Citations

ABSTRACT Objectives To evaluate the impact of semaglutide on body mass index (BMI) and cardiometabolic markers in adolescents with obesity and genetic variants associated with monogenic or syndromic obesity. Methods A retrospective chart review was conducted in adolescents with severe obesity who underwent multigene panel testing and were treated with semaglutide. Results Twenty‐seven adolescents (mean age 15 ± 1.9 years); BMI % of the 95th percentile 158 ± 29; (70% White) were treated with semaglutide for a mean of 10 ± 4.7 months. Participants were classified into three groups: (1) Dominant or Known Risk Variants ( n = 7); (2) Carriers of Rare Variants in Recessive Genes ( n = 10); and (3) Negative or Unmatched Genetic Findings ( n = 10). All groups showed reductions in BMI, which was not different between the groups. Adolescents with dominant or known risk variants experienced a significant decrease in BMI % of the 95th percentile (−17, (IQR −26 to −10) p = 0.022) and in BMI by −9.4% ± 7% ( p = 0.035). Significant improvements in median non‐HDL cholesterol (−16 mg/dL), total cholesterol (−15 mg/dL), and HbA1c (−0.3%) were noted in children with dominant or known risk variants ( p = 0.036). Conclusions Semaglutide was associated with significant reductions in BMI and cardiometabolic markers in adolescents (majority White) with dominant or known risk variants for monogenic obesity.

ABSTRACT Background LINS1 , the human homolog of the Drosophila segment polarity gene, encodes a key regulator of the Wingless/Wnt signaling pathway. While numerous genes have been implicated in intellectual disability (ID), only a limited number have been conclusively associated with autosomal recessive intellectual disability (ARID). Variants in LINS1 have been identified as one such cause. Methods In this study, we employed exome sequencing (ES) to investigate the genetic basis of ID in two consanguineous Iranian families. This variant was confirmed by Sanger sequencing, and segregation analysis supported its pathogenicity. Additionally, in silico analyses were conducted to explore the protein–protein interaction network of LINS1 and its functional connections to ID‐associated proteins. Results We identified a novel homozygous missense variant in LINS1 (c.1354G>C), leading to an alanine‐to‐proline substitution (p.Ala452Pro) in exon six. Conclusion Our findings provide new molecular and clinical insights into the role of LINS1 in ARID, expanding the genetic landscape of ID. This discovery has significant implications for genetic counseling and prenatal diagnosis, aiding in the identification of at‐risk couples.

Abstract Background Integrating advanced artificial intelligence (AI) into clinical decision-support often requires the sharing of sensitive patient data with external services, raising privacy concerns. Homomorphic encryption (HE) allows computing directly on encrypted data, without revealing the underlying patient information. Objectives To develop a large language model (LLM)-assisted diagnosis framework while preserving patient privacy in the clinical text analysis, by leveraging HE and using rare disease (RD) diagnosis as a representative application. To demonstrate HE does not hinder the system performance. Materials and Methods Texts from patient histories and a RD knowledge base were embedded by LLMs into vectors, then encrypted using HE to obscure private information while retaining the semantic nuances. Diagnostic recommendations were generated by computing and ranking the similarities between the patient history and RD vectors in the encrypted space. The system was evaluated using 50 synthetic case reports (5 RDs, each with 10 reports). Results Applying HE did protect private information from reverse-embedding attacks. HE imposed little disruption to the diagnostic accuracy, with normalized discounted cumulative gains (nDCG) of 0.6108 ± 0.3412 (encrypted) versus 0.6083 ± 0.3415 (unencrypted). The accuracy and computational performance were tunable and consistent, as demonstrated across five different LLMs. Discussion Our privacy-preserving framework opens tremendous opportunities toward hosting and serving powerful AI solutions across institution boundaries, which would remove the need for local deidentification and incentivize users to access secure external decision-support services. Conclusions Integrating HE with LLM retrieval can promote the dissemination of nonredundant, high-capacity AI services by preserving both privacy and accuracy.

