Likely pathogenic variant in the BICD2 gene in fetus presenting with non-immune hydrops

Trio exome sequencing was performed on a fetus presenting with severe hydrops fetalis at 21 + 0 weeks gestation. A novel de novo BICD2 missense variant was identified in the fetus. Pathogenic variants in the BICD2 gene are associated with lower extremity-predominant spinal muscular atrophy. The variant was initially classified as a variant of uncertain clinical significance (VUS) as at the time of analysis and initial report, pathogenic variants in the BICD2 gene specifically had not been associated with fetal hydrops and no other abnormalities had been detected. It was agreed in multidisciplinary team discussions to include the variant in the report as a VUS recommending phenotypic follow-up. The pregnancy was terminated and post-mortem findings were in keeping with a BICD2-pathogenic variant. In addition, a paper was published reporting another case with a pathogenic BICD2 variant presenting with fetal hydrops. The variant classification was then upgraded to class 4 likely pathogenic and reported as consistent with the diagnosis. This case demonstrates the importance of reporting these new gene/phenotypes in enabling others in the classification of variants, staying up-to-date with literature and following up phenotype for class 3 variants of interest.     

Prenatal diagnosis of a lethal form of Netherton syndrome by SPINK5 mutation analysis

Netherton syndrome (NS) is a severe autosomal recessive ichthyosis with no specific treatment or prenatal diagnosis available at present. The recent identification of SPINK5, which encodes a serine protease inhibitor, as the defective gene enables DNA-based prenatal diagnosis to be carried out. Here we report the first direct molecular prenatal diagnosis of a lethal form due to a recurrent SPINK5 mutation in three consanguineous Turkish families. XmnI restriction enzyme digestion and DNA sequencing demonstrated that each deceased affected child was homozygous for mutation 153delT inherited from each parent. Analysis of fetal DNA from amniotic fluid cells in Family 1 and from a chorionic villus sampling in Family 3 showed that the fetus was heterozygous for 153delT in both cases. The pregnancies were carried to term and the newborns were unaffected. In Family 2, fetal DNA analysis from chorionic villus biopsy showed in a first pregnancy that the fetus was homozygous for 153delT. The pregnancy was terminated at 13 weeks and DNA analysis of fetal keratinocytes confirmed the prenatal prediction. In a second pregnancy in Family 2, fetal DNA analysis showed heterozygosity for 153delT, and the pregnancy was continued. Direct SPINK5 mutation analysis in families at risk for NS represents the first early, rapid and reliable method for prenatal diagnosis of this life-threatening form of ichthyosis. Copyright © 2002 John Wiley & Sons, Ltd.     

Fetoscopic laser photocoagulation versus expectant management for stage I twin-to-twin transfusion syndrome: A systematic review and meta-analysis

To investigate the outcomes of asymptomatic stage I twin-to-twin transfusion syndrome (stage I TTTS) among patients treated with fetoscopic laser photocoagulation (FLP) versus expectant management. Databases such as PubMed, Web of Science and Scopus were systematically searched from inception up to March 1st, 2022. The primary outcome was at least one fetal survival at birth and secondary outcomes included gestational age at delivery, preterm premature rupture of membranes < 32 weeks, preterm birth < 32 weeks, and single and dual fetal survival. Five studies were included in the meta-analysis. There was no significant difference in terms of at least one survival (odds ratio (OR) = 1.40, 95%CI= (0.26, 7.43), P = 0.70), single survival (OR = 0.87, 95%CI= (0.51, 1.48), P = 0.60) and dual survival (OR = 1.63, 95%CI= (0.74, 3.62), P = 0.23) among FLP and expectant groups. Gestational age at delivery (mean difference = 1.19, 95%CI= (−0.25, 2.63), P = 0.10), the risk of PTB<32 weeks (OR = 0.88, 95%CI= (0.50, 1.54), P = 0.65), and pPROM<32 weeks (OR = 1.80, 95% CI= (0.41, 7.98), P = 0.44) were also comparable between the groups. Routine FLP of the placental anastomoses before 26 weeks of gestation is unlikely to be beneficial among asymptomatic stable stage I TTTS patients without cervical shortening as the procedure does not offer a survival advantage compared with expectant management.     

