigation for patients with developmental delay (DD), intellectual disability (ID), autistic spectrum disorder (ASD), and multiple congenital anomalies (MCA). It is widely used in the prenatal and postnatal settings for detection of chromosomal aberrations. This is a retrospective review of all array comparative genomic hybridization (aCGH/ array CGH) findings ascertained in two major prenatal and postnatal genetic diagnostic centers in Hong Kong from June 2012 to December 2017. Medical records were reviewed for cases with pathogenic and variants of uncertain clinical significance (VUS). Classification of copy number variants (CNVs) was based on current knowledge and experience by August 2018. The aims of this review are to study the diagnostic yield of array CGH application in prenatal and postnatal settings in Hong Kong and to describe the spectrum of abnormalities found. Prenatal indications included abnormal ultrasound findings, positive Down syndrome screening, abnormal noninvasive prenatal test results, advanced maternal age and family history of chromosomal or genetic abnormalities. Postnatal indications included unexplained DD, ID, ASD, and MCA. A total of 1,261 prenatal subjects and 3,096 postnatal patients were reviewed. The prenatal diagnostic yield of pathogenic CNV and VUS (excluding those detectable by karyotype) was 3.5%. The postnatal diagnostic yield of pathogenic CNV was 15.2%. The detection rates for well-defined microdeletion and microduplication syndromes were 4.6% in prenatal and 6.1% (1 in 16 index patients) in postnatal cases, respectively. Chromosomes 15, 16, and 22 accounted for over 21 and 25% of pathogenic CNVs detected in prenatal and postnatal cohorts, respectively. This review provides the first large scale overview of genomic imbalance of mostly Chinese patients in prenatal and postnatal settings.

Knowledge, attitude and ethical consideration of Chinese couples requesting preimplantation genetic testing in Hong Kong.

AIM: Increasing preimplantation genetic testing (PGT) cycles are being performed in Hong Kong. This study aims to evaluate the knowledge, attitude and ethical consideration of Chinese couples toward PGT. METHODS: Couples requesting PGT between June 2013 and March 2014 were invited to complete a questionnaire. RESULTS: Total 49 couples (49 women, 47 men) completed the questionnaires. Eighteen couples (37%) were waiting for PGT (pre-PGT group), 15 couples (31%) were undergoing PGT (PGT group) and 16 couples (32%) had completed at least one PGT cycle (post-PGT group). Only 53% of the couples could tell the recurrent risk, and 31% (with monogenic disorders) could tell the mode of inheritance of their condition. The acceptability of PGT (>80%) and attitude toward the embryo fate (58-78%) were good. The post-PGT group had more concern than the PGT and pre-PGT groups on the prenatal diagnostic testing (**P = 0.007). 12.5% of the couples worried about the transfer of healthy embryos with carrier state and they all had monogenic disorders. If the prenatal testing confirmed an affected fetus, a higher percentage (32%) in the Post-PGT group disagreed to terminate the pregnancy in contrast to a much lower 6% in the pre-PGT group (**P = 0.02). Three-quarter of the couples opted to tell their child about their conception through PGT. CONCLUSION: Chinese couples in Hong Kong had an overall good acceptability and positive attitude toward PGT. We appreciate the difficulties the couples have gone through PGT. A checklist on what to cover pre-during-post-PGT in the counseling process is needed.

Mitotic chromosome alignment ensures mitotic fidelity by promoting interchromosomal compaction during anaphase.

Chromosome alignment at the equator of the mitotic spindle is a highly conserved step during cell division; however, its importance to genomic stability and cellular fitness is not understood. Normal mammalian somatic cells lacking KIF18A function complete cell division without aligning chromosomes. These alignment-deficient cells display normal chromosome copy numbers in vitro and in vivo, suggesting that chromosome alignment is largely dispensable for maintenance of euploidy. However, we find that loss of chromosome alignment leads to interchromosomal compaction defects during anaphase, abnormal organization of chromosomes into a single nucleus at mitotic exit, and the formation of micronuclei in vitro and in vivo. These defects slow cell proliferation and are associated with impaired postnatal growth and survival in mice. Our studies support a model in which the alignment of mitotic chromosomes promotes proper organization of chromosomes into a single nucleus and continued proliferation by ensuring that chromosomes segregate as a compact mass during anaphase.

Factors associated with common and atypical chromosome abnormalities after positive combined first-trimester screening in Chinese women: a retrospective cohort study.

