Purpose Polygenic risk scores (PRS) have shown promise in predicting disease susceptibility, but their accuracy varies across populations due to limited representation of non-European ancestries in genomic studies. While European-derived PRS demonstrate some transferability to Asian populations, optimizing these scores for specific populations remains crucial for improving risk prediction. Methods Using data from the Taiwan Precision Medicine Initiative (TPMI) (n=46,422) and an external validation cohort (n=891), we developed an approach to optimize European-derived PRS for breast cancer prediction in East Asians. Our method involved two key steps: (1) replacing European PRS variants with Asian-specific SNPs within the same LD blocks (r2>0.8), and (2) incorporating additional population-specific variants. We validated this approach using both breast and prostate cancer datasets. Results The optimized PRS (PRSEUR_replace+TPMI) showed improved predictive performance compared to the original European PRS (PRSEUR) in our main cohort, with an increased AUC from 0.608 to 0.617 and ORs per SD from 1.47 (95% CI: 1.36-1.60) to 1.51 (95% CI: 1.39-1.63). Individuals in the top 5% of PRSEUR_replace+TPMI demonstrated a 2.09-fold increased risk of developing breast cancer compared to those in the 40-60th percentile. External validation confirmed enhanced performance, and similar improvements were observed when applying this method to prostate cancer prediction. Conclusions Our study presents a practical approach for optimizing European-derived PRS in non-European populations, particularly beneficial for populations with limited genetic data. As genetic data collection expands in these populations, this approach may help reduce healthcare disparities in precision medicine implementation.
Purpose Clinical genetic testing demand has increased in the era of precision medicine. However, availability of cancer genetic services remains limited in the US, prompting a rise in telehealth delivery. Through our Telegenetics program we seek to promote genetic service delivery across the US and here we assess engagement through registrations with local providers using a service delivery model. Methods This report describes the Penn Telegenetics Program experience across four research and clinical activities using an in-home collaborative local provider model. We report clinical procedures and our initial experience implementing the collaborative local provider model across four research and clinical activities in the Penn Telegenetics Program. We present descriptive findings of the registrations and in cases of refusals, the rationale provided. Results From 2018-2025, 473 providers (89.4%) successfully registered. Providers were predominately MD/DO licensed (85.0%). Family medicine was the most frequent speciality (54.3%), followed by internal medicine (20.9%) and clinical oncology (11.8%). Most providers were in suburban locations by zip codes (56.2%), 20.1% were in rural zip codes. Only 56 providers declined collaboration (10.6%); the most common reasons reported were preferring local genetic services (22.5%) and not being comfortable as the ordering provider (22.5%). Conclusion Our data demonstrate that most local providers are willing to collaborate with a centralized telegenetics program. Still subsequent engagement from local providers in follow-up questions or other referrals remain a missed opportunity to improve telegenetics access. Refining procedures to increase collaborative care and engagement may provide opportunities to increase access to cancer genetic testing.
Purpose Fanconi anemia (FA) is a rare monogenic chromosome breakage syndrome that presents variable morphologic abnormalities and progressive bone marrow failure. Based on over 30 years of diagnostic experience, our main goal was to describe the Portuguese FA population and assess potential clinical/analytical phenotypic correlations with both molecular variants and chromosome instability (CI). Methods We evaluated the in-house database from the Cytogenetics Laboratory of the School of Medicine and Biomedical Sciences, University of Porto, which provides nation-wide CI testing since 1993. Results Ninety-three FA cases were diagnosed between January 1993 and October 2025, one in the prenatal setting due to severe malformations. Molecular characterization was available for 50 of these cases. Of these, 45 carried FANCA variants in homozygosity or compound heterozygosity, with 38% (Romani ethnicity) harboring the homozygous NM_000135.4:c.295C>T p.(Gln99Ter) founder variant. Five additional cases carried variants in FANCD2, FANCG, FANCJ or PALB2. The most common clinical presentation comprised both hematological and morphological phenotypes, observed in 47% of cases. Isolated hematological and morphological presentations were observed in 27% and 13% of cases, respectively, while the remaining 13% of patients were asymptomatic.Cytogenetic diagnosis using the standard DEB test was extremely accurate. Follow-up cytogenetic assessment revealed a likely somatic genetic reversal in two cases occurring years after the diagnosis, suggesting the importance of the reevaluation of the DEB test. CI correlated significantly with the hematological phenotype and red blood cell analytic parameters. Conclusion Our data allowed the characterization of the Portuguese FA cohort from a clinical, cytogenetic, and molecular perspective, including the identification of population-specific molecular findings and associations between CI and clinical features. Findings related to cytogenetic assessment proved useful not only for diagnosis but also for FA follow-up and prognostic purposes.