Prenatal diagnosis for arginase deficiency by second-trimester fetal erythrocyte arginase assay and first-trimester ARG1 mutation analysis

Hyperargininemia is a progressive neurometabolic disorder caused by deficiency of hepatic cytosolic arginase I, resulting from mutations in the ARG1 gene. We diagnosed arginase deficiency in a three-year-old male child of first-cousin Palestinian Arab parents. Prenatal diagnosis of an unaffected fetus was achieved in the second trimester of a subsequent pregnancy by cordocentesis and analysis of arginase activity in fetal erythrocytes. ARG1 mutation analysis in the proband revealed homozygosity for a deletion of 10 753 bp extending from the first intron to beyond the poly (A) site of the gene. This is the first gross deletion in the ARG1 gene to be identified and the first mutation to be described in an arginase-deficient patient of this ethnic origin. The identification of the ARG1 deletion in this family enabled first-trimester prenatal diagnosis in a subsequent pregnancy by multiplex PCR analysis performed on chorionic villous DNA. Copyright © 2004 John Wiley & Sons, Ltd.     

Two unrelated fetuses with ITPR1 missense variants and fetal hydrops

We describe two fetuses from unrelated families with likely pathogenic variants in ITPR1 that presented with nonimmune fetal hydrops. Trio exome sequencing revealed a de novo heterozygous likely pathogenic missense variant c.7636G > A (p.Val2531Met) in ITPR1 (NM_001378452.1) in proband 1 and a de novo heterozygous likely pathogenic missense variant c.34G > A [p.Gly12Arg] in proband 2. Variants in ITPR1 have been associated with several genetic conditions, including spinocerebellar ataxia 15, spinocerebellar ataxia 29, and Gillespie syndrome. Our report on two patients details a previously undescribed severe fetal presentation of nonimmune hydrops fetalis associated with missense variants in the ITPR1 gene.     

Hormetic protection of Drosophila melanogaster middle-aged male flies from heat stress by mildly stressing them at young age

Previous studies have shown that exposing flies to hypergravity (3g or 5g) for the first 2 weeks of adult life slightly increases longevity of male flies and survival time at 37°C for both sexes, and delays an age-linked behavioral change. The present experiment tested whether the hypergravity could also protect flies from four successive deleterious non-lethal heat shocks at 4 and 5 weeks of age. Males that lived in hypergravity for the first 2 weeks of adult life lived slightly longer (ca. +15% or 1.2 day) after heat shocks (30 min or 45 min at 37°C) than flies that always lived at 1g, but this positive effect of hypergravity was not observed in females. Therefore, hypergravity exposure at young age can help the male flies recovering from a heat shock at older ages.     

Prenatal detection of fetal hemoglobin E gene from maternal plasma

In order to provide a noninvasive prenatal diagnosis of the hemoglobin E (Hb E) related disorder, we have evaluated the possibility of identifying the fetal β^E-globin gene in maternal plasma. The analysis was performed during 8 to 18 weeks of gestation using DNA extracted from 200 µL of plasma from pregnant women whose husbands carried Hb E. The β^E-globin mutation in maternal plasma was detected by a nested PCR amplification followed by the Mnl I restriction analysis. The result was compared with that of routine analysis of the CVS specimens. Among the five pregnant women examined, the fetal β^E-globin gene was identified in maternal plasma in three of them and the result was completely concordant with the conventional CVS analysis. This simple noninvasive prenatal detection of the fetal β^E-globin gene should prove useful in a prevention and control program of Hb E/β-thalassemia in countries where the β^E-globin gene is prevalent. Copyright © 2003 John Wiley & Sons, Ltd.     

