RESUMO
The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders1-4. Cerebral organoids enable the study of neurodevelopmental disorders in a human context. We have developed the CRISPR-human organoids-single-cell RNA sequencing (CHOOSE) system, which uses verified pairs of guide RNAs, inducible CRISPR-Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Here we show that perturbation of 36 high-risk autism spectrum disorder genes related to transcriptional regulation uncovers their effects on cell fate determination. We find that dorsal intermediate progenitors, ventral progenitors and upper-layer excitatory neurons are among the most vulnerable cell types. We construct a developmental gene regulatory network of cerebral organoids from single-cell transcriptomes and chromatin modalities and identify autism spectrum disorder-associated and perturbation-enriched regulatory modules. Perturbing members of the BRG1/BRM-associated factor (BAF) chromatin remodelling complex leads to enrichment of ventral telencephalon progenitors. Specifically, mutating the BAF subunit ARID1B affects the fate transition of progenitors to oligodendrocyte and interneuron precursor cells, a phenotype that we confirmed in patient-specific induced pluripotent stem cell-derived organoids. Our study paves the way for high-throughput phenotypic characterization of disease susceptibility genes in organoid models with cell state, molecular pathway and gene regulatory network readouts.
Assuntos
Transtorno do Espectro Autista , Encéfalo , Deficiências do Desenvolvimento , Organoides , Análise da Expressão Gênica de Célula Única , Humanos , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Transtorno Autístico/complicações , Transtorno Autístico/genética , Transtorno Autístico/patologia , Encéfalo/citologia , Encéfalo/metabolismo , Linhagem da Célula/genética , Cromatina/genética , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Edição de Genes , Mutação com Perda de Função , Mosaicismo , Neurônios/metabolismo , Neurônios/patologia , Organoides/citologia , Organoides/metabolismo , RNA Guia de Sistemas CRISPR-Cas , Transcrição GênicaRESUMO
OBJECTIVES: This retrospective study aimed to identify quantitative magnetic resonance imaging markers in the brainstem of preterm neonates with intraventricular hemorrhages. It delves into the intricate associations between quantitative brainstem magnetic resonance imaging metrics and neurodevelopmental outcomes in preterm infants with intraventricular hemorrhage, aiming to elucidate potential relationships and their clinical implications. MATERIALS AND METHODS: Neuroimaging was performed on preterm neonates with intraventricular hemorrhage using a multi-dynamic multi-echo sequence to determine T1 relaxation time, T2 relaxation time, and proton density in specific brainstem regions. Neonatal outcome scores were collected using the Bayley Scales of Infant and Toddler Development. Statistical analysis aimed to explore potential correlations between magnetic resonance imaging metrics and neurodevelopmental outcomes. RESULTS: Sixty preterm neonates (mean gestational age at birth 26.26 ± 2.69 wk; n = 24 [40%] females) were included. The T2 relaxation time of the midbrain exhibited significant positive correlations with cognitive (r = 0.538, P < 0.0001, Pearson's correlation), motor (r = 0.530, P < 0.0001), and language (r = 0.449, P = 0.0008) composite scores at 1 yr of age. CONCLUSION: Quantitative magnetic resonance imaging can provide valuable insights into neurodevelopmental outcomes after intraventricular hemorrhage, potentially aiding in identifying at-risk neonates. Multi-dynamic multi-echo sequence sequences hold promise as an adjunct to conventional sequences, enhancing the sensitivity of neonatal magnetic resonance neuroimaging and supporting clinical decision-making for these vulnerable patients.
