SickKids Foundation

Inherited retinal dystrophies (IRDs) are a genetically diverse group of vision loss disorders with over 360 implicated genes. However, 30-50% of cases remain unresolved after panel-based clinical testing and may benefit from exome or genome sequencing for a genetic diagnosis. To manage the extensive and analytically demanding datasets generated by genome sequencing, we developed ReDGAP (Retinal Degeneration Genome Analysis Pipeline), a phenotype-guided, semi-automated genome analysis pipeline that integrates clinical phenotyping with flexible variant scoring to prioritize variants of interest (https://github.com/vincentlab-la/ReDGAP). The pipeline supports the joint analysis of multiple variant classes, using an evidence-weighted scoring system informed by in silico predictors. Validation in eleven previously solved IRD cases achieved a 100% re-identification rate. Application to five unsolved cases yielded diagnoses in four (80%), including intronic variants in CRB1 and HGSNAT, a tandem duplication in OAT, and a 5'UTR deletion affecting a retina-specific promoter of RPGRIP1. Functional validation confirmed transcript-level disruptions in three variants, while computational analysis demonstrated regulatory impact in the fourth. Integrating phenotypic data with broad variant analysis offers a tailored model for improving IRD diagnostics, enabling timely molecular diagnoses and informing eligibility for emerging gene-targeted therapies. This positions ReDGAP as a tailored, clinically relevant model for investigating rare diseases within the evolving landscape of precision health.

Although machine learning has transformed protein structure prediction of folded protein ground states with remarkable accuracy, intrinsically disordered proteins and regions (IDPs/IDRs) are defined by diverse and dynamical structural ensembles that are predicted with low confidence by algorithms such as AlphaFold and RoseTTAFold. We present a new machine learning method, IDPForge (IntrinsicallyDisorderedProtein,FOlded and disorderedRegionGEnerator), that exploits a transformer protein language diffusion model to create all-atom IDP ensembles and IDR disordered ensembles that maintains the folded domains. IDPForge does not require sequence-specific training, back transformations from coarse-grained representations, nor ensemble reweighting, as in general the created IDP/IDR conformational ensembles show good agreement with solution experimental data, and options for biasing with experimental restraints are provided if desired. We envision that IDPForge with these diverse capabilities will facilitate integrative and structural studies for proteins that contain intrinsic disorder, and is available as an open source resource for general use.

Newborns with d-transposition of the great arteries (TGA) without adequate intracardiac shunting of oxygenated blood are at imminent risk of severe hypoxia at birth. Using fetal echocardiography and cardiac magnetic resonance imaging (CMR) in room air (RA) and during acute maternal hyperoxygenation (AMH), we sought to identify predelivery imaging features predictive of neonatal hypoxia and the need for urgent balloon atrial septostomy (BAS) within the first 3 h after birth. This was a prospective single-center cohort study of pregnancies with TGA with an intact ventricular septum (IVS) or a single ventricular septal defect (VSD) ≤ 4 mm. Fetal echocardiography and, if feasible, CMR were conducted concurrently at 34-38 weeks' gestation. Cardiac structures, including the foramen ovale (FO) and atrial septum, were examined using two-dimensional and Doppler echocardiography. CMR was used to quantify fetal weight, brain volume and vascular oxygen saturation (SaO2). Both imaging modalities were used to assess fetal vascular blood flows in RA and during AMH. Postnatal data collected included preductal oxygen saturation (SpO2) and the need for and timing of BAS. Univariable logistic regression analysis was used to evaluate associations between predelivery imaging features and the need for urgent neonatal BAS. Of 34 newborns with TGA/IVS (n = 29) or TGA/VSD (n = 5), 23 (68%) underwent neonatal BAS, including 12 cases of urgent BAS < 3 h after birth for persistent preductal SpO2 < 70%. A fetal echocardiogram was obtained in all cases, while 26/34 (76%) underwent CMR, including 9/12 (75%) cases that underwent urgent BAS. On univariable logistic regression analysis, abnormal atrial septal flap morphology in RA (P = 0.004), effective FO size ≤ 3.4 mm during AMH (P = 0.0024) and constricted or continuously reversed diastolic flow across the ductus arteriosus (DA) during AMH (P = 0.0006) were the most significant predictors of urgent neonatal BAS. On CMR, fetuses with an ascending aorta (AAo)/main pulmonary artery (MPA) SaO2 ratio > 1 during AMH were significantly more likely to undergo urgent BAS postnatally (odds ratio, 28.6 (95% CI, 1.1-620.3); P = 0.0084). In fetuses with TGA, predelivery assessment of atrial septal morphology in RA, as well as effective FO size, DA flow pattern and AAo/MPA SaO2 ratio > 1 during AMH, are the most useful variables for predicting the need for urgent neonatal BAS. © 2026 International Society of Ultrasound in Obstetrics and Gynecology.