Association between low fetal fraction in cell-free DNA screening and fetal chromosomal aberrations: A systematic review and meta-analysis

Objective

To perform a systematic review and meta-analysis of the available literature on low fetal fraction (LFF) in cell-free DNA (cfDNA) screening and the risk of fetal chromosomal aberrations.

Method

We searched articles published between January 2010 and May 2021 in PubMed and EMBASE databases. Risk of bias was assessed using QUADAS-2.

Results

Twenty-seven studies met the inclusion criteria, comprising data of 243,700 singleton pregnancies. Compared to normal fetal fraction, LFF was associated with a higher risk of trisomy 13 (OR 5.99 [3.61–9.95], I ² of heterogeneity = 0%, n = 22 studies), trisomy 18 (OR 4.46 [3.07–6.47], I ² = 0%, n = 22 studies), monosomy X (OR 5.88 [2.34–14.78], I ² = 18%, n = 10 studies), and triploidy (OR 36.39 [9.83–134.68], I ² = 61%, n = 6 studies), but not trisomy 21 (OR 1.25 [0.76–2.03], I ² = 36%, n = 23 studies). LFF was also associated with a higher risk of various other types of fetal chromosomal aberrations (OR 4.00 [1.78–9.00], I ² = 2%, n = 11 studies). Meta-analysis of proportions showed that absolute rates of fetal chromosomal aberrations ranged between 1% and 2% in women with LFF. A limitation of this review is the potential risk of ascertainment bias because of differences in outcome assessment between pregnancies with LFF and those with normal fetal fraction. Heterogeneity in population characteristics or applied technologies across included studies may not have been fully addressed.

Conclusion

An LFF test result in cfDNA screening is associated with an increased risk of fetal trisomy 13, trisomy 18, monosomy X, and triploidy, but not trisomy 21. Further research is needed to assess the association between LFF and other specific types of fetal chromosomal aberrations.     

Non-invasive prenatal detection of achondroplasia in size-fractionated cell-free DNA by MALDI-TOF MS assay

Achondroplasia is the most common form of short-limbed dwarfism in humans and is caused by mutations in the FGFR3 gene. Currently, prenatal diagnosis of this disorder relies on invasive procedures. Recent studies have shown that fetal single gene point mutations could be detected in cell-free DNA (cf-DNA) from maternal plasma by either the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) assay with single allele base extension reaction (SABER) approach or the size fractionation of cf-DNA in maternal plasma. Here, we combined the two approaches to non-invasively examine the fetal G1138A mutation in maternal plasma. cf-DNA was extracted from maternal plasma samples obtained from two pregnant women at risk for achondroplasia. The fetal G1138A mutation was determined by the analysis of size-fractionated cf-DNA in maternal plasma using MALDI-TOF MS with SABER approach and homogenous MassEXTEND (hME) assay, respectively. The fetal G1138A mutation was detectable in the two achondroplasia-affected pregnancies by the analysis of cf-DNA in maternal plasma using MALDI-TOF MS. However, the size-fractionation approach led to a more precise detection of the fetal mutation in both analyses. This analysis would be suitable for non-invasive prenatal diagnosis of diseases caused by fetal single gene point mutations. Copyright © 2007 John Wiley & Sons, Ltd.     

SMARCC1 is a susceptibility gene for congenital hydrocephalus with an autosomal dominant inheritance mode and incomplete penetrance

A Jewish couple of mixed origin was referred for genetic counseling following termination of pregnancy at 18 weeks of gestation due to severe ventriculomegaly with aqueduct stenosis. Trio exome sequencing revealed a loss-of-function heterozygous variant in the SMARCC1 gene inherited from an unaffected mother. The SMARCC1 gene is associated with embryonic neurodevelopmental processes. Recent studies have linked perturbations of the gene with autosomal dominant congenital hydrocephalus, albeit with reduced penetrance. However, these studies were not referenced in the SMARCC1 OMIM record (*601732) and the gene was not considered, at the time, an OMIM morbid gene. Following our case and appeal, SMARCC1 is now considered a susceptibility gene for hydrocephalus. This allowed us to reclassify the variant as likely pathogenic and empowered the couple to make informed reproductive choices.     