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Tronco Encefálico , Recém-Nascido Prematuro , Imageamento por Ressonância Magnética , Humanos , Masculino , Feminino , Imageamento por Ressonância Magnética/métodos , Recém-Nascido , Estudos Retrospectivos , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/crescimento & desenvolvimento , Lactente , Hemorragia Cerebral Intraventricular/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/etiologia , Idade GestacionalRESUMO
Background Data on the diagnostic accuracy of ultralow-dose (ULD) CT protocols for periodic surveillance in recipients of lung transplant are lacking. Purpose To assess the potential for radiation dose reduction using ULD photon-counting CT (PCT) to detect lung abnormalities in recipients of lung transplant during repeat CT follow-up. Materials and Methods Consecutive adult recipients of lung transplant undergoing same-day standard-of-care low-dose (LD) and ULD PCT from March 2023 to May 2023 were prospectively included. The ULD protocols were performed with two target effective doses comprising 20% (hereafter, ULD1) and 10% (hereafter, ULD2) of the standard LD protocol. The 1-mm reconstructions were reviewed by three readers. Subjective image quality, the visibility of certain anatomic structures (using a five-point Likert scale), and the presence of lung abnormalities were independently assessed. The χ2 or t tests were used to evaluate differences between the ULD1 and ULD2 protocols. Results A total of 82 participants (median age, 64 years [IQR, 54-69 years]; 47 male) were included (41 participants for each ULD protocol). The mean effective doses per protocol were 1.41 mSv ± 0.44 (SD) for LD, 0.26 mSv ± 0.08 for ULD1, and 0.17 mSv ± 0.04 for ULD2. According to three readers, the subjective image quality of the ULD images was deemed diagnostic (Likert score ≥3) in 39-40 (ULD1) and 40-41 (ULD2) participants, and anatomic structures could be adequately visualized (Likert score ≥3) in 33-41 (ULD1) and 34-41 (ULD2) participants. The detection accuracy for individual lung anomalies exceeded 70% for both ULD protocols, except for readers 1 and 3 detecting proximal bronchiectasis and reader 3 detecting bronchial wall thickening and air trapping. No evidence of a statistically significant difference in noise (P = .96), signal-to-noise ratio (P = .77), or reader accuracy (all P ≥ .05) was noted between the ULD protocols. Conclusion ULD PCT was feasible for detecting lung abnormalities following lung transplant, with a tenfold radiation dose reduction. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Ciet in this issue.
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Transplante de Pulmão , Pulmão , Doses de Radiação , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X/métodos , Idoso , Estudos Prospectivos , Pulmão/diagnóstico por imagem , Fótons , Pneumopatias/diagnóstico por imagemRESUMO
Prenatal alcohol exposure (PAE) can change the normal trajectory of human fetal brain development and may lead to long-lasting neurodevelopmental changes in the form of fetal alcohol spectrum disorders. Currently, early prenatal patterns of alcohol-related central nervous system changes are unclear and it is unknown if small amounts of PAE may result in early detectable brain anomalies. This super-resolution fetal magnetic resonance imaging (MRI) study aimed to identify regional effects of PAE on human brain structure. Fetuses were prospectively assessed using atlas-based semi-automated 3-dimensional tissue segmentation based on 1.5 T and 3 T fetal brain MRI examinations. After expectant mothers completed anonymized PRAMS and TACE questionnaires for PAE, fetuses without gross macroscopic brain abnormalities were identified and analyzed. Linear mixed-effects modeling of regional brain volumes was conducted and multiple comparisons were corrected using the Benjamini-Hochberg procedure. In total, 500 pregnant women were recruited with 51 reporting gestational alcohol consumption. After excluding confounding comorbidities, 24 fetuses (26 observations) were identified with PAE and 52 age-matched controls without PAE were analyzed. Patients with PAE showed significantly larger volumes of the corpus callosum (P ≤ 0.001) and smaller volumes of the periventricular zone (P = 0.001). Even minor (1-3 standard drinks per week) PAE changed the neurodevelopmental trajectory.