Purposfe White-Sutton syndrome (WHSUS) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function alterations in the POGZ gene. WHSUS exhibits variable expressivity, often overlapping with other neurodevelopmental disorders. In this study, we characterized a distinct DNA methylation epigenetic signature (episignature) that differentiates WHSUS from unaffected individuals, as well as from individuals with other neurodevelopmental disorders that also have episignatures, using a cohort of both published and unpublished cases of POGZ haploinsufficiency. Methods Thirteen DNA samples from peripheral blood of individuals with pathogenic or likely pathogenic heterozygous alterations in POGZ were used to identify the episignature and develop a predictive diagnostic biomarker. The diagnostic model, validated with 4 samples from confirmed WHSUS cases, was then applied to investigate the methylation patterns in 7 individuals with variants of uncertain significance (VUS) in POGZ. Results Using genome-wide DNA methylation analysis, a predominantly hypomethylated DNA methylation profile specific to WHSUS was identified. A sensitive and specific classifier model was then constructed based on this profile. Gene set enrichment analysis revealed terms related to various cellular processes, and functional correlation analysis indicated potential common pathways with other genetic disorders. Conclusion We identified a novel, and robust episignature in WHSUS caused by POGZ haploinsufficiency. This episignature facilitates the identification and diagnosis of individuals with WHSUS, as well as the reclassification of VUS associated with this condition.
Purpose: This retrospective study examined the clinical and genetic characteristics of pediatric patients undergoing clinical exome sequencing (ES) and evaluated the performance of a commercially available artificial intelligence (AI) platform that was integrated into our analysis pipeline. Methods: ES was performed in 822 consecutive patients at a single clinical laboratory. AI-based tools were used to jointly assess genetic information and the proband’s Human Phenotype Ontology terms to support variant prioritization during the initial case review. Results: A definitive molecular diagnosis was established in 22% (181 of 822) of index cases, while 40% (325 of 822) had variants of uncertain significance. Among those with a definitive diagnosis, 93% (168 of 181) had a single finding and 7% (13 of 181) had multiple findings. Of the 152 reported pathogenic/likely pathogenic variants in the fully resolved cases, 98.7% were successfully flagged by AI, and 75.0% ranked among the top 10 “most likely” variants. Conclusion: Clinical ES provides a substantial diagnostic yield in complex pediatric disorders. Integration of AI-powered platforms can accelerate phenotype-driven variant prioritization and facilitate rare disease diagnostics, but underscores the need for careful validation and optimization in clinical workflows.