X-linked pyruvate dehydrogenase complex deficiency due to a novel PDHA1 variant associated with structural brain abnormalities in a fetus

We report a case of pyruvate dehydrogenase E1 alpha subunit deficiency associated with a novel hemizygous PDHA1 variant presenting prenatally as multiple structural brain abnormalities in a male fetus. A healthy Finnish couple was initially referred to the Fetomaternal Medical Center because of suspected fetal choroid plexus cyst at 11 + 2 weeks of pregnancy. At 20 + 0 weeks, multiple abnormalities were observed with ultrasound including narrow thorax, slightly enlarged heart, hypoplastic cerebellum, absent cerebellar vermis and ventriculomegaly. Autopsy and genetic analyses were performed after the termination of pregnancy. The findings of macroscopic examination included cleft palate, abnormally overlapping position of fingers and toes and dysmorphic facial features. Neuropathological examination confirmed the absence of corpus callosum, cerebellar hypoplasia and ventriculomegaly. Nodular neuronal heterotopia was also observed. Trio exome sequencing revealed a novel hemizygous de novo variant c.1144C>T p.(Gln382*) in the PDHA1 gene, classified as likely pathogenic. We suggest that inherited metabolic disorders should be kept in mind as differential diagnoses in fetuses with structural brain abnormalities.     

Perinatal outcome after selective fetal reduction in monochorionic twin pregnancies: A comparison of techniques over a 20-year period

Objective

To assess the perinatal outcome after fetal reduction in complicated monochorionic (MC) twin pregnancies by comparing different techniques.

Methods

A retrospective cohort study at a national referral center comparing data between four techniques: interstitial laser coagulation, radiofrequency ablation (RFA), fetoscopic laser coagulation (FLC) and bipolar cord coagulation (BCC). The primary outcome was the mortality of the co-twins. Secondary outcomes were preterm pre-labor rupture of membranes (PPROM), gestational age at delivery and neonatal morbidity.

Results

259 MC twin pregnancies underwent selective fetal reduction: 29 IL, 64 RFA, 85 FLC and 81 BCC. The perinatal mortality rate was 29% and fetal demise of the co-twins occurred in 19%. The lowest mortality rate was seen after BCC (17%, p = 0.012). PPROM occurred in 18% patients without significant differences between techniques. The mean gestational age at delivery in liveborn children was 35 weeks and did not differ between techniques. Severe cerebral injury and neonatal morbidity were reported in 4% and 14%, respectively, without significant differences between techniques.

Conclusions

Selective fetal reductions in MC twins are precarious procedures with an increased risk of perinatal mortality of the co-twins. Our results show the lowest mortality rates after BCC. However, high PPROM rates were seen irrespective of the technique.     

Prenatal diagnosis of fragile x syndrome: (cgg)n expansion and methylation of chorionic villus samples

Fragile X syndrome is the most common form of inherited mental retardation, due to an expansion of the (CGG)_n trinucleotide repeat in the FMR-1 gene and hypermethylation of its 5′ upstream CpG island. Two major problems remain to be resolved for fragile X prenatal diagnosis: the abnormal methylation patterns of chorionic villus samples (CVS) and the inability to predict the mental status of females with the full mutation. We present here the results of ten prenatal diagnoses of fragile X syndrome using Southern blotting and polymerase chain reaction (PCR) amplification, and the analysis of 50 further CVS to test the methylation status of the CpG island of the FMR-1 gene. In the ten ‘at-risk’ CVS, eight normal (five males and three females) and two affected male fetuses were detected. Absence of methylation in the CVS was observed in two cases, which was not found upon subsequent examination of the newborn or of fetal tissues. In the 50 CVS not ‘at risk’ for fragile X syndrome, abnormal fragment patterns for probe StB12.3 were detected in 32 per cent for female and 24 per cent for male fetuses. This abnormal pattern could be due to absent or partial methylation of the CpG island of the FMR-1 gene in chorionic villus tissues.     

