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Background: Chromosomal‐microarray‐analysis (CMA) may reveal susceptibility‐loci (SL) of varied penetrance for autism‐spectrum‐disorder (ASD) and other neurodevelopmental conditions. Attitudes of women/parents to disclosure of SL during pregnancy are understudied. Methods: A multiple‐choice questionnaire was distributed to postpartum women. Data were collected on women's interest to receive prenatal genetic information with various levels of penetrance. Results: Women's (n = 941) disclosure choices were dependent on the magnitude of risk: approximately 70% supported disclosure of either full or 40% penetrance, 53% supported disclosure at a 20% risk threshold, and 40% supported disclosure at 10% or less. Although most women supported, rejected or were indecisive about disclosure consistently across all risk levels, nearly one‐quarter (24%) varied their responses based on penetrance, and this was associated with religiosity, education, parity and concern about fetal health (p‐values <0.04). Among those who varied their choices, the risk threshold was lower among secular women (20%) than among ultraorthodox women (40%). In a multivariable analysis, ultraorthodox women were much less likely to vary their choices on ASD disclosure compared with secular women (aOR = 0.37, p < 0.001). Conclusion: Women's attitudes toward disclosure are influenced by the level of risk and their individual characteristics. We therefore encourage engaging women/couples in disclosure decisions regarding uncertain and probabilistic results from prenatal genomic tests. Key points: What's already known about this topic? Disclosure policy of susceptibility‐loci (SL) ranges from full disclosure via the disclosure of SLs with 20% and above penetrance to parental choice regarding low penetrance SL.When offered a choice, women tend to request maximum information on their fetuses. What does this study add? Women's attitudes toward the disclosure of genetic information are influenced not only by the severity of the condition but also by the level of risk.Choices are associated with women's cultural characteristics. [ABSTRACT FROM AUTHOR]

Genomic disorders result from heterozygous copy number variants (CNVs). Homozygous deletions spanning numerous genes are rare, despite the potential contribution of consanguinity to such instances. CNVs in the 22q11.2 region are mediated by nonallelic homologous recombination between pairs of low copy repeats (LCRs), from amongst eight LCRs designated A‐H. Heterozygous distal type II deletions (LCR‐E to LCR‐F) have incomplete penetrance and variable expressivity, and can lead to neurodevelopmental issues, minor craniofacial anomalies, and congenital abnormalities. We report siblings with global developmental delay, hypotonia, minor craniofacial anomalies, ocular abnormalities, and minor skeletal issues, in whom chromosomal microarray identified a homozygous distal type II deletion. The deletion was brought to homozygosity as a result of a consanguineous marriage between two heterozygous carriers of the deletion. The phenotype of the children was strikingly more severe and complex than that of the parents. This report suggests that the distal type II deletion harbors a dosage‐sensitive gene or regulatory element, which leads to a more severe phenotype when deleted on both chromosomes. [ABSTRACT FROM AUTHOR]

Background Copy number variants (CNVs) associated with late-onset medical conditions are rare but important secondary findings in chromosomal microarray analysis (CMA) performed during pregnancy. Here, we critically review the cases at two tertiary centres to assess the criteria which guide the disclosure of such findings and develop a disclosure decision tool (DDT) aimed at facilitating disclosure decision. Parental decisions on receiving CNVs associated with risks for late-onset conditions were also recorded. Methods Prenatal CMAs in Hadassah and Shaare Zedek Medical Centers from November 2013 to October 2021 were reviewed for CNVs associated with late-onset conditions. The DDT proposed uses a five-parameter scoring system, which considers the severity, median age of onset, penetrance, understanding of genotype-phenotype correlation and actionability of the finding. Results Out of 16 238 prenatal CMAs, 16 (0.1%) harboured CNVs associated with late-onset conditions, 15 of which were disclosed. Outcome information was available on 13 of the 16 pregnancies, all of which continued to delivery. Conclusions Our suggested DDT will help clinicians to quantitatively weigh the variables associated with CNVs of this type and arrive at a well thought out clinical decision regarding disclosure. Although the prevalence of late-onset conditions as a major finding in the prenatal setup is low, it is expected to rise with the increasing use of non-invasive CMA testing and whole exome and genome sequencing. [ABSTRACT FROM AUTHOR]