Purpose:DDX23, a member of the DEAD-box RNA helicase superfamily, is crucial for RNA processing and translation initiation during gametogenesis and cell division. This study aims to determine the disease-causing potential and clinical relevance of rare de novo DDX23 missense variants identified in individuals with neurodevelopmental and cardiopulmonary anomalies. Methods:Clinical and genetic analyses were performed on 3 individuals presenting with developmental delay or intellectual disability, facial dysmorphisms, brain structural abnormalities, and cardiopulmonary defects. Exome sequencing identified rare de novo monoallelic missense variants at p.Arg528-p.(Arg528Cys), p.(Arg528His), or p.(Arg528Gln)-in DDX23. In silico prediction tools were used to assess the potential functional impact of these variants. To test their disease-causing role in vivo, wild-type and two mutant DDX23 alleles, p.(Arg528Cys) and p.(Arg528His), were expressed ubiquitously or in a tissue-specific manner in a humanized Drosophila model. Results:All 3 individuals carried a de novo missense variants at p.Arg528-p.(Arg528Cys), p.(Arg528His), or p.(Arg528Gln)-all predicted in silico to be deleterious, with dominant effects. Expression of the p.(Arg528Cys) and p.(Arg528His) alleles in Drosophila resulted in severely compromised development and survival, with either ubiquitous or tissue-specific expression leading to a complete loss of progeny. These findings demonstrate a robust functional impact of the variants consistent with a gain-of-function mechanism. Conclusion:Our study identifies recurrent de novo missense variants in DDX23 as the genetic cause of a neurodevelopmental syndrome. Functional assays in Drosophila confirm the disease-causing potential of these variants and support a gain-of-function mechanism for the p.(Arg528Cys) and p.(Arg528His) alleles.
Newborn screening is one of the most successful public health programs in the U.S. with thousands of lives saved or improved each year through early identification and treatment of conditions. The mandatory nature of state newborn screening programs demands a high bar and rigorous scientific evidence for selecting conditions that should be included. Despite the development of new treatments for rare disorders and numerous pilot studies utilizing genomic newborn screening, recent changes at the federal level have made the addition of new conditions recommended for newborn screening challenging.
Purpose This study aimed to expand the clinical and biological understanding of POT1 tumor predisposition syndrome and raise awareness of its broad tumor spectrum and association with ultralong telomeres. Methods We conducted a retrospective analysis of 44 individuals carrying pathogenic or likely pathogenic POT1 variants identified between 2018 and 2025. Clinical, pathologic, and demographic data were extracted from medical records. Telomere length was assessed using in-gel hybridization of telomeric restriction fragments. Results Of 44 heterozygotes, 31 had the c.233T>C; p.(Ile78Thr) variant, 8 had c.1672dup; p.(Tyr558Leufs∗6), and 5 had other frameshifting, likely loss-of-function variants. Cancer was diagnosed in 27 heterozygotes (61%), totaling 84 primary malignancies (range: 0-8 per person), with most cases (79%) occurring after the age of 50 years. Melanoma (34%) and breast cancer in females (45%) were the most common. Additional tumors included papillary thyroid carcinoma, desmoid tumors, and diverse malignant and benign neoplasms. Colonic polyps were frequent. POT1 heterozygotes with the p.(Ile78Thr) variant exhibited significantly longer telomeres than control participants, with a 62-year-old woman showing comparable or even longer telomeres than her children. Conclusion POT1 pathogenic variants confer susceptibility to a wide tumor spectrum, notably melanoma and, unexpectedly, breast cancer. At least some of these variants are linked to ultralong telomeres, consistent with findings from this study and others. These findings support incorporating POT1 into multigene panels and suggest telomere length as a potential biomarker for diagnosis.
Purpose Genetic testing (GT) is crucial for Stargardt disease (STGD) diagnosis and clinical trial (CT) eligibility; however, predictors of GT completion remain understudied. We identified factors associated with GT completion and characterized CT participation among genetically confirmed patients. Methods We retrospectively reviewed 280 patients with clinically diagnosed STGD who were evaluated at a US tertiary referral center (2003-2024). Multivariable logistic regression was used to identify predictors of GT completion. Results Among 280 participants, 246 (88%) completed GT. GT completion was significantly less likely in participants who were Black (odds ratio [OR]: 0.40, 95% CI: 0.16-0.98), under/uninsured (OR: 0.47, 95% CI: 0.19-0.97), without genetic counseling (GC) (OR: 0.09, 95% CI: 0.03-0.22), or without reproductive plans (OR: 0.35, 95% CI: 0.14-0.89). Clinical factors (eg, age of onset, visual acuity, and family history) showed no significant associations. Common reasons for noncompletion included loss to follow-up (41%), patient refusal (26%), and awaiting GC (24%). Among 223 ABCA4-positive participants, 45 (20%) enrolled in CTs, with most (91%) completing GC. Conclusion Despite high overall GT completion rates, significant racial and socioeconomic disparities exist. GC emerged as the strongest modifiable factor, conferring over 10-fold higher odds of GT completion. Socioeconomic barriers drive testing disparities in STGD, rather than disease severity or clinical characteristics.