Prenatal diagnosis of Milroy's primary congenital lymphedema

Milroy's primary congenital lymphedema (PCL) (hereditary lymphedema type I, Milroy disease) is present at birth, and mostly affects the dorsal aspects of feet. It is mostly a life-long condition but does not affect longevity. Complications are rare except for chronic discomfort and warmness of affected areas. PCL is an autosomal dominant disease with incomplete penetrance due to a mutation in the gene locus encoding for VEGFR3 with resultant dysgenesis of microlymphatic vessels. We report on two fetuses where ultrasonographic examination at 15 weeks of gestation showed significant edema of the dorsal aspects of both feet with no evidence of other major malformations. Whereas in one fetus the edema resolved completely, it persisted in the second fetus and proved after birth to be of lymphedematous nature. To the best of our knowledge, this is the first report of early prenatal diagnosis of primary congenital lymphedema via fetal ultrasonographic examination and of spontaneous resolution of lymphedema during fetal life. Copyright © 2002 John Wiley & Sons, Ltd.     

Transcervical (TC) and transabdominal (TA) CVS for prenatal diagnosis in rotterdam: Experience with 3611 cases

Data from 3611 consecutive CVS (TC, N= 1780; TA, N= 1831) were analysed with emphasis put on influence of maternal and gestational age at CVS on the fetal loss rate < 28 weeks. For TC-CVS the gestational age varied from 9.3–11.6 weeks, for TA-CVS from 9.3–20 weeks. Sampling efficacy at first attempt was 86.5 per cent and 95 per cent respectively. In 4.6 per cent an abnormal result was established. In older mothers (N=2362) the fetal loss rate was significantly higher (p = <0.05) when sampled before 12 weeks (TC-CVS 6.2 per cent, TA-CVS 5.8 per cent). When the CVS (TA) was performed after 12 weeks the fetal loss rate decreased to 2.4 per cent. In 1079 younger women the fetal loss rate remained low (TC 2.8 per cent; TA < 12 weeks 1.8 per cent; TA > 12 weeks 1.7 per cent) and was not influenced by gestational age at the time of sampling. We concluded both methods safe and reliable when the choice of application considers maternal age.     

First-trimester fetal sex determination in maternal serum using real-time PCR

An Erratum has been published for this article in Prenatal Diagnosis 22(13) 2002, 1241. Fetal sex prediction can be achieved using PCR targeted at the SRY gene by analysing cell-free fetal DNA in maternal serum. Unfortunately, the results reported to date show a lack of sensitivity, especially during the first trimester of pregnancy. Therefore, determination of fetal sex by maternal serum analysis could not replace karyotype analysis following chorionic villus sampling. A new highly sensitive real-time PCR was developped to detect an SRY gene sequence in maternal serum. Analysis was performed on 121 pregnant women during the first trimester of pregnancy (mean gestational age: 11.8 weeks). Among them, 51 had at least one previous male-bearing pregnancy. Results were compared with fetal sex. SRY PCR analysis of maternal serum was in complete concordance with fetal sex. Among the 121 pregnant women, 61 were bearing a male fetus and 60 a female fetus. No false-negative results were observed. Furthermore, no false-positive results occurred, even though 27 women carrying a female fetus during the current pregnancy had at least one previous male-bearing pregnancy. This study demonstrates that a reliable, non-invasive sex determination can be achieved by PCR analysis of maternal serum during the first trimester of pregnancy. This non-invasive approach for fetal sex prediction should have great implications in the management of pregnant women who are carriers of an X-linked genetic disorder. Prenatal diagnosis might thus be performed for male fetuses only, avoiding invasive procedures and the risk of the loss of female fetuses. Copyright © 2001 John Wiley & Sons, Ltd.     