Fetal Alcohol Spectrum Disorder (FASD) is a set of developmental malformations caused by alcohol consumption during pregnancy. Fetal Alcohol Syndrome (FAS), the strongest manifestation of FASD, results in short stature, microcephally and facial dysmorphogenesis including microphthalmia. Using Xenopus embryos as a model developmental system, we show that ethanol exposure recapitulates many aspects of FAS, including a shortened rostro-caudal axis, microcephally and microphthalmia. Temporal analysis revealed that Xenopus embryos are most sensitive to ethanol exposure between late blastula and early/mid gastrula stages. This window of sensitivity overlaps with the formation and early function of the embryonic organizer, Spemann's organizer. Molecular analysis revealed that ethanol exposure of embryos induces changes in the domains and levels of organizer-specific gene expression, identifying Spemann's organizer as an early target of ethanol. Ethanol also induces a defect in convergent extension movements that delays gastrulation movements and may affect the overall length. We show that mechanistically, ethanol is antagonistic to retinol (Vitamin A) and retinal conversion to retinoic acid, and that the organizer is active in retinoic acid signaling during early gastrulation. The model suggests that FASD is induced in part by an ethanol-dependent reduction in retinoic acid levels that are necessary for the normal function of Spemann's organizer. Keywords: FAS; FASD; Retinol; Vitamin A; Fetal alcohol syndrome; gsc; Cyp26; Embryonic organizer; Gastrula; Xenopus

Objective: To explain the importance of identifying an etiology for the pathological finding of nonimmune hydrops fetalis (NIHF) and to explore the impact of exome sequencing in recurrent NIHF. In addition, we present two cases of pregnancies affected with recurrent NIHF, in which genetic investigation was advantageous. Methods: Our study aimed to investigate the genetic background, if available, of all fetuses with NIHF referred to our tertiary medical center from January 2013 to August 2020. We summarized the etiology of NIHF if known, sonographic findings, genetic investigation and the pregnancies' outcomes. Results: We encountered 144 families with NIHF. Genetic investigation was performed by chromosomal microarray analysis (CMA) in 63 (63/144. 44%) fetuses. Seventeen of 63 (27%) had a positive CMA result. In the negative CMA group, 15 (15/46, 33%) opted for exome sequencing, of which seven exomes were positive (47%). Among these, there were four couples with recurrent pregnancies affected by hydrops. Among the remaining 11 exome investigations for non‐recurrent hydrops, another three were diagnostic. Conclusion: As identifying the etiology of the NIHF is an invaluable tool for the prognosis of the pregnancy, exome sequencing can provide further elucidation of the underlying pathogenesis of NIHF. Thus, genetic investigation should be recommended for cases of NIHF. Key points: What is already known about this topic? Exome sequencing has high diagnostic yield in detecting monogenic disordersA delineated monogenic etiology for the cause of a sonographic finding will help parents make informed decisions regarding family planningAdditionally, an inherited pathogenic variant of a dominant mode from a mildly affected parent to a severely affected fetus might be surprising but invaluable for the parents What does this study add? Exome sequencing is a powerful tool in the investigation of recurrent nonimmune hydrops fetalis (NIHF) and thus clinicians should consider embedding trio‐exome sequencing in the investigation of cases of unexplained NIHFWe describe seven monogenic etiologies for NIHF. The novel variants in the PIEZO1, GLDN and FOXC2 and DOK7 genes were identified in recurrent cases through exome sequencing and are related to the outlined clinical manifestations [ABSTRACT FROM AUTHOR]

