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Objective: Mitochondrial complex‐I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. Methods: This was a multicenter retrospective case series including five fetuses from three non‐related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non‐immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. Results: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. Conclusions: Mitochondrial complex‐I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex‐I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non‐immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. Linked article: There is a comment on this article by Finsterer. Click here to view the Correspondence. [ABSTRACT FROM AUTHOR]

Genome-wide sequencing, which includes exome sequencing and genome sequencing, has revolutionized the diagnostics of genetic disorders in both postnatal and prenatal settings. Compared to exome sequencing, genome sequencing enables the detection of many additional types of genomic variants, although this depends on the bioinformatics pipelines used. Variant classification might vary among laboratories. In the prenatal setting, variant classification may change if new fetal phenotypic features emerge as the pregnancy progresses. There is still a need to evaluate the incremental diagnostic yield of genome sequencing compared to exome sequencing in the prenatal setting. This article reviews the advantages and limitations of genome sequencing, with an emphasis on fetal diagnostics., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study investigates distal 2q13 microdeletion, presenting the largest cohort to date, including prenatal cases, alongside a comprehensive literature review. A retrospective analysis was conducted on distal 2q13 microdeletions from clinical charts and laboratory reports. The cohort was divided into "clinically indicated" and "not-clinically indicated" groups based on the reason for chromosomal microarray testing. Clinical cases from medical literature were reviewed and compared with our cohort. The study included 25 cases: 17 index patients and 8 family members, with 47% males and 53% females. Of these, 2 were postnatal and 15 were prenatal. In the "clinically indicated" group, 35% had abnormalities on prenatal ultrasound, while 65% in the "not-clinically indicated" group had no major anomalies. Inheritance was 50% paternal in the "clinically indicated" group, and in the "not-clinically indicated" group, 44% paternal, 22% maternal, and 33% de novo. Symptoms varied from asymptomatic to severe developmental issues. Literature review identified 51 postnatal cases, with intellectual disability, and dysmorphism being common features. Familial cases showed 20% de novo, 20% maternal, 21.5% paternal, and 40% unknown inheritance. Distal 2q13 microdeletion is linked to cognitive impairment risk and should be reported in test results based on parental preferences, requiring special considerations for clinical classification and reporting., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Objective: To investigate how many novel pathogenic (P) and likely pathogenic (LP) nonprotein-truncating or noncanonical splicing variants would be classified as variants of unknown significance (VUS) if they were detected in fetuses without abnormalities., Methods: The study included 156 patients with neurodevelopmental disorders diagnosed through postnatal exome sequencing. Causative P/LP nonprotein-truncating and noncanonical splicing variants were retrospectively reclassified in cases without specific prenatal manifestations, disregarding postnatal symptoms., Results: Of the 156 patients, 72 had a nontruncating or noncanonical splicing variant. Six patients were excluded for having more than one possible causative variant. Twelve patients had prenatal malformations known to be associated with the diagnosed disorder; therefore, variant interpretation remained unchanged. In 33 of the 54 remaining cases, the variant had been previously reported as P/LP. Reclassification of the other 21 LP/P variants revealed that 16 would have been classified as VUS if detected prenatally., Conclusion: In our cohort, ∼24% (16/66) of causative nonprotein-truncating/noncanonical splicing variants would have been classified as VUS if sequencing had been conducted during pregnancy. The potential for false-negative results, stemming from limitations in the phenotypic information available prenatally, should be discussed with prospective parents. The criteria for classifying and reporting variants in the prenatal setting may require adjustment., (© 2024 John Wiley & Sons Ltd.)