BACKGROUND: When cell-free DNA (cfDNA) testing is used as a secondary screening tool following combined first-trimester screening (cFTS), cFTS is used to estimate the prior risk for chromosome abnormalities. This study aimed to assess the factors that are associated with common and atypical abnormalities following cFTS, including cFTS risk, advanced maternal age, increased nuchal translucency (NT) ≥3.5 mm, and abnormal levels of serum markers. METHODS: We reviewed a historical cohort of 1855 Chinese women carrying singleton pregnancies with a positive cFTS [at a threshold of 1:250 for trisomy (T) 21 or 1:180 for T18] in one public hospital over a five-year period. All chromosome abnormalities were confirmed by invasive prenatal diagnosis (IPD) with karyotyping, with or without array comparative genomic hybridization. Using multivariable binary logistic regression analysis, we determined the parameters that were associated with common and atypical abnormalities. RESULTS: Overall, the prevalence of common and atypical abnormalities was 6.2 and 1.2%, respectively, and the prevalence increased with the risk of T21 by cFTS. In pregnancies with a risk of T21 > 1 in 100, a high risk of both T21 and T18, an increased NT, or a pregnancy-associated plasma A (PAPP-A) level <  0.2 multiple of medians (MoM), the prevalence of common abnormalities was 12.2, 64.7, 25.5 and 33.8%, respectively, while that of atypical abnormalities was 1.6, 3.9, 4.2, and 7.4%, respectively. In the multivariable binary logistic regression analysis, out of these four factors, only two (increased NT and PAPP_A <  0.2 MoM) were significant predictors of common and atypical abnormalities, respectively. Of all positive cFTS pregnancies, 50.4% did not have any of these four factors, and the prevalence of common and atypical abnormalities was 1.1 and 0.6%, respectively. There were three atypical abnormalities, all of which were mosaicism, and they were detected among women with IPD alone. The ages of these women were ≥ 35 years. All three pregnancies were continued after proper counseling. After giving birth, only one child had mild abnormalities, while the other two were phenotypically normal. CONCLUSIONS: Our study identified factors associated with common and atypical abnormalities after cFTS. These factors can be used to estimate the prior risk for these abnormalities to help with post-cFTS counseling in terms of choosing between cfDNA testing and IPD.

Combined Pathology-Driven Algorithmic Testing and Integrated Reporting for Bone Marrow Examination.

CONTEXT.­: The College of American Pathologists published guideline recommending bone marrow synoptic reporting for hematologic neoplasms. OBJECTIVE.­: To evaluate the impact of pathology-driven algorithmic testing (PDAT) with integrated reporting for bone marrow examination on test utilization, ability to render a specific World Health Organization diagnosis, and clinician satisfaction 1 year after implementation. DESIGN.­: We reviewed the hematopathology reports, integrated synoptic reports, and ancillary test results generated during a 12-month period. The initial diagnosis from the hematopathology report was compared with the final diagnosis on the integrated synoptic reports. Test utilization data were compared with a previous year in which ancillary testing was ordered at clinician discretion. Clinicians were anonymously surveyed to assess their satisfaction with PDAT and integrated reporting. RESULTS.­: Integrated reporting resulted in a World Health Organization diagnosis for 80 of 85 cases (94%) compared with 54 (64%) for the hematopathology report alone. Unnecessary testing decreased from 45% pre-PDAT (124 of 274 cases) to 0.7% PDAT (2 of 268 cases), and PDAT resulted in fewer omissions of necessary tests. Clinicians preferred PDAT and valued integrated reporting for a variety of reasons, including the ease of finding relevant prognostic information. CONCLUSIONS.­: Pathology-driven algorithmic testing with integrated reporting improves the pathologist's ability to render a specific World Health Organization diagnosis and improves test utilization. Clinicians prefer PDAT to clinician-ordered testing. This is the first study to examine how synoptic reporting can modify hematologic diagnoses.

Health professionals' involvement and information provision in genetic counseling following prenatal diagnosis of sex chromosome aneuploidy in Hong Kong.

This study supports training in genetic counseling for obstetricians and adoption of a multidisciplinary approach in the counseling process following prenatal diagnosis of sex chromosome aneuploidy.

Identifying the genetic causes for prenatally diagnosed structural congenital anomalies (SCAs) by whole-exome sequencing (WES).

