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Objective: To present both our center's and previously reported experience of prenatal diagnosis of Coffin‐Siris syndrome (CSS) with regard to the laboratory testing and fetal features of this syndrome. Methods: This was a retrospective study of eight pregnancies with fetal CSS identified by prenatal or postnatal genetic testing. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, chromosomal microarray and exome sequencing (ES) results, and pregnancy outcomes. Results: A total of eight cases of fetal CSS based on molecular testing were detected. Two cases presented with an increased nuchal translucency (NT) in the first trimester. The remaining six were identified at the second trimester scan. Agenesis of the corpus callosum (ACC) was the most common sonographic finding, accounting for 5/7 (71.4%) cases in which a second trimester sonogram was performed: four had ACC as an isolated finding, and one had additional features of cerebellar hypoplasia and left congenital diaphragmatic hernia. Conclusion: CSS should be included in the differential diagnosis when ACC is found by prenatal ultrasound. Both chromosomal microarray and ES should be options when counseling patients with a structurally anomalous fetus. Key points: What is already known on this topic?Coffin‐Siris syndrome (CSS) is inherited in an autosomal dominant manner; most affected individuals have the disorder as the result of de novo CSS‐causing variants of genes in the BAF complex.In postnatal patients, the diagnosis is based on the presence of major and at least one minor clinical sign. What this study adds?CSS should be included in the differential diagnosis when a fetus presents with agenesis of the corpus callosum.In addition to chromosomal microarray, exome sequencing should be an option when counseling patients with a structurally anomalous fetus. [ABSTRACT FROM AUTHOR]

What's already known about this topic? In almost all cases of Hb Bart's hydrops fetalis, α0‐thalassemia can be confirmed by testing of parental blood.Germline mosaicism occurs most of the time in autosomal dominant and X‐linked recessive disorders. What does this study add? The present case is the first documentation of germline mosaicism for an α‐thalassemia deletion.Since almost all fetuses affected with Hb Bart's hydrops fetalis present with cardiomegaly on ultrasound, sonographers in regions with high α‐thalassemia prevalence should be sensitive to the cardiothoracic ratio. [ABSTRACT FROM AUTHOR]

Objective: We aimed to investigate the value of exome sequencing (ES) in fetuses with callosal anomalies (CA) with or without other structural anomalies, but with normal findings by karyotyping and chromosome microarray analysis (CMA). Methods: Cases with CA with or without other structural anomalies were screened for eligibility. Fetuses with abnormal karyotyping or CMA results were excluded. We performed ES on DNA samples from eligible fetus‐parental trios and identified diagnostic genetic variants based on the ultrasonographic features. Results: A total of 50 eligible fetus‐parental trios were successfully analyzed by ES. We found 17 likely pathogenic or pathogenic variants in 14 genes from 17 fetuses, with a total proportion of diagnostic genetic variants equal to 34.0% (17/50). Of the 17 cases with a diagnosis, 10 (29.4%, 10/35) were isolated and 7 (43.8%, 7/15) were non‐isolated. Pregnancy outcome data showed that 70.0% (7/10) of the surviving isolated CA fetuses with negative ES results had a good prognosis in early childhood. Conclusions: Our study used ES prenatally for CA and showed that ES can be used diagnostically to define the molecular defects that underlie unexplained CA. Most subjects with isolated CA with negative results for genetic causes will have a favorable prognosis in early childhood. Key points: What is already known on this topic? CNVs and monogenic causes have been shown to be associated with callosal anomalies (CA).Approximately 28.8%–50% of children with CA experienced general intellectual, academic, executive, social and/or behavioral difficulties and approximately 20%–71.2% were functioning at a level comparable to typically developing children. What does this study add? This study analyzed the use of exome sequencing (ES) in a group of fetuses with CA and the total proportion of diagnostic genetic variants was 34.0%.Most subjects with isolated CA with negative results for genetic causes will have a favorable prognosis in early childhood. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to explore the utility of rapid medical trio exome sequencing (ES) for prenatal diagnosis using the skeletal dysplasia as an exemplar.Method: Pregnant women who were referred for genetic testing because of ultrasound detection of fetal abnormalities suggestive of a skeletal dysplasia were identified prospectively. Fetal samples (amniocytes or cord blood), along with parental blood, were send for rapid copy number variations testing and medical trio ES in parallel.Results: Definitive molecular diagnosis was made in 24/27 (88.9%) cases. Chromosomal abnormality (partial trisomy 18) was detected in one case. Sequencing results had explained the prenatal phenotype enabling definitive diagnoses to be made in 23 cases. There were 16 de novo dominant pathogenic variants, four dominant pathogenic variants inherited maternally or paternally, two recessive conditions with pathogenic variants inherited from unaffected parents, and one X-linked condition. The turnaround time from receipt of samples in the laboratory to reporting sequencing results was within 2 weeks.Conclusion: Medical trio ES can yield very timely and high diagnostic rates in fetuses presenting with suspected skeletal dysplasia. These definite diagnoses aided parental counseling and decision making in most of cases. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the utility of clinical exome sequencing (ES)‐based carrier screening in Chinese consanguineous couples. Methods: Consanguineous couples were screened for autosomal recessive (AR) disorders using the clinical ES of 5000 genes associated with human diseases. Results: We recruited 14 couples who elected to have sequencing. One couple was related as first cousins and 13 as second cousins. Both partners carrying the same pathogenic variant were detected in four couples. One couple was found in which one partner carried a splice variant, and the other had a missence variant of the same gene. These five couples were identified as being at risk of having a child affected by an AR disorder. Conclusion: Our study demonstrates that ES‐based preconception screening yields a clinical value for Chinese consanguineous couples. It enables to detect at‐risk couples for rare AR diseases. Key points: What is already known on this topic?Consanguinity increases the chance that couples will both carry the same recessive variant, with a corresponding increase in the birth prevalence of recessive disordersPreconception genetic testing enables couples to learn about their reproductive risk and consider the most complete range of reproductive options What this study adds?We first report the experience of exome‐based preconception screening in Chinese consanguineous couplesConsidering that very rare autosomal recessive diseases are more frequent in the offspring of consanguineous couples compared to panmictic populations, exome‐based approaches are preferable for such unions if they can be carefully educated and counseled [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]