Objective: Significant discrepancy exists between laboratories in classification and reporting of copy number variants (CNVs). Studies exploring factors affecting prenatal CNV management are rare. Our "virtual fetus" pilot study examines these factors., Method: Ten prenatally diagnosed CNVs of uncertain significance (VUS) > 1Mb, encompassing OMIM-morbid genes, inherited from healthy parents, were classified by 15 MD geneticists from laboratory, prenatal, and preimplantation genetic testing (PGT) units. Geneticists addressed factors affecting classification, obligation to report, and recommendation for invasive testing or PGT., Results: CNVs were classified likely benign (10.7%), VUS (74.7%), likely pathogenic (8.7%), or pathogenic (6.0%). Classification discrepancy was higher for losses versus gains. Classifying pathogenic/likely pathogenic was more common for losses (adjusted odds ratio [aOR] 10.9, 95% CI 1.55-76.9), and geneticists specializing in gynecology (aOR 4.9, 95% CI 1.03-23.3). 84.0% of respondents would report CNVs, depending on classification and family phenotype. Invasive testing in pregnancies was recommended for 29.3% of CNVs, depending on the classification and geneticist's specialization. PGT was recommended for 32.4%, depending on classification, experience years, and family's phenotype (38.0% for patients undergoing in vitro fertilization irrespectively, 26.7% otherwise)., Conclusion: Factors affecting CNV classification/reporting are mainly dosage, family phenotype, geneticist specialization and experience. Understanding factors from our pilot study may facilitate developing an algorithm for clinical consensus and optimal management., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Background: The rate of clinically significant copy number variants in chromosomal microarray analysis in low-risk pregnancies is approximately 1%. However, these results include copy number variants with low and variable penetrance, although some patients might be interested only in the detection of high-penetrant variants., Objective: This study aimed to calculate the prevalence of high-penetrant copy number variants in a large cohort of low-risk pregnancies., Study Design: This retrospective study was performed using microarray results of pregnancies with normal ultrasound and maternal serum screening. All clinically significant (pathogenic and likely pathogenic) copy number variants were recorded. Of these, only high-penetrant findings were selected. Findings with low and medium penetrance and copy number variants with unknown clinical penetrance, including uniparental disomy of segments not related to known imprinted syndromes, mosaic aneuploidy of <50%, and segmental mosaicism, were excluded. The calculation was performed for the overall cohort, for women aged >35 years and women aged <35 years, and after omission of noninvasive prenatal screening theoretically detectable findings (trisomies 13, 18, and 21)., Results: Clinically significant copy number variants were detected in 118 of 7734 cases (1.50% or 1:65), and high-penetrant copy number variants were detected in 33 of 7734 cases (0.43% or 1:234). In women aged ≥35 years, the rates of high-penetrant copy number variants were 29 of 5734 cases (0.51% or 1:198) and 4 of 2000 cases (0.20% or 1:500) in women aged <35 years (P=.0747). Following the omission of 12 theoretically noninvasive prenatal screening-detectable findings, the rates of high-penetrant copy number variants declined to 21 of 7722 cases (0.27% or 1:368) in the whole cohort-18 of 5723 cases (0.31% or 1:318) in woman aged ≥35 years and 3 of 1999 cases (0.15% or 1:666) in younger women (P=.319)., Conclusion: The risk of high-penetrant copy number variants in low-risk pregnancies exceeds the risk of miscarriage after invasive testing, even after normal noninvasive prenatal screening results. These results are of importance to genetic counselors and obstetricians, to facilitate maternal informed decision-making when considering invasive prenatal testing in low-risk pregnancies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Exome sequencing (ES) could detect pathogenic variants that are unrelated to the test indication, including findings that may have an impact for patients considering conception/reproduction (reproduction-related findings [RRFs]), deliberately searched secondary findings (SFs), and incidental findings (IFs). We aimed to examine the detection rate of clinically actionable findings and to present counseling dilemmas in 840 parents of probands undergoing clinical trio ES testing., Methods: RRFs/IFs/SFs were actively searched for in the parents as part of ES data analysis. Variants were filtered by frequency, mode of inheritance, ClinVar classification, presence in local pathogenic variant databases, and protein-truncating effect., Results: In 14 of 420 families (3.3%), 15 RRFs were detected. Shared parental heterozygous status for autosomal recessive disorders was identified in 23.3% of consanguineous and 1.8% of nonconsanguineous couples. SFs were found in 22 of 840 individuals (2.6%), including 15 variants (7 founder variants) in cancer-predisposing genes and 4 in cardiac disease-related genes. IFs were found in 3 individuals without reported symptoms. Overall, variants of potential medical importance were detected in 9.3% of families. Challenges related to the decision whether to report variants included unreported parental phenotype, presymptomatic testing, variable disease expressivity, potential medical implications for children who are already born, and medicolegal aspects., Conclusion: Active search for RRFs, IFs, and SFs yields a high rate of findings, which may contribute to individual medical care in parents of probands undergoing ES. A structured approach to overcome the challenges associated with reporting these findings should be considered before such an active search can be broadly adopted in clinical genomic data analysis., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors.)