BACKGROUND: Whole-exome sequencing (WES) has become an invaluable tool for genetic diagnosis in paediatrics. However, it has not been widely adopted in the prenatal setting. This study evaluated the use of WES in prenatal genetic diagnosis in fetuses with structural congenital anomalies (SCAs) detected on prenatal ultrasound. METHOD: Thirty-three families with fetal SCAs on prenatal ultrasonography and normal chromosomal microarray results were recruited. Genomic DNA was extracted from various fetal samples including amniotic fluid, chorionic villi, and placental tissue. Parental DNA was extracted from peripheral blood when available. We used WES to sequence the coding regions of parental-fetal trios and to identify the causal variants based on the ultrasonographic features of the fetus. RESULTS: Pathogenic mutations were identified in three families (n = 3/33, 9.1%), including mutations in DNAH11, RAF1 and CHD7, which were associated with primary ciliary dyskinesia, Noonan syndrome, and CHARGE syndrome, respectively. In addition, variants of unknown significance (VUSs) were detected in six families (18.2%), in which genetic changes only partly explained prenatal features. CONCLUSION: WES identified pathogenic mutations in 9.1% of fetuses with SCAs and normal chromosomal microarray results. Databases for fetal genotype-phenotype correlations and standardized guidelines for variant interpretation in prenatal diagnosis need to be established to facilitate the use of WES for routine testing in prenatal diagnosis.

Paternal uniparental disomy of chromosome 19 in a pair of monochorionic diamniotic twins with dysmorphic features and developmental delay.

BACKGROUND: We 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). METHODS: Whole-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. RESULTS: Conventional 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. CONCLUSION: Imprinting 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.

A fetus coexisting with a complete hydatidiform mole with trisomy 9 of maternal origin.

A complete hydatidiform mole (CHM) coexisting with a viable fetus is a rare finding in pregnancies. Accurate diagnosis often relies on ultrasonographic, histopathological and molecular techniques in the definite diagnosis. To the best of our knowledge, a liveborn fetus coexisting with CHM with trisomy 9 has not been described. The use of molecular genotyping and immunohistochemical laboratory investigations enabled the CHM to be fully characterized. Postzygotic diploidization of a triploid conception arising from dispermy is the proposed mechanism of its formation.

Bridging the gap from prenatal karyotyping to whole-genome array comparative genomic hybridization in Hong Kong: survey on knowledge and acceptance of health-care providers and pregnant women.

PURPOSE: The use of array comparative genomic hybridization (aCGH) has been increasingly widespread. The challenge of integration of this technology into prenatal diagnosis was the interpretation of results and communicating findings of unclear clinical significance. This study assesses the knowledge and acceptance of prenatal aCGH in Hong Kong obstetricians and pregnant women. The aim is to identify the needs and gaps before implementing the replacement of karyotyping with aCGH. Questionnaires with aCGH information in the form of pamphlets were sent by post to obstetrics and gynecology doctors. METHOD: For the pregnant women group, a video presentation, pamphlets on aCGH and a self-administered questionnaire were provided at the antenatal clinic. RESULT: The perception of aCGH between doctors and pregnant women was similar. Doctors not choosing aCGH were more concerned about the difficulty in counseling of variants of unknown significance and adult-onset disease in pregnant women, whereas pregnant women not choosing aCGH were more concerned about the increased waiting time leading to increased anxiety. Prenatal aCGH is perceived as a better test by both doctors and patients. CONCLUSION: Counseling support, training, and better understanding and communication of findings of unclear clinical significance are necessary to improve doctor-patient experience.

First Report of a Novel Deletion Due to εγδß-Thalassemia in a Chinese Family.

A fetus of Chinese descent presented with ultrasound features of anemia at 20 weeks' gestation. Father had low a mean corpuscular volume (MCV) level. Multiplex gap-polymerase chain reaction (gap-PCR) excluded common α-thalassemia (α-thal) deletions and mutations and PCR sequencing of the α1- and α2-globin genes were negative. The fetus had a normal karyotype. Array comparative genomic hybridization (aCGH) showed a single copy loss of 189.87 kb in chromosome 11p15.4, involving the whole ß-globin gene cluster, inherited from the father. Multiplex ligation-dependent probe amplification (MLPA) confirmed the deletion included the ε-globin gene, confirming the diagnosis of heterozygous (εγδß)0-thalassemia [(εγδß)0-thal], also inherited from the father. The fetus had a worsening anemic condition in utero and required a transfusion at 26 weeks' gestation, raising the hemoglobin (Hb) level from 5.3 to 12.6g/dL. A cesarean-section was subsequently performed at 32 weeks' gestation because of reduced fetal movements, and a 1650g baby girl with good Apgar scores was delivered. Hemoglobin at birth was 12.8g/dL, gradually dropping to 6.8 g/dL, requiring three neonatal transfusions. Her condition gradually stabilized after 2 months with Hb stable at 8.0 g/dL. Family screening by MLPA showed that the paternal grandmother carried the same deletion. The deletion in this case is distinct and is the reported first case. The deletion transmitted across three successive generations with great phenotypic variation. The final adult phenotype of (εγδß)0-thal is usually mild, therefore, with accurate prenatal diagnosis this condition is salvageable by in utero and early neonatal transfusions, preventing adverse pregnancy and neonatal outcomes.

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

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.