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Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Feminino , Efeitos Tardios da Exposição Pré-Natal/diagnóstico por imagem , Encéfalo , Feto/diagnóstico por imagem , Corpo Caloso , Imageamento por Ressonância Magnética/métodosRESUMO
Colorectal cancer is the second most common cancer diagnosed in women and third most common in men. Laparoscopic resection has become the standard surgical technique worldwide given its notable benefits, mainly the shorter length of stay and less postoperative pain. The aim of this systematic review was to evaluate the current literature on postoperative pain management following laparoscopic colorectal surgery and update previous procedure-specific pain management recommendations. The primary outcomes were postoperative pain scores and opioid requirements. We also considered study quality, clinical relevance of trial design, and a comprehensive risk-benefit assessment of the analgesic intervention. We performed a literature search to identify randomised controlled studies (RCTs) published before January 2022. Seventy-two studies were included in the present analysis. Through the established PROSPECT process, we recommend basic analgesia (paracetamol for rectal surgery, and paracetamol with either a nonsteroidal anti-inflammatory drug or cyclo-oxygenase-2-specific inhibitor for colonic surgery) and wound infiltration as first-line interventions. No consensus could be achieved either for the use of intrathecal morphine or intravenous lidocaine; no recommendation can be made for these interventions. However, intravenous lidocaine may be considered when basic analgesia cannot be provided.
Assuntos
Cirurgia Colorretal , Laparoscopia , Dor Pós-Operatória , Feminino , Humanos , Masculino , Acetaminofen/uso terapêutico , Analgésicos Opioides/uso terapêutico , Cirurgia Colorretal/efeitos adversos , Laparoscopia/efeitos adversos , Lidocaína/uso terapêutico , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND AND PURPOSE: Intracranial hemorrhage (ICH) has emerged as a notable concern in Chiari II malformation (CM II), yet its origins and clinical implications remain elusive. This study aims to validate the in utero prevalence of ICH in CM II and investigate contributing factors, and visualize the findings in a network format. MATERIALS AND METHODS: A single-center retrospective review of fetal MRI scans obtained in fetuses with CM II (presenting January 2007 to December 2022) was performed for ICH utilizing EPI-T2* blood-sensitive sequence. Fetuses with aqueduct stenosis (AS) were included as a control group. The incidence of ICH and corresponding gestational ages were compared between CM II and AS cases, and morphometric measurements (inner/outer CSF spaces, posterior fossa, venous structure) were compared among the 4 1:1 age-matched groups: CM II+ICH, CM II-ICH, AS+ICH, and AS-ICH. Additionally, a co-occurrence network was constructed to visualize associations between phenotypic features in ICH cases. RESULTS: A total of 101 fetuses with CM II and 90 controls with AS at a median gestational age of 24.4 weeks and 22.8 weeks (P = .138) were included. Prevalence of ICH in fetuses with CM II was higher compared with the AS cases (28.7% versus 18.9%, P = .023), accompanied by congested veins (deep vein congestion mainly in young fetuses, and cortical veins may also be affected in older fetuses). ICH was notably correlated with specific anatomic features, essentially characterized by reduced outer CSF spaces and clivus-supraocciput angle. The co-occurrence network analysis reveals complex connections including bony defects, small posterior fossa dimensions, vermis ectopia, reduced CSF spaces, as well as venous congestion and venous sinus stenosis as pivotal components within the network. CONCLUSIONS: The high prevalence of ICH-detected by fetal MRI-among fetuses with CM emphasizes the pathophysiologic importance of venous congestion, ICH, and vasogenic edema. As indicators of disease severity, these features may serve as helpful additional imaging biomarkers for the identification of potential candidates for fetal surgery.
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Malformação de Arnold-Chiari , Hemorragias Intracranianas , Imageamento por Ressonância Magnética , Humanos , Feminino , Malformação de Arnold-Chiari/diagnóstico por imagem , Malformação de Arnold-Chiari/complicações , Estudos Retrospectivos , Gravidez , Imageamento por Ressonância Magnética/métodos , Hemorragias Intracranianas/diagnóstico por imagem , Adulto , Índice de Gravidade de Doença , Idade Gestacional , Doenças Fetais/diagnóstico por imagem , Prevalência , Diagnóstico Pré-Natal/métodosRESUMO
Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC), characterized by the absence of an interhemispheric white matter tract that connects distant cortical regions. Here, we find that neurons expressing SATB2, a determinant of callosal projection neuron (CPN) identity, show impaired maturation in ARID1B+/- neural organoids. Molecularly, a reduction in chromatin accessibility of genomic regions targeted by TCF-like, NFI-like, and ARID-like transcription factors drives the differential expression of genes required for corpus callosum (CC) development. Through an in vitro model of the CC tract, we demonstrate that this transcriptional dysregulation impairs the formation of long-range axonal projections, causing structural underconnectivity. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous axonogenesis defects in SATB2+ neurons as a cause of ACC in ARID1B patients.