Purpose: Women carriers of FMR1 premutation are at increased risk of early ovarian dysfunction and even premature ovarian insufficiency. The aim of this study was to examine a possible association between FMR1 permutation and numeric sex chromosome variations., Methods: A retrospective case-control study conducted in the reproductive center of a university-affiliated medical center. The primary outcome measure was the rate of sex chromosomal numerical aberrations, as demonstrated by haplotype analyses, in FMR1 premutation carriers compared to X-linked preimplantation genetic testing for monogenic/single gene defect (PGT-M) cycles for other indications that do not affect the ovarian follicles and oocytes., Results: A total of 2790 embryos with a final genetic analysis from 577 IVF PGT-M cycles were included in the final analysis. Mean age was similar between the groups, however, FMR1 carriers required more gonadotropins, and more women were poor responders with three or less oocytes collected. The ratio of embryos carrying a numeric sex chromosome variation was similar: 8.3% (138/1668) of embryos in the FMR1 group compared to 7.1% (80/1122) in the controls. A subgroup analysis based on age and response to stimulation has not demonstrated a significant difference either., Conclusions: Although carriers of FMR1 premutation exhibit signs of reduced ovarian response, it does not seem to affect the rate of numeric sex chromosomal variation compared to women undergoing PGT-M for other indications. This suggests that the mechanism for chromosomal number aberrations in women at advanced maternal age are different to those FMR1 premutation carriers with poor ovarian reserve., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Local and worldwide prenatal charts for estimated fetal weight and postnatal charts for head circumference are gender specific. However, prenatal head circumference nomograms are not gender customized., Objective: This study aimed to create gender-customized curves to assess between-gender head circumference differences and to study the clinical significance of using such gender-customized curves., Study Design: A single-center retrospective study was conducted between June 2012 and December 2020. Prenatal head circumference measurements were obtained from routine estimated fetal weight ultrasound scans. Postnatal head circumference measurement at birth and gender were retrieved from computerized neonatal files. Head circumference curves were created, and the normal range was defined for the male and female subpopulations. After applying gender-specific curves, we analyzed the outcome of cases classified as microcephaly and macrocephaly according to non-gender-customized curves, which were reclassified as normal according to gender-specific curves. For these cases, clinical information and postnatal long-term outcomes were retrieved from patients' medical records., Results: The cohort included 11,404 participants (6000 males and 5404 females). The curve for male head circumference was significantly higher than the female curve for all gestational weeks ( P <.0001). Applying gender customized curves resulted in fewer cases of male fetuses defined as 2 standard deviations above the normal range and female fetuses defined as 2 standard deviations below of the normal range. Cases reclassified as normal head circumference after the application of gender-customized curves were not related to increased adverse postnatal outcomes. The rate of neurocognitive phenotypes was not higher than the expected rate in both male and female cohorts. Polyhydramnios and gestational diabetes mellitus were more common in the normalized male cohort, whereas oligohydramnios, fetal growth restriction, and cesarean delivery were more common in the normalized female cohort., Conclusion: Prenatal gender-customized curves for head circumference can reduce the overdiagnosis of microcephaly in females and macrocephaly in males. According to our results, gender-customized curves did not affect the clinical yield of prenatal measurements. Therefore, we suggest that gender-specific curves be used to avoid unnecessary workup and parental anxiety., (© 2023 The Authors.)

