Search

Objective: To report a case of a fetus with multiple congenital anomalies and suspected Barth syndrome, highlighting potential phenotypic expansion of the syndrome., Methods: A 32-year-old G4P2011 patient was referred at 18w5d gestation for suspected fetal encephalocele. Serial imaging, including ultrasound and MRI, was performed to evaluate fetal anomalies. Doppler studies assessed fetal development and postnatal findings were documented. Genetic variants were identified using trio whole exome sequencing., Results: Initial ultrasound revealed occipital encephalocele, right renal aplasia, and abnormal vertebral curvature. Follow-up MRI confirmed occipital encephalocele and identified Chiari malformation but normal renal morphology. Phenotypic evolution included intrauterine growth restriction (IUGR), right renal hypoplasia, cardiomegaly, polyhydramnios, and hydrops fetalis. Delivery occurred via cesarean section at 30w6d due to non-reassuring Doppler findings. Postnatally, the neonate exhibited esophageal atresia, vertebral segmentation and rib morphology defects, and right renal aplasia. The neonate died on the first day of life due to cardiac decompensation. Genetic testing identified a TAFAZZIN c.589G>A p.(Gly197Arg) pathogenic variant, consistent with Barth syndrome., Conclusion: The presentation of IUGR, cardiomyopathy, and hydrops fetalis aligns with Barth syndrome. However, the additional findings of occipital encephalocele, renal aplasia, and vertebral and rib anomalies suggest a potential phenotypic expansion of Barth syndrome., (© 2025 John Wiley & Sons Ltd.)

Gain-of-function variants in the WDR44 gene have recently been associated with an X-linked ciliopathy-related neurodevelopmental phenotype. Here, we report on a WDR44 loss-of-function (LOF) variant identified in the genome sequence from a male fetus enrolled in the Prenatal Genetic Diagnosis by Genomic Sequencing (PrenatalSEQ) multicenter study. The phenotype is consistent with the described X-linked ciliopathy that includes developmental delay, microcephaly, congenital heart defects, kidney abnormalities, cryptorchidism, musculoskeletal abnormalities, craniofacial dysmorphism, and effusions. This is the first report of a WDR44 LOF variant in an affected individual with a prenatal presentation and supports LOF as a mechanism for the X-linked WDR44 ciliopathy-related phenotype., (© 2024 Wiley Periodicals LLC.)

Purpose: To describe the association between geographic location of residence and use of aneuploidy screening or prenatal genetic counseling and how it is modified by maternal race and ethnicity., Methods: Retrospective cohort of individuals at a tertiary care center between 2017-2019. County of residence was classified as rural or metropolitan based in US Office of Management and Budget 2019 definitions. Maternal race and ethnicity were self-identified. Our composite outcome was defined as use of aneuploidy screening or genetic counseling visit. The composite outcome was compared by geographic location and ethnicity. Logistic regression was used to model the relationship between geographic location and the composite outcome., Results: A total of 8774 pregnancies were included. Of these, 4770 (54%) had genetic screening, and 3781 (43%) had at least 1 genetic counseling visit. Rural patients were significantly less likely to have the composite outcome compared with metropolitan peers (37.1% vs 47.2%, P < .001). In addition, we identified differences in the composite outcome between White rural patients and LatinX rural patients (37.7% vs 35.6%, P < .001) and between Asian rural patients and LatinX and Black rural patients (41.0% vs 35.6%, P < .001; 41.0% vs 36.8%, P < .001). Logistic regression demonstrated that rural patients were significantly less likely to have the composite outcome compared with metropolitan peers, after adjusting for LatinX ethnicity and gestational age at first prenatal visit (OR 0.72, [0.55, 0.95], P = .002)., Conclusion: Rural, minority patients were significantly less likely to receive reproductive genetic services compared with metropolitan peers extending our knowledge of disparities in maternity care., Competing Interests: Conflict of Interest Asha N. Talati receives research support from the National Institutes of Health, Billion to One, and The Greenwall Foundation. Divya P. Mallampati receives salary support from the Department of Health and Human Services. Neeta L. Vora receives research support from National Institutes of Health and received supplies in kind from Illumina unrelated to this research., (Copyright © 2024. Published by Elsevier Inc.)