Abstract Disclosure: M. Salama: None. F. Pinto e Vairo: None. D. Hassan: None. S. Pittock: None. A. Lteif: None. O. Olson: None. A. Al Nofal: None. K. Leopold: None. S. Kumar: None. Objective: This study aimed to evaluate the effects of semaglutide on body mass index (BMI) and cardiometabolic profiles in adolescents with genetic variants associated with a likely high risk of monogenic obesity. Methods: A retrospective chart review was conducted for adolescents with severe obesity who underwent multigene panel testing for monogenic obesity and were treated with semaglutide. Results: Data from 27 adolescents were analyzed. At baseline, the median BMI percent of the 95th percentile (IQR) was 148 (135-189), with a mean age (SD) of 15.5 years (1.93) at treatment initiation and a median (IQR) treatment duration of 8 months (6-12). The median semaglutide dose (IQR) was 1.7 mg weekly (1.0- 2.4). Seven participants comprised the ‘’likely monogenic risk’’ group, characterized by predicted deleterious variants in dominant genes and/or carrying known dominant risk alleles. Twenty patients formed the “indetermined/negative “group, defined as harboring single rare variants in recessive genes or negative panel testing. In the likely monogenic risk group, weight loss was 8.5% with a median decrease in BMI % of the 95th %ile of 17 (95% CI 1.5- 22, p = 0.02). In the indetermined/negative group, weight loss was 7.6% with a median decrease in BMI % of the 95th %ile of 14 (95% CI 11.5- 27.5, p = <0.001). There was no statistically significant difference in median BMI % of the 95th % ile reduction between the two groups (p = 0.8) or BMI percent change (p = 0.89). Cardiometabolic changes in the likely monogenic risk group included reductions in HbA1c by 0.3% (95% CI: 0.15- 0.4, p = 0.03), total cholesterol by 15 mg/dL (95% CI: 7- 48, p = 0.03), and non-HDL cholesterol by 16.5 mg/dL (95% CI: 12- 40, p = 0.03). No significant changes were observed in fasting blood glucose, triglycerides, LDL cholesterol, HDL cholesterol, or ALT levels. The indetermined/negative group exhibited a significant reduction in HbA1c by 0.25% (95% CI 0.1 - 0.7| p = 0.009). Conclusion: Semaglutide treatment was associated with significant reductions in BMI and improvements in several cardiometabolic parameters in adolescents with likely high-risk monogenic obesity variants. These findings suggest semaglutide as a potentially effective therapeutic option for managing severe obesity in this population. Larger prospective studies are warranted to confirm and further assess these outcomes. Presentation: Monday, July 14, 2025

ABSTRACT Background & Aims Steatotic liver disease (SLD) is characterised by liver fat accumulation exceeding 5%. Lean body weight (BMI ≤ 25 kg/m 2 ) with non‐alcoholic SLD is a rare phenotype, and the balance of risks related to metabolic conditions or genetic predisposition, or the risk of progressive liver disease, is not known. This study evaluates clinical and genetic predictors of non‐alcoholic SLD and advanced liver disease in lean individuals. Methods We used International Classification of Disease codes, radiology and pathology review to identify 177 lean non‐alcoholic SLD cases (47 cryptogenic, 130 MASLD), 677 matched lean controls, and 3090 overweight/obese SLD cases in the Mayo Clinic Biobank and Tapestry databases. We performed case–control and cross‐sectional comparisons of clinical and genetic factors between these groups, using univariable and multivariable analyses. Results Lean individuals with non‐alcoholic SLD exhibited metabolic and genetic profiles that were intermediate between those of lean controls without SLD and overweight/obese SLD individuals, including intermediate rates of diabetes, hypertension, hyperlipidaemia and of homozygosity for the risk allele of PNPLA3 . Multivariable analysis indicated that diabetes was an independent predictor of SLD among lean individuals. Among lean individuals with non‐alcoholic SLD, those with metabolic‐associated SLD (MASLD), as compared to those with cryptogenic SLD (without metabolic risk factor), were more likely to be homozygous for risk alleles in GCKR . The Fib‐4 score, a tool for screening advanced liver disease in SLD, accurately predicted advanced fibrosis among lean individuals with non‐alcoholic SLD. Conclusion Diabetes serves as a primary predictor of non‐alcoholic SLD in lean individuals. These results support the recommendation to screen for SLD in patients with diabetes, regardless of BMI. The GCKR risk allele is associated with MASLD in lean individuals, and the risk factors for cryptogenic SLD remain unclear.

