Exome sequencing improves genetic diagnosis of fetal increased nuchal translucency.

OBJECTIVE: The aim of this retrospective study is to determine the monogenic syndromes in fetuses with isolated first-trimester increased nuchal translucency (NT) in order to provide more accurate parental counseling. METHODS: Medical trio exome sequencing (ES) was performed on DNA extracted from chorionic villi in 73 fetuses with isolated first-trimester increased NT (≥3.5 mm) and normal chromosomal microarray analysis (CMA). This testing targets coding exons for 4200 clinically relevant disease-causing genes. The interpretation of variants was performed according to the American College of Medical Genetics guidelines. RESULTS: Pathogenic variants were detected in four cases in which phenotypes and genotypes correlate well. Medical trio ES offered a 5.5% (4/73) increase in diagnostic rate over CMA in cases with isolated increased NT. Three of four cases with pathogenic variants developed structural anomalies on ultrasound at mid pregnancy, leading to the pregnancy termination. Only one case with a pathogenic variant demonstrated normal ultrasound throughout pregnancy. CONCLUSION: Our results indicate that after a normal CMA, fetuses with isolated first-trimester increased NT have a 1.4% (1/73) risk of significant childhood genetic syndromes caused by known disease-causing variants, which will not be detectable on prenatal ultrasound. This information may be useful in parental counseling.

Congenital Cystic Diaphragm with Diaphragmatic Eventration in a Fetus: A Case Presentation.

Introduction: Congenital diaphragmatic eventration (CDE) is defined as the abnormal elevation of the diaphragm, due to incomplete muscularization of the diaphragm with a thin membranous sheet replacing normal diaphragmatic muscle. Case report: We report a prenatal case with a diaphragmatic mesothelial cyst combined with CDE. Conclusion: A large cystic mass between the thoracic wall and the liver in early pregnancy is highly suggestive of cystic diaphragm.

Prenatal diagnosis of 17q12 deletion syndrome: a retrospective case series.

The 17q12 deletion syndrome is a chromosomal anomaly resulting from the interstitial microdeletion of the long arm of chromosome 17. The aim of this study was to present the experience on prenatal diagnosis of 17q12 deletion to further define the prenatal phenotypes of this syndrome. Eleven pregnancies with foetal 17q12 deletion detected by chromosomal microarray (CMA) were retrospectively included at a single Chinese tertiary medical centre. Clinical data were reviewed for these cases, including the maternal demographics, foetal ultrasound findings, CMA results and pregnancy outcomes. The deletion sizes of 17q12 ranged from 1.42 to 1.94 Mb. The deletion had arisen de novo in 10 cases and inherited from one of the parents in one case. Variable kidney abnormalities were found by ultrasound in all of the cases, with bilateral or unilateral hyperechogenic kidneys being the most common findings. This study indicates that a strikingly high correlation between prenatal hyperechogenic kidneys and 17q12 deletion, and prenatal testing with CMA should be offered to the foetal cases of hyperechogenic kidneys. Impact statement What is already known on this subject? 17q12 deletion syndrome is a cause of renal abnormalities, maturity-onset diabetes of the young and neurodevelopmental disorders. Prenatal diagnosis has been reported in several isolated cases with the use of microarray-based technologic means. What do the results of this study add? The results provide further evidence that a strikingly high correlation between prenatal hyperechogenic kidneys and 17q12 deletion, and genetic testing should be offered to foetal cases with hyperechogenic kidneys. A rare prenatal case of 17q12 deletion with multiple structural malformations and anhydramnios is presented. What are the implications of these findings for clinical practice and/or further research? There should be a high index of suspicion of carriers in parents when 17q12 deletion is confirmed prenatally. An extremely wide phenotype spectrum of this deletion should be emphasised in the prenatal counselling.

A cost-effectiveness analysis comparing two different strategies in advanced maternal age: Combined first-trimester screening and maternal blood cell-free DNA testing.