Assuntos
Axônios , Corpo Caloso , Proteínas de Ligação a DNA , Organoides , Fatores de Transcrição , Humanos , Corpo Caloso/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Organoides/metabolismo , Axônios/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Transcrição Gênica , Neurônios/metabolismoRESUMO
BACKGROUND AND PURPOSE: The radiologic evaluation of ongoing myelination is currently limited prenatally. Novel quantitative MR imaging modalities provide relaxometric properties that are linked to myelinogenesis. In this retrospective postmortem imaging study, the capability of Synthetic MR imaging and MR fingerprinting-derived relaxometry for tracking fetal myelin development was investigated. Moreover, the consistency of results for both MR approaches was analyzed. MATERIALS AND METHODS: In 26 cases, quantitative postmortem fetal brain MR data were available (gestational age range, 15 + 1 to 32 + 1; female/male ratio, 14/12). Relaxometric measurements (T1-/T2-relexation times) were determined in the medulla oblongata and the midbrain using Synthetic MR imaging/MR fingerprinting-specific postprocessing procedures (Synthetic MR imaging and MR Robust Quantitative Tool for MR fingerprinting). The Pearson correlations were applied to detect relationships between T1-relaxation times/T2-relaxation times metrics and gestational age at MR imaging. Intraclass correlation coefficients were calculated to assess the consistency of the results provided by both modalities. RESULTS: Both modalities provided quantitative data that revealed negative correlations with gestational age at MR imaging: Synthetic MR imaging-derived relaxation times (medulla oblongata [r = -0.459; P = .021]; midbrain [r = -0.413; P = .040]), T2-relaxation times (medulla oblongata [r = -0.625; P < .001]; midbrain [r = -0.571; P = .003]), and MR fingerprinting-derived T1-relaxation times (medulla oblongata [r = -0.433; P = .035]; midbrain [r = -0.386; P = .062]), and T2-relaxation times (medulla oblongata [r =-0.883; P < .001]; midbrain [r = -0.890; P < .001]).The intraclass correlation coefficient analysis for result consistency between both MR approaches ranged between 0.661 (95% CI, 0.351-0.841) (T2-relaxation times: medulla oblongata) and 0.920 (95% CI, 0.82-0.965) (T1-relaxation times: midbrain). CONCLUSIONS: There is a good-to-excellent consistency between postmortem Synthetic MR imaging and MR fingerprinting myelin quantifications in fetal brains older than 15 + 1 gestational age. The strong correlations between quantitative myelin metrics and gestational age indicate the potential of quantitative MR imaging to identify delayed or abnormal states of myelination at prenatal stages of cerebral development.