ABSTRACT Post‐translational modifications, such as glycosylation and phosphorylation, play a critical role in protein trafficking, interactions, and stability. Disruptions in these pathways can lead to glycosylphosphatidylinositol (GPI) deficiencies, which present with a spectrum of clinical features, including congenital anomalies, dysmorphic features, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGV , a key mannosyltransferase in GPI biosynthesis, cause Hyperphosphatasia with Impaired Intellectual Development Syndrome 1 (HPMRS1), a rare disorder characterized by hyperphosphatasia, seizures, developmental delay, hypotonia, abnormal MRI findings, and distinct facial dysmorphisms. Fewer than 30 cases have been reported to date. We conducted a case study and literature review; with clinical data obtained from medical records. A 2‐year‐old female presented with developmental delay, myoclonic epilepsy, hypotonia, and mild facial dysmorphism. Laboratory results showed elevated alkaline phosphatase (899 U/L) and low pyridoxal 5′‐phosphate levels in cerebrospinal fluid (CSF). Brain MRI revealed diffuse cerebral volume loss and ventriculomegaly. Trio genome sequencing identified two PIGV variants: c.1415T>C‐p.(Leu472Pro) and c.524T>C‐p.(Leu175Pro). Functional studies using PIGV ‐knockout HEK293 cells transfected with wild‐type or mutant PIGV constructs demonstrated reduced GPI‐anchored protein (GPI‐AP) expression under weaker promoters, indicating impaired enzymatic activity. We report two novel PIGV variants associated with HPMRS1, emphasizing the value of functional assays in variant interpretation. Our findings also highlight the diagnostic relevance of alkaline phosphatase measurement in patients with refractory seizures.

ABSTRACT Background and hypothesis Podocytopathy associated with likely pathogenic/pathogenic variants of Transient receptor potential cation channel subfamily C member 6 (TRPC6) (TRPC6-AP) has been recognized for about 20 years. As a result of its rarity however, the spectrum of clinical phenotypes and genotype–phenotype correlation of TRPC6-AP remains poorly understood. Here, we characterized clinical, histological and genetic correlates of familial and sporadic patients with TRPC6-AP. Methods In this multicentre observational study, an online questionnaire followed by a systematic literature review was performed to create a cohort with comprehensive data on genetic and clinical outcomes [age of onset, clinical presentation, treatment response, kidney biopsy findings and progression to kidney failure (KF)]. Logistic regression, Cox proportional hazards model and Kaplan–Meier analyses investigated the associations between genetic variants and disease progression. Results Among 87 families (96 familial and 45 sporadic cases), 31 distinct missense TRPC6 variants (including 2 novel) were identified, with c.2683C>T p.(Arg895Cys) and c.523C>T p.(Arg175Trp) the commonest variants. Proteinuric kidney disease/nephrotic syndrome was the most common clinical presentation (83.7%), while focal segmental glomerulosclerosis was the most common histological finding (89.4%). By 33 (interquartile range 17–40) years, 48.9% (69/141) of patients had progressed to KF. Sporadic TRPC6-AP demonstrated an earlier progression to KF than familial cases (P = .001) and were more likely to present with nephrotic syndrome [odds ratio 4.34 (1.85–10.15); P = .001]. Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs 44.4%; P = .004). Compared with patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to KF earlier [median kidney survival of 21 years, hazard ratio 2.985 (95% confidence interval 1.40–5.79); and 38 years, hazard ratio 1.65 (95% confidence interval 1.01–2.81), respectively, log-rank P = .005]. Conclusion Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.

Background and Aims: Metabolic dysfunction–associated steatotic liver disease affects about a third of adults worldwide and is projected soon to be the leading cause of liver cirrhosis. It occurs when fat accumulates in hepatocytes and can progress to metabolic dysfunction–associated steatohepatitis, liver cirrhosis, and HCC. Metabolic dysfunction–associated steatotic liver disease pathogenesis is believed to involve a combination of genetic and environmental risk factors. Single nucleotide polymorphisms have been implicated, but non-syndromic monogenic causes are lacking. Approach and Results: We identified a novel genetic variant in a familial case of metabolic dysfunction–associated steatohepatitis and performed deep variant functional analysis, including protein modeling, dynamics, and cell-based assays to assess molecular mechanisms of dysfunction and altered cellular signaling. We analyzed exome sequencing data of 3904 individuals with steatotic liver disease (SLD) to identify additional cases and establish the link between specific gene variants and SLD diagnosis. We discovered and functionally validated the NM_000245.4:c.3505A>T; p.(Ile1169Phe) variant in the MET (mesenchymal-epithelial transition) kinase domain as a monogenic cause of SLD. Subsequently, we detected additional ultra-rare, previously uninterpreted, and likely deleterious variants in MET from screening sequencing data. Among individuals with confirmed SLD based on electronic record review, 1.1% (45/3904) had rare predicted deleterious MET variants. Eight of 45 (17.7%) individuals had predicted deleterious variants in the MET kinase domain confirmed to be functionally like the familial case variant. Conclusions: We report the first germline nonmalignant rare MET -driven disease, a monogenic form of SLD.