Case Report: Prenatal Recurrent Microcephaly and Corpus Callosum Abnormalities in a Chinese Family with Novel Biallelic SASS6 Mutations.

INTRODUCTION: Primary microcephaly (MCPH) is not an uncommon disorder with multiple etiologies. There are a growing number of MCPH-related genes discovered due to the extensive application of whole-exome sequencing (WES) in clinical and research settings. Biallelic mutations in the SASS6 gene cause an extremely rare MCPH, type 14. To date, only two families with SASS6 gene-related microcephaly have been reported. CASE DESCRIPTION: We report a case of recurrent congenital microcephaly in a Chinese family. The two affected fetuses presented with microcephaly early in the second trimester with agenesis of the corpus callosum. In the first affected fetus, trio WES detected two compound heterozygous candidate variants c.1139T>C(p.L380P) and c.1223C>G (p.T408S) in the SASS6 gene. Another affected fetus also inherited both variants, while the normal child carried neither variant through Sanger sequencing analysis. Both variants were classified as a variant of uncertain significance according to the current American College of Medical Genetics and Genomics guidelines. CONCLUSION: We reported novel biallelic variants in the SASS6 gene, encoding the SAS6 centriolar assembly protein, associated with prenatal onset of autosomal recessive microcephaly. We postulate that the pathomechanism of the compound heterozygous variants in close proximity could potentiate the overall coiled instability leading to the phenotypic features of our case.

Cat-Ear-Line: A Sonographic Sign of Cortical Development?

OBJECTIVES: Diagonal echogenic lines outside the lateral ventricle have often been observed in the anterior coronal planes of the normal fetal brain by neurosonography. We have observed abnormal shapes of these echogenic lines in cases of malformation of cortical development (MCD). We named the ultrasound finding "cat-ear-line" (CEL). This study aimed to examine how and when CEL develops in normal cases compared with MCD cases. METHODS: We retrospectively examined the fetal brain volume dataset acquired through transvaginal 3D neurosonography of 575 control cases and 39 MCD cases from 2014 to 2020. We defined CEL as the hyperechogenic continuous lines through subplate (SP) and intermediate zone (IZ), pre-CEL as the lines that existed only within the SP, and abnormal CEL as a mass-like or mosaic shadow-like structure that existed across the SP and IZ. All fetuses in the MCD group had some neurosonographic abnormalities and were ultimately diagnosed with MCD. RESULTS: The CEL was detected in 97.9% (369/377) of the control group from 19 to 30 weeks. The CEL visualization rate of the MCD group in the same period was 40.0% (14/35) which was significantly lower than that of the control group (P < .001). CONCLUSIONS: From this study, it appears that the CEL is an ultrasound finding observed at and beyond 19 weeks in a normally developing fetus. In some MCD cases, pre-CEL at and beyond 19 weeks or abnormal CEL was observed. Maldeveloped CEL at mid-trimester may help identify cases at-risk of subsequent MCD.

Prospective Evaluation of International Prediction of Pregnancy Complications Collaborative Network Models for Prediction of Preeclampsia: Role of Serum sFlt-1 at 11-13 Weeks' Gestation.

The study aimed to investigate whether serum sFlt-1 (soluble fms-like tyrosine kinase-1) at 11-13 weeks' gestation in pregnancies that subsequently developed preeclampsia was different from those without preeclampsia and compare screening performance of the International Prediction of Pregnancy Complications (IPPIC) reported models, which include various combinations of maternal factors, systolic blood pressure, diastolic blood pressure, PlGF (placental growth factor) and sFlt-1 and the competing risk (CR) models, which include various combinations of maternal factors, mean arterial pressure (MAP) and PlGF for predicting any-onset, early-onset, and late-onset preeclampsia. This was a prospective multicenter study in 7877 singleton pregnancies. The differences of the predictive performance between the IPPIC and CR models were compared. There were 141 women (1.79%) who developed preeclampsia, including 13 cases (0.17%) of early-onset preeclampsia and 128 cases (1.62%) of late-onset preeclampsia. In pregnancies that developed preeclampsia compared to unaffected pregnancies, median serum sFlt-1 levels and its MoMs were not significantly different (p>0.05). There was no significant association between gestational age at delivery and log10 sFlt-1 and log10 sFlt-1 MoM (p>0.05). The areas under the curve of CR models were significantly higher than the IPPIC models for the prediction of any-onset and late-onset preeclampsia but not for early-onset preeclampsia. In conclusion, there are no significant differences in the maternal serum sFlt-1 levels at 11-13 weeks' gestation between women who subsequently develop preeclampsia and those who do not. Moreover, the CR models for the prediction of any-onset and late-onset preeclampsia perform better than the IPPIC reported model.

Impact of replacing or adding placental growth factor on Down syndrome screening: A prospective cohort study.

