P104: Gene-specific ACMG/AMP variant classification rules for ornithine transcarbamylase, N-acetylglutamate synthase, and carbamylphosphate synthetase 1*

Methods: A systematic literature search was conducted to address the scope and frequency of ophthalmic, renal/genitourinary, neurological/neurodevelopmental manifestations in publications from January 1998 to March 2025.Every reported case was curated individually, and associated manifestations were compiled using structured Human Phenotype Ontology (HPO) terminology in an Airtable relational database.Demographics, age of onset, body mass index (BMI), and gene variants were also captured in the database.After deduplication and cleaning, data were analyzed at the child and parent term ontology levels.Corrected frequencies (percent affected over screened) were reported for the entire dataset, by age group, and by gene altered, together with median age of onset and interquartile range (IQR) for each manifestation.Results: Out of 415 screened publications, we identified 261 containing individual patient data eligible for curation.From these, 1,776 individual patients (44.8% male, 36.6% female, and 18.6% unspecified) were cataloged for over 500 manifestations.Ethnicity was sparsely reported.Among cataloged cases, 86.2% received genetic testing.Variants were reported for 93.2% of tested patients and among them, 24.0% had at least one variant in BBS1, 18.8% in BBS10, 12.5% in BBS2, and 8.3% in BBS12.The most frequent variant was BBS1 M390R (13.1%) followed by BBS10 C91LfsX5 (5.6%).Patients with likely biallelic results in the most frequently altered genes were grouped into BBS1 (N=347), BBS10 (279), BBS2 (123), and BBS12 (107) cohorts for phenotypic analysis.Among ophthalmological manifestations, rod-cone dystrophy was highest in BBS2 (92.9%) and lowest in BBS12 (69.8%).Night blindness, an early symptom of retinal disease, was more commonly reported in BBS1 (93.2%) and BBS10 (95.4%) than in BBS2 (86.4%), and lowest in BBS12 (57.7%).BBS1 cases had the highest median age of onset of rod-cone dystrophy (21.5 years), presenting in young adults.The median age of onset for all other groups was 13-14 years.Abnormalities of the kidney overall ranged from 36.3% (BBS1) to 53.4% (BBS10).Renal cysts were more commonly recorded with BBS12 cases (45.5%) than in the other groups (23.1-33.9%).Reports of chronic kidney disease, instead, were highest in BBS10 (17.7%) and BBS2 (13.3%) than in BBS1 (8.0%) and BBS12 (6.7%).Genitourinary abnormalities were more commonly documented in BBS2 (70.8%) and BBS12 (66.7%).Neurodevelopmental delay was highest in BBS10 (69.9%) with similar prevalence in all other groups (57.8-60.0%),yet intellectual disability was less commonly mentioned in BBS10 (35.7%).Overall, when compared with frequencies in the original Beales criteria, chronic kidney disease, renal cysts, and neurodevelopmental delay appear to be more frequent in published cases, while other manifestations (eg, ataxia, speech deficit, and micropenis) are less frequently reported. Conclusion:The analysis of 1,776 individual published patients linked with discrete HPO phenotypes and genetic data supports the existing understanding that not every major feature is present in all patients, presenting a diagnostic challenge.The data confirmed that there is heterogeneity in BBS clinical presentations, or prevalence and age of onset of certain manifestations, in patients with biallelic variants in one of four BBS-associated genes studied.As genetic testing is integrated into standard practice, knowledge of genotype-phenotype correlations becomes increasingly critical in the counseling and management of patients.Future analyses of this dataset could help define the minimal constellation of clinical manifestations that, in the presence of biallelic variants, establishes a molecular diagnosis of BBS, redefining the current diagnostic approach.