The Fontan procedure has significantly improved survival in patients with single-ventricle physiology; however, multisystem complications have become a major source of late morbidity and mortality. In 2020, the Hospital for Sick Children (SickKids) established a dedicated paediatric Fontan Long-Term Follow-up Clinic. This study evaluated the prevalence and spectrum of cardiac and extracardiac morbidities in the clinic cohort since inception. This single-centre retrospective study included all patients referred between January 2020 and December 2024. Standardized assessments comprised cardiac evaluations (echocardiography, Holter monitoring, exercise testing, cardiac MRI) and extracardiac investigations of hepatic, renal, hematologic, endocrine, growth, and neurodevelopmental status. Fontan-associated liver disease (FALD) was graded using MR elastography and imaging findings. A total of 161 patients (mean age 13.2 ± 3.7 years; 58.4% male) were assessed at a mean of 9.5 ± 4.3 years post-Fontan completion. Tricuspid atresia was the most common diagnosis (26.1%). Cardiac function was generally preserved, with mean predicted peak VO₂ of 63.6 ± 17.6%. Moderate or severe atrioventricular valve regurgitation occurred in 21.5%, and ventricular dysfunction in 5.6%. Moderate or greater FALD was observed in 8.0%, with mean magnetic resonance elastography 4.58 kPa (Interquartile range, 4.03-5.40). Lymphopenia (64.6%), thrombocytopenia (16.8%), vitamin D deficiency (41.9%), and reduced bone density (28.0%) were frequent. Neurodevelopmental challenges were common (39.8% learning difficulties). Despite preserved cardiac performance, Fontan patients exhibited a high burden of hepatic, hematologic, endocrine, skeletal, and neurocognitive morbidities. Multidisciplinary, longitudinal follow-up is essential to optimize outcomes and quality of life.

Antenatal hydronephrosis (HN) is the most common congenital urinary tract abnormality, but management is controversial. Current guidelines recommend continuous antibiotic prophylaxis (CAP), voiding cystourethrogram (VCUG), and diuretic renal scintigraphy (DRS) for high-grade HN, yet these measures may expose many asymptomatic infants to unnecessary antibiotics, radiation, and anesthesia. We evaluated whether a selective approach-reserving CAP for hydroureteronephrosis (HUN), limiting VCUG to HUN or confirmed urinary tract infection (UTI), and using DRS only when ultrasound trends were equivocal-could reduce interventions without increasing adverse outcomes. We conducted a retrospective cohort study of 1,008 consecutive infants (< 24months) with isolated HN or HUN (2015 and 2025). Patients were grouped by treatment era: 2015-2018 (pre-protocol), 2019-2021 (implementation), and 2022-2025 (post-clinic). Outcomes included use and duration of CAP, VCUG, and DRS, UTI incidence, and timing of surgery. VCUG (52% → 28%) and DRS (58% → 30%) use declined significantly over time. Median CAP duration decreased from 7.7 to 2.9months (p < 0.001). Surveillance UTI rates remained stable (2-4%, p = 0.74). In isolated HN, CAP conferred no measurable benefit (number needed to treat [NNT] 100), whereas in HUN, CAP reduced infections (6% vs. 21%; NNT 27). Selective management of antenatal HN-avoiding routine CAP, VCUG, and DRS in most infants-safely reduces unnecessary interventions without increasing UTI risk or delaying surgery. CAP should be reserved for higher-risk groups, such as infants with HUN, particularly uncircumcised males. These findings support updating international guidelines toward risk-based, individualized care.