Objective: To examine the effect of maternal age on the rate of clinically significant chromosomal microarray analysis results in pregnancies with abnormal maternal serum screening and to establish the residual risk for abnormal microarray findings after omitting noninvasive prenatal testing (NIPT)-detectable aberrations in pregnancies with abnormal maternal serum screening., Methods: This retrospective study included all chromosomal microarray analysis tests performed in pregnancies with abnormal maternal serum screening and normal ultrasonogram results over the years 2013-2021. The rate of clinically significant (pathogenic and likely pathogenic) chromosomal microarray analysis findings was compared with a local control cohort of 7,235 pregnancies with normal maternal serum screening and ultrasonogram results, stratified by maternal age. Calculation of residual risk for clinically significant chromosomal microarray analysis results after normal NIPT was performed by omission of common NIPT-detectable anomalies. Systematic review for studies examining the yield of chromosomal microarray analysis in pregnancies with abnormal maternal serum screening was performed from inception to October 2021, with no time or language restrictions., Results: Of the 559 amniocenteses performed due to abnormal maternal serum screening, 21 (3.8%; 95% CI 2.4-5.7%) clinically significant chromosomal microarray analysis results were found. The residual risk for chromosomal microarray analysis aberrations after theoretically normal NIPT was estimated to be 2.0% (95% CI 1.1-3.6%) (1/50) and was significantly higher for women younger than age 35 years with abnormal maternal serum screening, compared with women with low-risk pregnancies. Systematic review yielded six articles encompassing 4,890 chromosomal microarray analysis results in pregnancies with abnormal maternal serum screening, demonstrating 2.3% residual risk for chromosomal microarray analysis anomalies after theoretically normal NIPT., Discussion: Clinically significant chromosomal microarray analysis findings can be found in 1 of every 50 pregnancies with high-risk maternal serum screening after theoretically normal NIPT, implying that invasive testing and not NIPT should be recommended in such pregnancies. In addition, NIPT use as a first-tier screening modality instead of maternal serum screening would miss pregnancies at increased risk not only for common autosomal trisomies but for additional chromosomal microarray analysis-detectable disorders., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Chromosomal microarray analysis detects a clinically significant amount of copy number variants in approximately 1% of low-risk pregnancies. As the constantly growing use of noninvasive prenatal screening has facilitated the detection of chromosomal aberrations, defining the rate of abnormal chromosomal microarray analysis findings following normal noninvasive prenatal screening is of importance for making informed decisions regarding prenatal testing and screening options., Objective: To calculate the residual risk for clinically significant copy number variants following theoretically normal noninvasive prenatal screening., Study Design: The chromosomal microarray results of all pregnancies undergoing amniocentesis between the years 2013 and 2021 in a large hospital-based laboratory were collected. Pregnancies with sonographic anomalies, abnormal maternal serum screening, or multiple fetuses were excluded. Clinically significant (pathogenic and likely pathogenic) copy number variants were divided into the following: 3-noninvasive prenatal screening-detectable (trisomies 13, 18, and 21), 5- noninvasive prenatal screening-detectable (including sex chromosome aberrations), 5-noninvasive prenatal screening and common microdeletion-detectable (including 1p36.3-1p36.2, 4p16.3-4p16.2, 5p15.3-5p15.1, 15q11.2-15q13.1, and 22q11.2 deletions), and genome-wide