Assuntos
Imageamento por Ressonância Magnética , Bainha de Mielina , Humanos , Feminino , Imageamento por Ressonância Magnética/métodos , Masculino , Estudos Retrospectivos , Tronco Encefálico/diagnóstico por imagem , Idade Gestacional , Autopsia/métodos , GravidezRESUMO
PURPOSE: Neonates born at <â¯28 weeks of gestation are at risk for neurodevelopmental delay. The aim of this study was to identify quantitative MR-based metrics for the prediction of neurodevelopmental outcomes in extremely preterm neonates. METHODS: T1-/T2-relaxation times (T1R/T2R), ADC, and fractional anisotropy (FA) of the left/right posterior limb of the internal capsule (PLIC) and the brainstem were determined at term-equivalent ages in a sample of extremely preterm infants (nâ¯= 33). Scores for cognitive, language, and motor outcomes were collected at one year corrected-age. Pearson's correlation analyses detected relationships between quantitative measures and outcome data. Stepwise regression procedures identified imaging metrics to estimate neurodevelopmental outcomes. RESULTS: Cognitive outcomes correlated significantly with T2R (râ¯= 0.412; pâ¯= 0.017) and ADC (râ¯= -0.401; pâ¯= 0.021) (medulla oblongata). Furthermore, there were significant correlations between motor outcomes and T1R (pontine tegmentum (râ¯= 0.346; pâ¯= 0.049), midbrain (râ¯= 0.415; pâ¯= 0.016), right PLIC (râ¯= 0.513; pâ¯= 0.002), and left PLIC (râ¯= 0.504; pâ¯= 0.003)); T2R (right PLIC (râ¯= 0.405; pâ¯= 0.019)); ADC (medulla oblongata (râ¯= -0.408; pâ¯= 0.018) and pontine tegmentum (râ¯= -0.414; pâ¯= 0.017)); and FA (pontine tegmentum (râ¯= -0.352; pâ¯= 0.045)). T2R/ADC (medulla oblongata) (cognitive outcomes (R2â¯= 0.296; pâ¯= 0.037)) and T1R (right PLIC)/ADC (medulla oblongata) (motor outcomes (R2â¯= 0.405; pâ¯= 0.009)) revealed predictive potential for neurodevelopmental outcomes. CONCLUSION: There are relationships between relaxometry/DTI-based metrics determined by neuroimaging near term and neurodevelopmental outcomes collected at one year of age. Both modalities bear prognostic potential for the prediction of cognitive and motor outcomes. Thus, quantitative MRI at term-equivalent ages represents a promising approach with which to estimate neurologic development in extremely preterm infants.
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Lactente Extremamente Prematuro , Imageamento por Ressonância Magnética , Humanos , Recém-Nascido , Feminino , Masculino , Imageamento por Ressonância Magnética/métodos , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/etiologia , Cápsula Interna/diagnóstico por imagem , Valor Preditivo dos TestesRESUMO
Deep learning models for medical image segmentation can fail unexpectedly and spectacularly for pathological cases and images acquired at different centers than training images, with labeling errors that violate expert knowledge. Such errors undermine the trustworthiness of deep learning models for medical image segmentation. Mechanisms for detecting and correcting such failures are essential for safely translating this technology into clinics and are likely to be a requirement of future regulations on artificial intelligence (AI). In this work, we propose a trustworthy AI theoretical framework and a practical system that can augment any backbone AI system using a fallback method and a fail-safe mechanism based on Dempster-Shafer theory. Our approach relies on an actionable definition of trustworthy AI. Our method automatically discards the voxel-level labeling predicted by the backbone AI that violate expert knowledge and relies on a fallback for those voxels. We demonstrate the effectiveness of the proposed trustworthy AI approach on the largest reported annotated dataset of fetal MRI consisting of 540 manually annotated fetal brain 3D T2w MRIs from 13 centers. Our trustworthy AI method improves the robustness of four backbone AI models for fetal brain MRIs acquired across various centers and for fetuses with various brain abnormalities.
