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The tightly-regulated spatial and temporal distribution of zinc ion concentrations within cellular compartments is controlled by two groups of Zn 2+ transporters: the 14-member ZIP/SLC39 family, facilitating Zn 2+ influx into the cytoplasm from the extracellular space or intracellular organelles; and the 10-member ZnT/SLC30 family, mobilizing Zn 2+ in the opposite direction. Genetic aberrations in most zinc transporters cause human syndromes. Notably, previous studies demonstrated osteopenia and male-specific cardiac death in mice lacking the ZnT5/ SLC30A5 zinc transporter, and suggested association of two homozygous frameshift SLC30A5 variants with perinatal mortality in humans, due to hydrops fetalis and hypertrophic cardiomyopathy. We set out to decipher the molecular basis of a severe hypotonia syndrome. Combining homozygosity mapping and exome sequencing studies of consanguineous Bedouin kindred, as well as transfection experiments and zinc monitoring in HEK293 cells, we demonstrate that a bi-allelic in-frame 3bp deletion variant in SLC30A5 , deleting isoleucine within the highly conserved cation efflux domain of the encoded ZnT5, results in lower cytosolic zinc concentrations, causing a syndrome of severe non-progressive neonatal axial and limb hypotonia with high-arched palate and respiratory failure. There was no evidence of hydrops fetalis, cardiomyopathy or multi-organ involvement. Affected infants required nasogastric tube or gastrostomy feeding, suffered from various degrees of respiratory compromise and failure to thrive and died in infancy. Thus, a biallelic variant in SLC30A5 (ZnT5), affecting cytosolic zinc concentrations, causes a severe hypotonia syndrome with respiratory insufficiency and failure to thrive, lethal by 1 year of age., Competing Interests: Vadim Dolgin, Pauline Chabosseau, Jacob Bistritzer, Iris Noyman, Orna Staretz‐Chacham, Ohad Wormser, Noam Hadar, Marina Eskin‐Schwartz, Bibi Kanengisser‐Pines, Ginat Narkis, Ramy Abramsky, Eilon Shany, Guy A. Rutter, Kyla Marks, and Ohad S. Birk declare that they have no conflict of interest. Guy A. Rutter has received grant funding from, and is a consultant for, Sun Pharmaceuticals Industries Ltd. This company was not involved in any way in the design or execution of the present study., (© 2024 The Author(s). JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Importance: National implementation of rapid trio genome sequencing (rtGS) in a clinical acute setting is essential to ensure advanced and equitable care for ill neonates., Objective: To evaluate the feasibility, diagnostic efficacy, and clinical utility of rtGS in neonatal intensive care units (NICUs) throughout Israel., Design, Setting, and Participants: This prospective, public health care-based, multicenter cohort study was conducted from October 2021 to December 2022 with the Community Genetics Department of the Israeli Ministry of Health and all Israeli medical genetics institutes (n = 18) and NICUs (n = 25). Critically ill neonates suspected of having a genetic etiology were offered rtGS. All sequencing, analysis, and interpretation of data were performed in a central genomics center at Tel-Aviv Sourasky Medical Center. Rapid results were expected within 10 days. A secondary analysis report, issued within 60 days, focused mainly on cases with negative rapid results and actionable secondary findings. Pathogenic, likely pathogenic, and highly suspected variants of unknown significance (VUS) were reported., Main Outcomes and Measures: Diagnostic rate, including highly suspected disease-causing VUS, and turnaround time for rapid results. Clinical utility was assessed via questionnaires circulated to treating neonatologists., Results: A total of 130 neonates across Israel (70 [54%] male; 60 [46%] female) met inclusion criteria and were recruited. Mean (SD) age at enrollment was 12 (13) days. Mean (SD) turnaround time for rapid report was 7 (3) days. Diagnostic efficacy was 50% (65 of 130) for disease-causing variants, 11% (14 of 130) for VUS suspected to be causative, and 1 novel gene candidate (1%). Disease-causing variants included 12 chromosomal and 52 monogenic disorders as well as 1 neonate with uniparental disomy. Overall, the response rate for clinical utility questionnaires was 82% (107 of 130). Among respondents, genomic testing led to a change in medical management for 24 neonates (22%). Results led to immediate precision medicine for 6 of 65 diagnosed infants (9%), an additional 2 (3%) received palliative care, and 2 (3%) were transferred to nursing homes., Conclusions and Relevance: In this national cohort study, rtGS in critically ill neonates was feasible and diagnostically beneficial in a public health care setting. This study is a prerequisite for implementation of rtGS for ill neonates into routine care and may aid in design of similar studies in other public health care systems.

Background: Hypoxic-ischemic encephalopathy (HIE) is an important contributor to disability worldwide. The current cardiotocography (CTG) predictive value for neonatal outcome is limited., Objective: To assess the association of intrapartum CTG deceleration and acceleration areas with early MRI cerebral pathology in infants with HIE., Methods: Term and near-term low-risk pregnancies that resulted in HIE, treated with therapeutic hypothermia with sufficient CTG records from a single, tertiary hospital between 2013 and 2021 were enrolled. Accelerations and decelerations areas, their minimum and maximum depths, and duration were calculated as well as the acceleration-to-deceleration area ratio during the 120 min prior to delivery. These data were assessed for associations with higher degrees of abnormality on early MRI scans., Results: A total of 77 infants were included in the final analysis. Significant associations between increased total acceleration area (p = 0.007) and between a higher acceleration-to-deceleration area ratio (p = 0.003) and better MRI results were detected., Conclusion: In neonates treated for HIE, acceleration area and acceleration-to-deceleration ratio are associated with the risk of neonatal brain MRI abnormalities. To increase the role of these measurements as a relevant clinical tool, larger, more powered prospective trials are needed, using computerized real-time analysis., Impact: The current cardiotocography predictive value for neonatal outcome is limited. This study aimed to assess the association of intrapartum deceleration and acceleration areas with the degree of cerebral injury in early cerebral MRI of neonates with encephalopathy. Lower acceleration area and acceleration-to-deceleration ratio were found to be associated with a higher degree of neonatal brain injury. Brain MRI is a marker of long-term outcome; its association with cardiotocography indices supports their association with long-term outcome in these neonates. Future computer-based CTG area analysis could assist in delivery room decision making to better time interventions and prevent hypoxic-ischemic encephalopathy., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Appearance of sleep cycling has been associated with good outcome in term and preterm infants, but the normal time of its appearance has not been determined. The objectives of this study were, to correlate the time of sleep cycling appearance and the length of quiet sleep in neonates with different degrees of mild perinatal stress., Methods: Three groups of term infants recorded with aEEG after birth were studied: infants delivered by planned cesarean section (group 1), infants with mild perinatal stress (group 2) and infants with mild neonatal encephalopathy (group 3). Groups were correlated with the appearance and length of quiet sleep., Results: In all, 132 infants were assessed. Quiet sleep appearance differed significantly between groups (p < 0.001). All infants in group 1 developed quiet sleep before the age of 6 h compared to 81% in group 2 and 52% in group 3 (p < 0.001). No differences in the quiet sleep length was found between groups. Belonging to group 3 (p < 0.001) and 1-min Apgar score (p = 0.002) significantly predicted a delay in appearance of the first quiet sleep period. Cesarean delivery significantly predicted an earlier appearance of quiet sleep (p < 0.001)., Conclusions: Appearance of quiet sleep after birth but not its length may be delayed in case of mild perinatal stress.