Introduction: Duplication of the renal collecting system is one of the most common variants of urinary tract anatomy. The objective of our study was to examine the risk for chromosomal aberrations in this isolated prenatal sonographic finding. Methods: Data from all chromosomal microarray analyses (CMA) reported to the Ministry of Health between January 2013 and September 2017 were retrospectively obtained from a computerized database. All pregnancies with a sonographic diagnosis of the isolated duplex renal collecting system and documentation of CMA result were included. Rate of abnormal CMA findings was compared to the general population risk, based on a systematic review encompassing 9272 cases with normal ultrasound and a local data of 5541 pregnancies undergoing CMA due to maternal request. Results: Two pathogenic CMA finding was found amongst 143 pregnancies with double collecting system (1.4%), not significantly different from the risk for abnormal CMA results in the general population. In addition, five variants of unknown significance were demonstrated (3.5%). Conclusion: To our best knowledge, this analysis is the first report describing the rate of chromosomal anomalies in pregnancies with isolated duplex renal collecting system. Its results suggest that routine invasive prenatal testing with CMA analysis in such cases is no more useful than in the general population. Prospective well-adjusted studies are needed to guide the optimal management of these pregnancies. [ABSTRACT FROM AUTHOR]

Clinical laboratory diagnostic evaluation of the genomes of children with suspected genetic disorders, including chromosomal microarray and exome sequencing, cannot detect copy number neutral genomic rearrangements such as inversions, balanced translocations, and complex chromosomal rearrangements (CCRs). We describe an infant with a clinical diagnosis of Cornelia de Lange syndrome (CdLS) in whom chromosome analysis revealed a de novo complex balanced translocation, 46,XY,t(5;7;6)(q11.2;q32;q13)dn. Subsequent molecular characterization by whole‐genome sequencing (WGS) identified 23 breakpoints, delineating segments derived from four chromosomes (5;6;7;21) in ancestral or inverted orientation. One of the breakpoints disrupted a known CdLS gene, NIPBL. Further investigation revealed paternal origin of the CCR allele, clustering of the breakpoint junctions, and molecular repair signatures suggestive of a single catastrophic event. Notably, very short DNA segments (25 and 41 bp) were included in the reassembled chromosomes, lending additional support that the DNA repair machinery can detect and repair such segments. Interestingly, there was an independent paternally derived miniscule complex rearrangement, possibly predisposing to subsequent genomic instability. In conclusion, we report a CCR causing a monogenic Mendelian disorder, urging WGS analysis of similar unsolved cases with suspected Mendelian disorders. Breakpoint analysis allowed for identification of the underlying molecular diagnosis and implicated chromoanagenesis in CCR formation. [ABSTRACT FROM AUTHOR]

Objective: To examine the risk for abnormal chromosomal microarray analysis (CMA) results among fetuses with an apparently isolated pelvic kidney. Methods: Data from all CMA analyses performed due to an isolated pelvic kidney reported to the Israeli Ministry of Health between January 2013 and September 2016 were retrospectively obtained. Risk estimation was performed comparing the rate of abnormal observed CMA findings to the general population risk, based on a systematic review encompassing 9272 cases and on local data of 5541 cases. Results: Of 120 pregnancies with an isolated pelvic kidney, two gain-of-copy number variants suggesting microduplication syndromes were demonstrated (1.67%). In addition, three variants of unknown significance were detected (2.5%). Conclusion: The risk for clinically significant CMA findings among pregnancies with an isolated single pelvic kidney was not significantly different compared to both control populations. The results of our study question the practice of routine CMA analysis in fetuses with an isolated pelvic kidney. [ABSTRACT FROM AUTHOR]

The laterality in the embryo is determined by left-right asymmetric gene expression driven by the flow of extraembryonic fluid, which is maintained by the rotary movement of monocilia on the nodal cells. Defects manifest by abnormal formation and arrangement of visceral organs. The genetic etiology of defects not associated with primary ciliary dyskinesia is largely unknown. In this study, we investigated the cause of situs anomalies, including heterotaxy syndrome and situs inversus totalis, in a consanguineous family. Whole-exome analysis revealed a homozygous deleterious deletion in the WDR16 gene, which segregated with the phenotype. WDR16 protein was previously proposed to play a role in cilia-related signal transduction processes; the rat Wdr16 protein was shown to be confined to cilia-possessing tissues and severe hydrocephalus was observed in the wdr16 gene knockdown zebrafish. The phenotype associated with the homozygous deletion in our patients suggests a role for WDR16 in human laterality patterning. Exome analysis is a valuable tool for molecular investigation even in cases of large deletions. [ABSTRACT FROM AUTHOR]