OBJECTIVE: To estimate cost efficacy of first-trimester screening strategies based on nuchal translucency (NT) and maternal blood cell-free DNA (cfDNA) testing in women with advanced maternal age (AMA). MATERIALS AND METHODS: This was a retrospective population-based analysis of all pregnant women with AMA booked for combined first-trimester screening (cFTS) in China over a 3-year period. The assumed screening strategies were the following: cFTS (Strategy 1), cfDNA testing as a first-tier investigation replacing biomarkers after NT measurement (Strategy 2), and cfDNA testing combined with dating ultrasound for all women (Strategy 3). The direct costs were compared between strategies. RESULTS: Strategy 1 was completed in 6443 women with AMA. The respective detection rates were 94.5% and 90.9% for trisomies 21 and 18, with a total screen-positive rate of 13.5%. Such a policy resulted in 871 invasive tests and a total cost of $747,870 or a cost of $116 per person tested. Strategy 2 would result in a total cost of $1,812,570, or a cost of $281 per person tested, with increased detection rates for trisomies 21 and 18, and a decreased number of invasive tests compared with strategy 1. The total cost of Strategy 3 would be $1,675,430, or a cost of $260 per person tested with the least number of invasive tests. CONCLUSION: The cfDNA modalities have the advantages of higher detection rate for common trisomies and lower screening-positive rate. However, the cost of cfDNA testing needs to decrease significantly if it is to replace the current cFTS practice in a population of AMA on a purely cost effectiveness basis.

δ-Thalassemia with Complete Absence of Hb A2 in a Chinese Family.

A Chinese family with δ-thalassemia (δ-thal) was found, in which the daughter is homozygous for δ-thal (HBD: c.-127T>C) with complete deficiency of Hb A2 and the mother is a heterozygote with low level of Hb A2. The father, however, is a heterozygote with a normal Hb A2 value due to coinheritance of a ß-thalassemia (ß-thal). Although no abnormal clinical or hematological findings were noted in the individuals with δ-thal, one should keep in mind that ß-thal can be missed during routine preliminary screening when ß-thal and δ-thal coexist in a subject.

Prenatal diagnosis of Wolf-Hirschhorn syndrome: Ultrasonography and molecular karyotyping results.

OBJECTIVE: To present the experience on prenatal diagnosis of Wolf-Hirschhorn syndrome (WHS) to further delineate the fetal presentation of this syndrome. STUDY DESIGN: This was a retrospective analysis of ten pregnancies with fetal WHS identified by chromosomal microarray (CMA). Clinical data were reviewed for these cases, including maternal demographics, indications for invasive testing, sonographic findings, CMA results and pregnancy outcomes. RESULTS: Three cases were diagnosed at the first trimester because of an increased NT or cystic hygroma. The remaining seven cases were identified at late gestation for abnormal ultrasound findings. CMA revealed 4p deletions to be terminal in all of the ten cases. Deletion sizes ranged from 2.05 to 19.02 Mb. CONCLUSION: Prenatal findings such as increased NT, severe and early onset intrauterine growth retardation, and renal dysplasia or oligohydramnios should warrant the diagnosis of WHS and invasive testing using CMA.

Application of noninvasive prenatal testing in pregnancies with fetal double bubble sign: Is it feasible?

OBJECTIVE: To evaluate the application of noninvasive prenatal testing as an alternative to invasive diagnostic testing in pregnancies with the double bubble sign. METHODS: This was a retrospective analysis of 92 pregnancies with fetal double bubble identified by prenatal ultrasound, in which invasive diagnostic testing was performed for genetic investigations using quantitative fluorescence PCR and chromosomal microarray. Noninvasive prenatal testing was assumed to provide to patients for screening for the common aneuploidies. RESULTS: Fetal trisomy 21 was detected in 8 of the 92 patients with prenatal double bubble. No other chromosomal anomalies or microscopic pathogenic copy-number variations (CNV) were found. Noninvasive prenatal testing could theoretically identified the affected pregnancies with trisomy 21 in this group with decreased number of invasive diagnostic testing. CONCLUSIONS: Noninvasive prenatal testing could be recommended for genetic evaluation of the etiology of prenatal double bubble after thorough pretest counseling.