noninvasive prenatal screening-detectable (including variants >7 Mb). The theoretical residual risk for clinically significant copy number variants was calculated following the exclusion of noninvasive prenatal screening-detectable findings., Results: Of the 7235 pregnancies, clinically significant copy number variants were demonstrated in 87 cases (1.2%). The residual risk following theoretically normal noninvasive prenatal screening was 1.07% (1/94) for 3-noninvasive prenatal screening, 0.78% (1/129) for 5- noninvasive prenatal screening, 0.74% (1/136) for 5- noninvasive prenatal screening including common microdeletions, and 0.68% (1/147) for genome-wide noninvasive prenatal screening. In the subgroup of 4048 pregnancies with advanced maternal age, the residual risk for clinically significant copy number variants following theoretically normal noninvasive prenatal screening ranged from 1.36% (1/73) for 3- noninvasive prenatal screening to 0.82% (1/122) for genome-wide noninvasive prenatal screening. In 3187 pregnancies of women <35 years, this residual risk ranged from 0.69% (1/145) for 3- noninvasive prenatal screening to 0.5% (1/199) for genome-wide noninvasive prenatal screening., Conclusion: The residual risk of clinically significant copy number variants in pregnancies without structural sonographic anomalies is appreciable and depends on the noninvasive prenatal screening extent and maternal age. This knowledge is important for the patients, obstetricians, and genetic counselors to facilitate informed decisions regarding prenatal testing and screening options., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: HNF1B deletion/intragenic mutations are the most commonly identified genetic cause of congenital anomalies of the kidney and urinary tract (CAKUT) suggested by fetal ultrasound findings such as: parenchymal hyperechogenicity, overt cystic changes or gross morphological urinary system (UT) abnormalities. The postnatal evolution of these 17q12 deletions encompassing the HNF1B gene-associated findings has not been assessed in depth., Methods: In this observational study, we present postnatal follow-up findings in 5 of 6 cases (one pregnancy was terminated on parental request) of fetal-onset cystic/hyperechogenic kidneys eventually diagnosed with 17q12 microdeletion encompassing the HNF1B gene between 2009 and 2017., Results: Complete normalization of kidney parenchymal abnormalities and of depressed neonatal renal function was observed in 4/5 and 5/5 patients within 2-4.9 years and 1.5-8 months, respectively. All 5 patients had preserved normal renal function at 3-11 years of follow-up. The evolving later-onset renal features included: hypomagnesemia, hyperuricemia, urinary tract infection (UTI), and bilateral grade 3-4 vesicoureteral reflux and bladder diverticula in 3, 3, 2, and 1 patient, respectively. HNF1B gene deletion-associated extra-renal manifestations with delayed presentation were global developmental delay/autistic spectrum disorder (ASD), rolandic-type seizures, overweight, and borderline fasting hyperglycemia observed in 1-2 patients each. Family history was positive for small-size or asymptomatic cystic kidneys with normal function, diabetes mellitus, seizures, and mental/psychiatric problems in 3/6 cases., Conclusions: Fetal-onset HNF1B deletion-associated kidneys' parenchymal abnormalities confirmed postnatally with initially depressed renal function might undergo complete resolution within several years and few months, respectively. However, later-onset urinary tract, metabolic, and neurodevelopmental features of this mutation might appear over years. Therefore, genetic molecular evaluation/diagnosis and continuous follow-up for evolving features are mandatory in affected children., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tp-21-386). The authors have no conflicts of interest to declare., (2021 Translational Pediatrics. All rights reserved.)