The effect of fetal gender on nuchal translucency at 10–14 weeks of gestation

Recent data have suggested that fetal nuchal translucency (NT) is affected by fetal gender. We investigated the size of this effect in 12 189 unselected pregnancies with known normal outcomes that had undergone NT measurements between 10 and 14 weeks of gestation. NT increased with gestation and was converted to multiples of the median (MoM) for the gestational day. The median NT MoM (95% CI) for female fetuses was 0.98 (0.97–0.99). This was significantly lower than that of the male fetuses (1.03; range1.02–1.04) (p<0.0005; Wilcoxon rank-sum test). The gender difference was not observed at 10 weeks but was observed from 11 weeks onwards. There is no obvious explanation for the above findings. Copyright © 2001 John Wiley & Sons, Ltd.     

Performance of comprehensive first trimester fetal anatomy assessment

Objective

Ultrasound assessment of the fetal anatomy and fetal echocardiography are feasible in the first trimester of pregnancy. This study was designed to assess the performance of a comprehensive fetal anatomy assessment in a high-risk population at a tertiary fetal medicine unit.

Methods

A retrospective review of high-risk patients undergoing comprehensive fetal anatomy ultrasound assessment between 11 weeks and 13 + 6 weeks of gestation was conducted. Findings of the early anatomy ultrasound scan were compared with those of the second trimester anatomy scan, and birth outcomes or post-mortem results.

Results

Early anatomy ultrasounds were performed in 765 patients. The sensitivity of the scan for detecting fetal anomalies compared to the birth outcome was 80.5% (95% CI 73.5–86.3) and specificity was 93.1% (95%CI 90.6–95.2). Positive and negative predictive values were 78.5% (95% CI 71.4–84.6) and 93.9% (95% CI 91.4–95.8), respectively. The most missed and overdiagnosed abnormalities were ventricular septal defects. The second trimester ultrasound had sensitivity of 69.0% (95% CI 55.5–80.5) and specificity of 87.5% (95% CI 84.3–90.2).

Conclusions

In a high-risk population, early assessments had similar performance metrics as the second trimester anatomy ultrasound. We advocate for a comprehensive fetal assessment in the care of high-risk pregnancies.     

Association of amnioinfusion volume at the time of surgery for twin-twin transfusion syndrome and latency to delivery

Objective

To evaluate the impact of amnioinfusion and other peri-operative factors on pregnancy outcomes in the setting of Twin-twin transfusion syndrome (TTTS) treated via fetoscopic laser photocoagulation (FLP).

Methods

Retrospective study of TTTS treated via FLP from 2010 to 2019. Pregnancies were grouped by amnioinfusion volume during FLP (<1 L vs. ≥1 L). The primary outcome was latency from surgery to delivery. An amnioinfusion statistic (AIstat) was created for each surgery based on the volume of fluid infused and removed and the preoperative deepest vertical pocket. Regression analysis was planned to assess the association of AIstat with latency.

Results

Patients with amnioinfusion of ≥1 L at the time of FLP had decreased latency from surgery to delivery (61 ± 29.4 vs. 73 ± 28.8 days with amnioinfusion <1 L, p < 0.001) and increased preterm prelabor rupture of membranes (PPROM) <34 weeks (44.7% vs. 33.5%, p = 0.042). Amnioinfusion ≥1 L was associated with an increased risk of delivery <32 weeks (aRR 2.6, 95% CI 1.5–4.5), 30 weeks (aRR 2.4, 95% CI 1.5–3.8), and 28 weeks (aRR 1.9, 95% CI 1.1–2.3). Cox-proportional regression revealed that AIstat was inversely associated with latency (HR 1.1, 95% CI 1.1–1.2).

Conclusion

Amnioinfusion ≥1 L during FLP was associated with decreased latency after surgery and increased PPROM <34 weeks.