Objective: GREB1L has been linked prenatally to Potter's sequence, as well as less severe anomalies of the kidney, uterus, inner ear, and heart. The full phenotypic spectrum is unknown. The purpose of this study was to characterize known and novel pre- and postnatal phenotypes associated with GREB1L., Methods: We solicited cases from the Fetal Sequencing Consortium, screened a population-based genomic database, and conducted a comprehensive literature search to identify disease cases associated with GREB1L. We present a detailed phenotypic spectrum and molecular changes., Results: One hundred twenty-seven individuals with 51 unique pathogenic or likely pathogenic GREB1L variants were identified. 24 (47%) variants were associated with isolated kidney anomalies, 19 (37%) with anomalies of multiple systems, including one case of hypoplastic left heart syndrome, five (10%) with isolated sensorineural hearing loss, two (4%) with isolated uterine agenesis; and one (2%) with isolated tetralogy of Fallot., Conclusion: GREB1L may cause complex congenital heart disease (CHD) in humans. Clinicians should consider GREB1L testing in the setting of CHD, and cardiac screening in the setting of GREB1L variants., (© 2024 John Wiley & Sons Ltd.)

Purpose: To evaluate whether deep prenatal phenotyping of fetal brain abnormalities (FBAs) increases diagnostic yield of trio-exome sequencing (ES) compared with standard phenotyping., Methods: Retrospective exploratory analysis of a multicenter prenatal ES study. Participants were eligible if an FBA was diagnosed and subsequently found to have a normal microarray. Deep phenotyping was defined as phenotype based on targeted ultrasound plus prenatal/postnatal magnetic resonance imaging, autopsy, and/or known phenotypes of other affected family members. Standard phenotyping was based on targeted ultrasound alone. FBAs were categorized by major brain findings on prenatal ultrasound. Cases with positive ES results were compared with those that have negative results by available phenotyping, as well as diagnosed FBAs., Results: A total of 76 trios with FBAs were identified, of which 25 (33%) cases had positive ES results and 51 (67%) had negative results. Individual modalities of deep phenotyping were not associated with diagnostic ES results. The most common FBAs identified were posterior fossa anomalies and midline defects. Neural tube defects were significantly associated with receipt of a negative ES result (0% vs 22%, P = .01)., Conclusion: Deep phenotyping was not associated with increased diagnostic yield of ES for FBA in this small cohort. Neural tube defects were associated with negative ES results., Competing Interests: Conflict of Interest Neeta Vora receives supplies in kind from Illumina for an NIH grant on whole genome sequencing unrelated to the data in this paper. All other authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

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&#95;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., (© 2023 John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

Exome sequencing is a powerful tool in prenatal and postnatal genetics and can help identify novel candidate genes critical to human development. We describe seven unpublished probands with rare likely pathogenic variants or variants of uncertain significance that segregate with recessive disease in TBC1D32, including four fetal probands in three unrelated pedigrees and three pediatric probands in unrelated pedigrees. We also report clinical comparisons with seven previously published patients. Index probands were identified through an ongoing prenatal exome sequencing study and through an online data sharing platform (Gene Matcher™). A literature review was also completed. TBC1D32 is involved in the development and function of cilia and is expressed in the developing hypothalamus and pituitary gland. We provide additional data to expand the phenotype correlated with TBC1D32 variants, including a severe prenatal phenotype associated with life-limiting congenital anomalies., (© 2023 Wiley Periodicals LLC.)

Purpose: To describe psychological outcomes among people with recurrent anomalous pregnancies pursuing trio-exome sequencing (exome sequencing (ES)) compared to those with one affected., Methods: We analyzed data from a prospective ES cohort, enrolling patients with major fetal anomaly and normal microarray. Participants completed validated scales before and after ES. We (1) compared responses of those with multiple anomalous pregnancies to those with one affected and (2) conducted linear regression to examine associations between multiple affected pregnancies and post-ES constructs., Results: Of 166 trios, 61 (37%) received results from ES. Forty (24%) had more than one affected pregnancy and 45% of those received a result explaining the fetal phenotype. All participants had clinically significant presequencing generalized psychological distress. For the 93 who completed the post-ES surveys, those with multiple affected pregnancies had higher psychological adaptation scores but worse test related distress scores (9.3 (6.2) versus 7.1(5.6), p = 0.12) and (14.3 (1.5) versus 15.4 (1.4), p = 0.01). In linear regression models, there were no significant differences in post-ES constructs after adjusting for clinically relevant covariates., Conclusions: All individuals experienced significant generalized psychological distress in the pre-ES period, extending our knowledge of how pregnancy history contributes to parental sequencing outcomes., (© 2023 John Wiley & Sons Ltd.)