OBJECTIVES: To assess whether adding placental growth factor (PlGF) or replacing pregnancy-associated plasma protein-A (PAPP-A) improves the first trimester combined test performance for trisomy 21. METHODS: A total of 11,518 women with a singleton pregnancy who underwent the first trimester combined test between December 2016 and December 2019 were included. PlGF was measured and estimated term risk for trisomy 21 was calculated by (1) adding PlGF to the combined test and (2) replacing PAPP-A with PlGF. RESULTS: Twenty-nine pregnancies had trisomy 21. The combined tests detection rate (DR), false positive rate (FPR) and screen positive rate (SPR) were 89.7%, 5.7% and 6% respectively. DR when adding PlGF to the combined test or replacing PAPP-A remained unchanged. Replacing PAPP-A by PlGF increased FPR and SPR to 6.2% and 6.4% respectively. Adding PlGF to the combined test gave FPR and SPR rates of 5.5% and 5.7% respectively. Change in FPR and SPR was not significant (p > 0.1 for all). CONCLUSION: Adding PlGF to the combined test or replacing PAPP-A with PlGF did not improve trisomy 21 DR and resulted in a non-significant marginal change in FPR and SPR.

The Use of Somatex Shunt for Fetal Pleural Effusion: A Cohort of 8 Procedures.

INTRODUCTION: Fetal pleural effusion may require in utero shunting which is associated with procedure-related complications. OBJECTIVE: To evaluate the efficacy and complications of the newly designed Somatex shunt in treating fetal pleural effusion. METHODS: Consecutive cases with primary fetal pleural effusion who were treated with the Somatex shunt between 2018 and 2019 were evaluated. Perinatal outcomes and complications were retrospectively analyzed. RESULTS: There were 6 cases of unilateral and 1 case of bilateral pleural effusion, and hence a total of 8 pleuroamniotic shunting procedures were performed. The median gestational age at diagnosis and shunting was 20.7 and 22.6 weeks, respectively. All 8 procedures were successful, achieving complete in utero drainage. All but one were live births (85.7%) with a median gestational age of 38 weeks. The single case of in utero death occurred 4.7 weeks after successful shunting, and no cause could be identified after autopsy. The rates of preterm birth and premature rupture of membranes were 33.3% (2/6) and 16.7% (1/6), respectively. Four of the 8 procedures (50%) had minor shunt-related complications such as dislodgement and entrapment, occurring at a median of 7.7 weeks after shunting. None of the shunts became blocked. CONCLUSIONS: The Somatex shunt is effective in relieving fetal pleural effusions with good survival rate. Overall, it was a safe instrument, though minor shunt complications occurred.

Low-pass genome sequencing-based detection of absence of heterozygosity: validation in clinical cytogenetics.

PURPOSE: Absence of heterozygosity (AOH) is a genetic characteristic known to cause human genetic disorders through autosomal recessive or imprinting mechanisms. However, the analysis of AOH via low-pass genome sequencing (GS) is not yet clinically available. METHODS: Low-pass GS (fourfold) with different types of libraries was performed on 17 clinical samples with previously ascertained AOH by chromosomal microarray analysis (CMA). In addition, AOH detection was performed with low-pass GS data in 1,639 cases that had both GS and high-probe density CMA data available from the 1000 Genomes Project. Cases with multiple AOHs (coefficient of inbreeding F ≥ 1/32) or terminal AOHs ≥5 Mb (suspected uniparental disomy [UPD]) were reported based on the guidelines of the American College of Medical Genetics and Genomics. RESULTS: Low-pass GS revealed suspected segmental UPD and multiple AOHs (F ≥ 1/32) in nine and eight clinical cases, respectively, consistent with CMA. Among the 1,639 samples, low-pass GS not only consistently detected multiple AOHs (F ≥ 1/32) in 18 cases, but also reported 60 terminal AOHs in 44 cases including four mosaic AOHs at a level ranging from 50% to 75%. CONCLUSION: Overall, our study demonstrates the feasibility of AOH analysis (≥5 Mb) with low-pass GS data and shows high concordance compared with CMA.

Procedure-Related Fetal Loss following Chorionic Villus Sampling after First-Trimester Aneuploidy Screening.

OBJECTIVE: The aim was to determine the institutional procedure-related fetal loss rate after chorionic villus sampling (CVS) and the factors which may identify pregnancies at increased risk of having a procedure-related loss. MATERIALS AND METHODS: Pregnancy outcomes were retrieved of all women having a singleton pregnancy and undergoing a CVS procedure between 2004 and 2013 at a university hospital in Hong Kong. The incidence of procedure-related fetal loss due to unintended miscarriages adjusted for the background loss incidence of miscarriages was determined. Multivariate regression was performed to examine the factors contributing to an unintended fetal loss and miscarriage. RESULTS: CVS was performed on 1,906 fetuses. The procedure-related fetal loss rate was 0.17% (95% CI -0.2 to 0.7). After multivariate analysis, a decreased plasma protein-A (PAPP-A) multiple of the median (OR 0.27; 95% CI 0.08-0.98, p = 0.046) was significantly associated with miscarriage in women who did not undergo a CVS. Patient-specific prediction of spontaneous abortion in women who did not undergo CVS was not statistically significant (AUC 0.56; 95% CI 0.49-0.6, p = 0.14). CONCLUSIONS: The CVS-related fetal loss rate adjusted for background loss was 0.17%. Pregnancies with reduced PAPP-A carry an increased risk of miscarriage irrespective of whether they had undergone an invasive procedure.