We describe a case of Beckwith-Wiedemann syndrome (BWS) demonstrating pre- and post-natal intra-familial variability. Our first encounter with the family occurred in the 1990s following the birth of 3 affected offspring. The first two pregnancies presented with exomphalos and elevated second trimester maternal serum alpha-fetoprotein (msAFP, 3.43 and 4.01 MOM, respectively) as well as elevated maternal human chorionic gonadotrophin (mhCG, 4.33 and 8.8 MOM, respectively). The diagnosis of BWS was confirmed postnatally in both cases. The third ongoing pregnancy presented only with elevated mhCG (7.09 MOM) and no malformation. Nonetheless BWS was suspected. The diagnosis was confirmed postnatally with clinical manifestations including macroglossia and cleft palate. Two affected female siblings were also diagnosed with Mullerian agenesis in adulthood. Suspecting a common genetic etiology, sequencing of the CDKN1C gene revealed a maternally inherited, likely pathogenic variant (NM&#95;000076.2: c.367&#95;385del; p.(Ala123Serfs*143)) causative of BWS. Chromosomal microarray and whole exome sequencing did not reveal any other pathogenic variant that would explain the Mullerian agenesis. One of the affected females underwent successful preimplantation genetic testing (PGT) with a surrogate and gave birth to a healthy female. To the best of our knowledge, this is the first report of Mullerian agenesis as a possible rare expansion of the BWS phenotype. In addition, this case highlights the potential role of abnormal second trimester biochemical markers (msAFP, mHCG) as possible indicators of BWS, especially in familial cases., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Objectives: Phacomatoses are a group of neuro-oculo-cutaneous syndromes/ neurocutaneous disorders, involving structures arising from the embryonic ectoderm. Most of phacomatoses including the most common ones:, neurofibromatosis type I and type II (NF1, NF2) and tuberosclerosis complex (TSC), are autosomal dominant genetic disorders with full penetrance and variable expression. As no effective treatment exists, the only way to prevent the disease, is by prenatal genetic diagnosis (either chorionic villus sampling-CVS or amniocentesis-AC) and termination of pregnancy or performing preimplantation genetic testing (PGT). As the risk for an affected offspring is 50% in every pregnancy of an affected parent, prenatal, and preimplantation testing are of great importance. However, those procedures are associated with technical and ethical concerns. This chapter shortly reviews the common phacomatoses emphasizes their genetics and inheritance. We will review the common methods for prenatal and preimplantation diagnoses and discuss its use in common phacomatoses., Conclusion: Phacomatoses are common autosomal dominant genetic conditions with variable expression. Ante-natal genetic diagnosis is an appropriate approach for family planning in individuals affected by phacomatosis or parents of an affected child.

Introduction: Our objective was to evaluate the incidence of chromosomal aberration (both microscopic and submicroscopic) and the clinical outcome of fetuses with isolated muscular ventricular septal defect (VSD). Material and methods: The study included 40 pregnant women whose fetuses were diagnosed with isolated muscular ventricular septal defect (mVSD). Of these, 30 patients underwent amniocentesis and 10 declined. All samples were tested by chromosomal microarray analysis (CMA). Of the 40 women in the study, 32 gave birth and the clinical outcome of the children was retrieved from the patients' medical records. Results: Of the 30 patients who underwent amniocentesis, one was detected with mosaic Klinefelter syndrome and one was detected with a pathogenic copy number variant unrelated to the VSD. Clinical follow-up was performed on 26 children after birth. The first postnatal echocardiography did not detect a VSD in 13 (50%) of the followed-up children. Spontaneous closure occurred in another eight (30.8%) children during the postnatal follow-up period. In only five children (19.2%) VSD was still detected by echocardiography after the first year of life. Discussion: Isolated muscular VSD diagnosed prenatally does not appear to be a significant risk factor for chromosomal abnormalities and has a favorable clinical outcome.

