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Objective: To evaluate the effectiveness of whole-genome array comparative genomic hybridization (aCGH) in prenatal diagnosis in Hong Kong., Methods: Array CGH was performed on 220 samples recruited prospectively as the first-tier test study. In addition 150 prenatal samples with abnormal fetal ultrasound findings found to have normal karyotypes were analyzed as a 'further-test' study using NimbleGen CGX-135K oligonucleotide arrays., Results: Array CGH findings were concordant with conventional cytogenetic results with the exception of one case of triploidy. It was found in the first-tier test study that aCGH detected 20% (44/220) clinically significant copy number variants (CNV), of which 21 were common aneuploidies and 23 had other chromosomal imbalances. There were 3.2% (7/220) samples with CNVs detected by aCGH but not by conventional cytogenetics. In the 'further-test' study, the additional diagnostic yield of detecting chromosome imbalance was 6% (9/150). The overall detection for CNVs of unclear clinical significance was 2.7% (10/370) with 0.9% found to be de novo. Eleven loci of common CNVs were found in the local population., Conclusion: Whole-genome aCGH offered a higher resolution diagnostic capacity than conventional karyotyping for prenatal diagnosis either as a first-tier test or as a 'further-test' for pregnancies with fetal ultrasound anomalies. We propose replacing conventional cytogenetics with aCGH for all pregnancies undergoing invasive diagnostic procedures after excluding common aneuploidies and triploidies by quantitative fluorescent PCR. Conventional cytogenetics can be reserved for visualization of clinically significant CNVs.

Hemophilia A is a rare bleeding disorder with variable expressivity and allelic heterogeneity. Despite the advancement of prenatal diagnostics and molecular studies, the number of studies reviewing the reproductive choices of hemophilia A carriers and affected individuals remains limited. Through this retrospective review, we hope to gain a deeper understanding of hemophilia A‐affected individuals' clinical and molecular characteristics, as well as the reproductive choices of the at‐risk couples. A total of 122 individuals harboring likely causative F8 gene alterations from 64 apparently unrelated families attending three centers between 3/2000 and 3/2023 were included in this study. Their clinical and molecular findings as well as reproductive choices were gathered in a clinical setting and verified through the electronic medical record database of the public health system. Forty‐seven affected males and 75 female heterozygous carriers were included in the analysis. Among 64 apparently unrelated families, 36 distinct pathogenic/likely pathogenic variants were identified, of which 30.6% (11/36) of variants were novel. While the majority of clinical findings and genotype–phenotype correlations appear to be in accordance with existing literature, female carriers who had no fertility intention were significantly more likely to have affected sons than those who had fertility intention (5/19 vs. 4/5; p = 0.047). Through this retrospective review, we summarized the clinical and molecular characteristics of 122 individuals harboring pathogenic/likely pathogenic F8 variants, as well as their fertility intentions and reproductive outcomes. Further studies are required to look into the considerations involved in reproductive decision‐making. [ABSTRACT FROM AUTHOR]

Objective: To review medical records of pregnant women with positive non-invasive prenatal testing (NIPT) results for sex chromosome abnormalities who attended Tuen Mun hospital between 2015 and 2021. Patient decision after prenatal diagnosis, confirmatory diagnostic testing results, and pregnancy/neonatal outcomes were summarised. Methods: Medical records of women with abnormal NIPT results for sex chromosome abnormalities who attended Tuen Mun Hospital between January 2015 and December 2021 were retrospectively reviewed. Results: 56 Chinese women attended our prenatal diagnostic clinic with abnormal NIPT results for sex chromosome abnormalities involving 45, X (n=17), 47, XXY (n=10), 47, XXX (n=6), 47, XYY (n=8), disproportionate level of sex chromosomes (n=9), copy number variants of sex chromosomes (n=3), and suspected maternal sex chromosome imbalance (n=3). 53 had singleton pregnancies and three had dichorionic-diamniotic twin pregnancies. 58.9% had conventional combined Down syndrome screening; 15.2% of them were at high risk for trisomy 21. 33 (58.9%) of the patients opted for invasive diagnostic test: amniocentesis (n=29), chorionic villus sampling (n=3), and chorionic villus sampling followed by amniocentesis (n=1). Confirmatory cytogenetic test results (including postnatal results) were available in 35 cases. The overall positive predictive value of NIPT to detect fetal sex chromosome aneuploidies was 71.4%; the value was 42.9% for detecting 45, X, 100% for detecting 47,XXY, 80% for detecting 47,XXX, and 83.3% for detecting 47,XYY. False positive results were observed in three cases of confined placental mosaicism and three cases of vanishing twin pregnancies. Two women with 47,XXX and one woman with mosaic 45,X/46,XX were also incidentally discovered. Conclusion: Positive NIPT results for sex chromosome abnormalities can be caused by true fetal sex chromosome abnormalities, confined placental mosaicism/placental mosaicism, vanishing twins, and maternal X chromosome abnormalities. Multidisciplinary management can help prenatal counselling and genetic diagnosis. Follow-up confirmatory cytogenetic analysis prenatally and/or postnatally is useful to characterise the numeric or structural fetal sex chromosome abnormalities and their mosaic patterns, and can maximise the benefits of prenatal genetic screening in obtaining more genetic information to support pregnancy management and clinical care of affected unborn child. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]