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Algoritmos , Inteligência Artificial , Imageamento por Ressonância Magnética , Feto/diagnóstico por imagem , Encéfalo/diagnóstico por imagemRESUMO
Background: There are known complications for fetuses after infection with SARS-CoV-2 during pregnancy. However, previous studies of SARS-CoV-2 in pregnancy have largely been limited to histopathologic studies of placentas and prenatal studies on the effects of different SARS-CoV-2 variants are scarce to date. To examine the effects of SARS-CoV-2 variants on the placenta and fetus, we investigated fetal and extra-fetal structures using prenatal MRI. Methods: For this prospective case-control study, two obstetric centers consecutively referred pregnant women for prenatal MRI after confirmed SARS-CoV-2 infection. Thirty-eight prenatal MRI examinations were included after confirmed infection with SARS-CoV-2 and matched 1:1 with 38 control cases with respect to sex, MRI field strength, and gestational age (average deviation 1.76 ± 1.65, median 1.5 days). Where available, the pathohistological examination and vaccination status of the placenta was included in the analysis. In prenatal MRI, the shape and thickness of the placenta, possible lobulation, and vascular lesions were quantified. Fetuses were scanned for organ or brain abnormalities. Findings: Of the 38 included cases after SARS-CoV-2 infection, 20/38 (52.6%) were infected with pre-Omicron variants and 18/38 (47.4%) with Omicron. Prenatal MRIs were performed on an average of 83 days (±42.9, median 80) days after the first positive PCR test. Both pre-Omicron (P = .008) and Omicron (P = .016) groups showed abnormalities in form of a globular placenta compared to control cases. In addition, placentas in the pre-Omicron group were significantly thickened (6.35, 95% CI .02-12.65, P = .048), and showed significantly more frequent lobules (P = .046), and hemorrhages (P = .002). Fetal growth restriction (FGR) was observed in 25% (n = 5/20, P = .017) in the pre-Omicron group. Interpretation: SARS-CoV-2 infections in pregnancy can lead to placental lesions based on vascular events, which can be well visualized on prenatal MRI. Pre-Omicron variants cause greater damage than Omicron sub-lineages in this regard. Funding: Vienna Science and Technology Fund.
RESUMO
Objective: Cardiac and extra-cardiac anomalies in 46 pre-natally diagnosed cases of heterotaxy were compared to post-natal anatomical patterns in order to reveal discordant findings. Second, the outcome of these fetuses was evaluated. Methods: Fetuses with heterotaxy, diagnosed in a tertiary referral centre, were analysed retrospectively. Based on the foetal abdominal situs view, right atrial isomerism (RAI) and left atrial isomerism (LAI) were defined as foetal sub-types. Post-natally, discordant anatomical patterns for broncho-pulmonary branching, atrial appendage morphology, and splenic status were further clarified with CT scans. In summary, the spectrum of pre-natally and post-natally detected cardiac and extra-cardiac anomalies is systematically reviewed. Necessary surgical interventions and mid-long-term outcomes were compared between the two sub-types in surviving infants. Results: A total of 46 fetuses with heterotaxy were included; LAI was diagnosed in 29 (63%) fetuses and RAI was diagnosed in 17 (37%) fetuses. Extra-cardiac anomalies were noted in 35% of fetuses. Seven out of the 29 fetuses (24%) with LAI had atrio-ventricular block (AVB) and four of these cases presented with hydrops. Twenty nine out of the 46 participating fetuses (63%) were live births, with 62% in the LAI group and 65% in the RAI group. Five fetuses were lost to follow-up. At the age of 1 year, the overall survival of live births [estimate (95% CI)] was 67% (48; 92%) in patients with LAI and 55% (32; 94%) in patients with RAI. At the age of 5 years, the estimates were 67% (48; 92%) in the LAI group and 46% (24-87%) in the RAI group. The median survival (first quartile; third quartile) was 11.1 (0.1; 14) years for patients with LAI and 1.3 (0.09; NA) years for patients with RAI. Of 17 children who had undergone cardiac surgery, five (29%) children achieved a bi-ventricular repair and 12 (70%) children achieved a uni-ventricular palliation. Three were primarily palliated, but converted to bi-ventricular thereafter. Foetal subtype definition of heterotaxy based on the abdominal situs and post-natal thoracic imaging studies showed a discordant pattern of broncho-pulmonary branching and atrial appendage anatomy in 40% of our live-born children. Conclusion: Heterotaxy is a rare and complex condition with significant morbidity and mortality related to severe cardiac and extra-cardiac associations. Accurate pre-natal diagnosis can help identify the fetuses at risk and allow for timely intervention in a multi-disciplinary setting. Further studies are warranted to shed light on the exact sub-type definition in fetuses with heterotaxy and the presence of discordant post-natal patterns.