Purpose: To understand motivations for and parental interpretation of results from trio-exome sequencing (ES) for fetal anomalies with a negative standard genetic diagnosis., Methods: Analysis of an ongoing, prospective prenatal trio-ES study of pregnancies with ultrasound-identified congenital anomalies and lack of a standard genetic diagnosis. After determination of pregnancy disposition, participants completed questionnaires and a semi-structured interview pre- and post-sequencing. Interviews were analyzed using a constructivist grounded theory methodology to identify themes. Associations between themes and ES result were also examined., Results: One hundred twenty-six trios have been sequenced. Of those, 45 (36%) resulted in fetal diagnosis. One hundred twenty-five women completed pre-sequencing surveys, and 91 women completed post-sequencing surveys. The main themes identified include (1) variable reasons to pursue ES, (2) limited expectations but high hopes from ES, (3) parental adaptation to uncertain results, (4) impact on personal health and reproduction, and (5) gratitude for the process., Conclusion: Participants pursued ES for various reasons, most often to identify a diagnosis and guide reproduction. Post-sequencing, most participants described the process, their interpretation of results, and the impact of receiving the results. Less frequently, but of most concern, participants expressed anxiety about testing and implications for themselves, relationships, and other family members, thus identifying an area of high need for additional support among patients undergoing prenatal ES., (© 2022 John Wiley & Sons Ltd.)

Objective: Sequencing cell-free DNA now allows detection of large chromosomal abnormalities and dominant Mendelian disorders in the prenatal period. Improving upon these methods would allow newborn screening programs to begin with prenatal genetics, ultimately improving the management of rare genetic disorders., Methods: As a pilot study, we performed exome sequencing on the cell-free DNA from three mothers with singleton pregnancies to assess the viability of broad sequencing modalities in a noninvasive prenatal setting., Results: We found poor resolution of maternal and fetal genotypes due to both sampling and technical issues., Conclusion: We find broad sequencing modalities inefficient for noninvasive prenatal applications. Alternatively, we suggest a more targeted path forward for noninvasive prenatal genotyping., (© 2021 John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

Purpose: To evaluate associations between prenatal trio exome sequencing (trio-ES) and psychological outcomes among women with an anomalous pregnancy., Methods: Trio-ES study enrolling patients with major fetal anomaly and normal microarray. Women completed self-reported measures and free response interviews at two timepoints: pre- (1) and post- (2) sequencing. Pre-sequencing responses were compared with post-sequencing responses; post-sequencing responses were stratified by women who received trio-ES results that may explain fetal findings, secondary findings (medically actionable or couples with heterozygous variants for the same recessive disorder), or negative results., Results: One hundred fifteen trios were enrolled. Of those, 41/115 (35.7%) received results from trio-ES, including 36 (31.3%) who received results that may explain the fetal phenotype. These women had greater post-sequencing distress compared with women who received negative results, including generalized distress (p = 0.03) and test-related distress (p = 0.2); they also had worse psychological adaptation to results (p = 0.001). Genomic knowledge did not change from pre- to post-sequencing (p = 0.51)., Conclusion: Women show more distress after receiving trio-ES results compared with those who do not, suggesting that women receiving results may need additional support or counseling to inform current and future reproductive decisions.

Persistent hypoxic or low-oxygen conditions in aquatic systems are becoming more frequent worldwide, causing large-scale mortalities to aquatic fauna. It is poorly understood, however, whether species can acclimate to long-term hypoxic conditions. In two experiments, we exposed juvenile freshwater fish (Murray cod, Maccullochella peelii ) to low-oxygen conditions and investigated acclimation effects. Experiment 1 determined how responses could be modified by exposure to different temperatures (20, 24 and 28°C) and oxygen conditions (control 6-8 mgO 2 L -1 and low-oxygen 3-4 mgO 2 L -1 ) over 30 days. Experiment 2 determined the acclimation ability of fish exposed to two temperatures (20 and 28°C) and low-oxygen conditions (3-4 mgO 2 L -1 ) for three different acclimation periods (7, 14 and 30 days). Responses were measured by determining critical oxygen tension ( P crit ), loss of equilibrium and aerobic capacity using resting respirometry. In experiment 1, resting oxygen requirements were negatively affected by long-term low-oxygen exposure except at the highest temperature (28°C). However, long-term acclimation in low-oxygen improved tolerance as measured by loss of equilibrium but not P crit . In experiment 2, fish could tolerate lower oxygen levels before reaching loss of equilibrium after 7 days acclimation, but this declined overtime. Murray cod were most tolerant to low-oxygen at the lowest temperature (20°C) and shortest exposure time (7 days). Extended low-oxygen exposure resulted in reduced aerobic capacity of fish particularly at the lowest temperature. While prior exposure to low-oxygen may allow fish to cope with hypoxic conditions better in the long-term, acclimation time was inversely related to tolerance, suggesting that resistance to hypoxia might decrease as a function of exposure time. Our study fills a much-needed gap in our understanding of how freshwater species acclimate to hypoxia, and in particular, how exposure to prolonged periods of low-oxygen and elevated temperatures affect organisms physiologically., (© The Author(s) 2019. Published by Oxford University Press and the Society for Experimental Biology.)