Background: Chromosomal microarray analysis is standard of care in fetuses with malformations, detecting clinically significant copy number variants in 5-7% of cases over conventional karyotyping. However, it also detects variants of uncertain significance in 1.6-4.2% of the cases, some of which are low-penetrance neuro-susceptibility loci. The interpretation of these variants in pregnancy is particularly challenging because the significance is often unclear and the clinical implications may be difficult to predict., Objective: The purpose of this study was to describe counseling dilemmas regarding low-penetrance neuro-susceptibility loci that are detected by prenatal chromosomal microarray analysis., Study Design: During the study period (January 2014 to December 2015), 700 prenatal chromosomal microarray analyses were performed. Cases were categorized as "indicated" (n=375) if there were abnormal sonographic findings or suggestive medical history and "patient choice" (n=325) in the presence of a structurally normal fetus with no other particular indication. The laboratory reported on copy number variants ≥400 Kb in size in loci known to be associated with genetic syndromes and ≥1 Mb in other areas of genome. Results were classified as gross aneuploidy, copy number variants, and normal. Copy number variants were categorized according to the American College of Medical Genetics standards and guidelines: pathogenic, variants of uncertain significance, or benign. Variants of uncertain significance were further subdivided into categories of likely pathogenic, variants of uncertain significance with no subclassification, and likely benign. Statistical analysis was performed with the use of Chi square test and Fisher's exact test to compare intergroup differences in incidence of the different result categories and demographic data., Results: Patient choice cases became more prevalent with time (35.5% in the beginning of the study, compared with 48.4% at the end of the study period). Clinically significant copy number variants were found in 14 of 375 (3.7%) of indicated cases vs only 2 of 325 (0.6%) of patient choice cases (P=.009). All "likely benign" variants consisted of low-penetrance neuro-susceptibility loci. The incidence thereof was similar between the indicated and patient choice groups (3.7% vs 3.4%; P=.85). In the indicated group, some variants of uncertain significance may have contributed to the abnormal anatomic findings. Conversely, in the patient choice group, the finding of low-penetrance neuro-susceptibility loci was often unexpected and confounding for prospective parents., Conclusion: Prenatal chromosomal microarray analysis added clinically significant information in both groups. However, it also detected low-penetrance neuro-susceptibility loci in approximately 3.5% of the cases. This fact should be conveyed during pretest counseling to allow patients to make informed choices, particularly when chromosomal microarray is to be performed for patient choice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Meconium-stained amniotic fluid (MSAF) is rarely observed in preterm pregnancies, and its clinical significance is undetermined. We evaluated the correlation between MSAF and obstetrical and perinatal complications prior to 34 weeks' gestation., Materials and Methods: Pregnancies complicated with MSAF between 24 and 34 weeks of gestation were compared with same gestational age-matched controls. The variables measured were: obstetrical complications: clinical chorioamnionitis, Intrahepatic Cohlestasis of Pregnancy - ICP, Intra Uterine Growth Restriction - IUGR, preeclampsia, gestational diabetes; nonobstetrical complications; and perinatal complications: cord around neck/body, Apgar <7 at 5 min, cord pH, Neonatal Intensive Care Unit - NICU admission, complications during NICU hospitalization, and composite outcome., Results: Higher incidence of clinical chorioamnionitis (15% versus 4.3%; p = 0.041) and higher incidence of cord around the neck/body were found in the MSAF group in comparison with the clear AF group (27.4% versus 18.4%; p = 0.04). No significant differences between the study's groups were found in nonobstetrical complications or other perinatal complications investigated in our study., Conclusion: MSAF in preterm pregnancy is an ominous sign for the occurrence of chorioamnionitis and for in utero cord compression. Therefore, MSAF in preterm pregnancies should be considered as a non-reassuring sign.

Objectives: The objective of this study is to evaluate the incidence of chromosomal aberration (both microscopic and sub-microscopic) in fetuses with an aberrant right subclavian artery (ARSA) detected by ultrasonographic anomaly scan., Methods: The study included 62 pregnant women whose fetuses were diagnosed with ARSA who were referred for genetic counseling. Of these, 55 patients underwent amniocentesis and 7 declined invasive testing. All 55 amniocentesis samples were tested by standard G-banding and chromosomal microarray, except for 2 samples for which only karyotype and fluorescence in situ hybridization for 22q11.2 deletions were performed., Results: Of the 55 women who underwent amniocentesis, 5 were detected with trisomy 21 (9.1%), all of whom had additional ultrasound findings. Among the 14 fetuses with ARSA and additional ultrasound findings, the incidence of trisomy 21 was 35.7%. In fetuses with isolated ARSA, no chromosomal aberrations were detected by standard cytogenetic analysis and only one (1.9%) deleterious copy number variants (CNV) was detected by chromosomal microarray., Conclusion: Aberrant right subclavian artery with additional ultrasound findings constitute a strong predictor for aneuploidy. However, when ARSA is found in isolation, it confers no increased risk for aneuploidy or pathogenic CNVs. © 2017 John Wiley & Sons, Ltd., (© 2017 John Wiley & Sons, Ltd.)