What would be missed in the first trimester if nuchal translucency measurement is replaced by cell free DNA foetal aneuploidy screening?

The aim of this study was to evaluate which chromosomal abnormalities in our cohort of foetuses with increased nuchal translucency (NT) in the first trimester of pregnancy could be detected by cell free (cf)DNA screening as well. There were 775 singleton pregnancies referred for cytogenetic testing due to an increased NT (≥3.0 mm). Chromosome aberrations were investigated using karyotyping or chromosomal microarray analysis (CMA). Karyotyping had been chosen for foetal cytogenetic testing by 446 patients, and CMA by 329 patients. Common aneuploidies (trisomies 21, 18, 13 and sex aneuploidies) were detected in 2.2% (99/446) and 1.8% (59/329) cases, respectively. In 329 with CMA testing, clinically significant copy number variations (CNVs) other than common aneuploidies were detected in 2.7% cases; among these, five had a pathogenic microscopic CNV, which could have been detected by karyotyping. There were four cases (1.2%) having a pathogenic submicroscopic CNV, which could have been missed by karyotyping. The total CMA detection rate (23.4%) was not statistically different from that (24.2%) by karyotyping (p > .05). The percentage of chromosomal aberrations, which cfDNA screening would miss in patients with increased NT in the first trimester, might be the same as in those with normal NT. Impact statement What is already known about this topic? First trimester NT is a powerful marker for screening for common aneuploidies. cfDNA screening is more accurate than any standard screening with NT. The need of NT in the era of prenatal screening using cfDNA is debated. What does this study add? An increased NT did not identify any additional aneuploidies that were detected by cfDNA screening. What are the implications of these findings for clinical practice and/or further research? The percentage of chromosomal aberrations which cfDNA screening would miss in patients with increased NT might be the same as in those with normal NT.

Hb A2-Tianhe (HBD: c.323G>A): First Report in a Chinese Family with Normal Hb A2-ß-Thalassemia Trait.

Coinheritance of δ-globin variants along with ß-globin gene defects can interfere with correct diagnosis of ß-thalassemia (ß-thal) trait. In this report, we present the coinheritance of a δ-globin variant, Hb A2-Tianhe [δ107(G9)Gly→Asp; HBD: c.323G>A] and a heterozygous ß-thal in a Chinese individual with microcytosis, hypochromia and a normal Hb A2 level.

Two α1-Globin Gene Point Mutations Causing Severe Hb H Disease.

Hb H disease is generally a moderate form of α-thalassemia (α-thal) that rarely requires regular blood transfusions. In this study, two Chinese families with members carrying transfusion-dependent Hb H disease were investigated for rare mutations on the α-globin genes (HBA1, HBA2). In one family, Hb Zürich-Albisrieden [α59(E8)Gly→Arg; HBA1: c.178G>C] in combination with the Southeast Asian (- -SEA) deletion was the defect responsible for the severe phenotype. In another family, a novel hemoglobin (Hb) variant named Hb Sichuan (HBA1: c.393_394insT), causes α-thal and a severe phenotype when associated with the - -SEA deletion. As these two HBA1 mutations can present as continuous blood transfusion-dependent α-thal, it is important to take this point into account for detecting the carriers, especially in couples in which one partner is already a known α0-thal carrier.

A Novel Frameshift Mutation at Codons 138/139 (HBB: c.417_418insT) on the ß-Globin Gene Leads to ß-Thalassemia.

We describe a new ß-thalassemic mutation in a Chinese subject. This allele develops by insertion of one nucleotide (+T) between codons 138 and 139 in the third exon of the ß-globin gene. The mutation causes a frameshift that leads to a termination codon at codon 139. In the heterozygote, this allele has the phenotype of classical ß-thalassemia (ß-thal) minor.