Hypoxic or oxygen-free zones are linked to large-scale mortalities of fauna in aquatic environments. Studies investigating the hypoxia tolerance of fish are limited and focused on marine species and short-term exposure. However, there has been minimal effort to understand the implications of long-term exposure on fish and their ability to acclimate. To test the effects of long-term exposure (months) of fish to hypoxia we devised a novel method to control the level of available oxygen. Juvenile golden perch (Macquaria ambigua ambigua), and silver perch (Bidyanus bidyanus), two key native species found within the Murray Darling Basin, Australia, were exposed to different temperatures (20, 24 and 28 °C) combined with normoxic (6-8 mgO 2  L -1 or 12-14 kPa) and hypoxic (3-4 mgO 2  L -1 or 7-9 kPa) conditions. After 10 months, fish were placed in individual respirometry chambers to measure standard and maximum metabolic rate (SMR and MMR), absolute aerobic scope (AAS) and hypoxia tolerance. Golden perch had a much higher tolerance to hypoxia exposure than silver perch, as most silver perch died after only 1 month exposure. Golden perch acclimated to hypoxia had reduced MMR at 20 and 28 °C, but there was no change to SMR. Long-term exposure to hypoxia improved the tolerance of golden perch to hypoxia, compared to individuals held under normoxic conditions suggesting that golden perch can acclimate to levels around 3 mgO 2 L -1 (kPa ~ 7) and lower. The contrasting tolerance of two sympatric fish species to hypoxia highlights our lack of understanding of how hypoxia effects fish after long-term exposure.

The extracellular region of the transmembrane neural cell adhesion molecule (NCAM-EC) is shed as a soluble fragment at elevated levels in the schizophrenic brain. A novel transgenic mouse line was generated to identify consequences on cortical development and function of expressing soluble NCAM-EC from the neuron-specific enolase promoter in the developing and mature neocortex and hippocampus. NCAM-EC transgenic mice exhibited a striking reduction in synaptic puncta of GABAergic interneurons in the cingulate, frontal association cortex, and amygdala but not hippocampus, as shown by decreased immunolabeling of glutamic acid decarboxylase-65 (GAD65), GAD67, and GABA transporter 1. Interneuron cell density was unaltered in the transgenic mice. Affected subpopulations of interneurons included basket interneurons evident in NCAM-EC transgenic mice intercrossed with a reporter line expressing green fluorescent protein and by parvalbumin staining. In addition, there appeared to be a reduction in excitatory synapses, as revealed by synaptophysin staining and apical dendritic spine density of cortical pyramidal cells. Behavioral analyses demonstrated higher basal locomotor activity of NCAM-EC mice and enhanced responses to amphetamine and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate compared with wild-type controls. Transgenic mice were deficient in prepulse inhibition, which was restored by clozapine but not by haloperidol. Additionally, NCAM-EC mice were impaired in contextual and cued fear conditioning. These results suggested that elevated shedding of NCAM perturbs synaptic connectivity of GABAergic interneurons and produces abnormal behaviors that may be relevant to schizophrenia and other neuropsychiatric disorders.

Electromyography can be a useful tool for the physiotherapist to obtain information about the timing or magnitude of muscle activity when investigating the neuromuscular reflexes, muscle performance or patterns of movement. The quality of the signal recorded is dependent on the correct siting of electrodes, adequate skin preparation and the characteristics of the EMG machine itself. In order to accurately interpret the EMG data the user must be able to recognize artefacts which may distort the recording, and must also choose a processing technique which is appropriate for the particular application. This paper will review all these areas and provide an introduction to EMG techniques for the intending user., (Copyright © 1983 Australian Physiotherapy Association. Published by . All rights reserved.)