Health-related social needs (HRSNs) may impact the receipt of genetic services, but the mechanisms are not well established. We aimed to evaluate the relationship between pediatric patients' HRSNs and referrals for genetic evaluation. We analyzed HRSN survey data collected during clinic visits across 47 primary care offices for children <3 years of age. Using hazard ratios adjusted (aHRs) for child characteristics, we evaluated the relative likelihood of referral for genetic evaluation based on categories of HRSN. The sample included 42,390 children, 470 of whom received a referral for genetic evaluation. Children who screened positive for any HRSN (n = 235/15,019) were more likely to be referred than children who did not screen positive (n = 235/27,371; aHR = 1.29, P = .009). Children were more likely to receive referrals if they were insured by Medicaid rather than commercial insurance (aHR = 2.32, P < .0001), and if they received care in academic primary care clinics rather than community ones (aHR = 2.52, P < .0001). Holding child characteristics and other HRSNs constant, parent-reported financial stress was associated with a higher likelihood of referral (aHR = 1.38, P = .004). Child race and ethnicity were not significant predictors of referral in adjusted analyses. Children in our sample with any HRSN were more likely to receive a referral for genetic evaluation, which is a key step toward genetic diagnosis. Our findings highlight the need to better understand the relationship between HRSNs and genetic referrals and services.
Purpose:Autism and Intellectual and Developmental Disorder (IDD) are neurodevelopmental conditions influenced by genetic factors. Health organizations recommend genetic testing as part of medical care for individuals diagnosed with autism and IDD. Genetic etiologies can improve counseling accuracy and refine patient treatment, but despite the benefits, studies show that patients often decline clinically offered testing. Methods:We analyzed data from 7539 health records of autistic individuals with IDD and identified 111 instances with documented refusal of genetic testing (GT). Then, we rechecked the charts with previously documented refusal 4 years later for subsequent acceptance. Results:Reasons for refusal were "access issues" (46.8%) predominantly related to "insurance/cost," "personal concerns" (21.6%) regarding "procedure" or "no interest," and "deferred" (19.8%); some refusals were "not specified" (13.5%). Of those individuals who initially declined genetic testing, 29 (26.1%) obtained testing upon follow-up review; the initial reason for refusal was not predictive of later completion of tests. Conclusion:These findings indicate a need to address external barriers, such as cost and insurance. Reducing discomfort and increasing accessibility to information regarding autism/IDD GT benefits, importance, and alternative DNA collection methods could also increase awareness, interest, and access to testing. Longitudinal results indicate that providers should follow up on GT for all autism/IDD patients who decline it.
Purpose:Genetic factors play a role in prostate cancer (PCa) development. This real-life, retrospective, multicenter study aimed to identify and characterize the germline genetic testing landscape in men with PCa and to assess the added benefit of next-generation sequencing (NGS) testing compared with testing for founder disease-causing variants. Methods:This study included all men who were referred for genetic counseling because of PCa. All patients were offered germline genetic testing. Demographic, clinical, and pathological information was retrieved from their medical records. Variant classification was determined using the American College of Medical Genetics and Genomics guidelines. Results:Of the 293 men with PCa tested, in 39 (13.3%), a positive genetic finding (pathogenic variant, likely pathogenic, or risk variant) was reported: 18 (6.1%) men had a positive test result for high-penetrance genes (BRCA1, BRCA2, ATM, NF1, and MSH6), and 21 (7.2%) had risk allele variants. One-third (33%) of the disease-causing or likely disease-causing variants identified through NGS in our PCa cohort were unique rather than founder variants. The only significant correlation between positive results and demographic or clinical factors was observed between a positive test result and a family history of cancer. Conclusion:Our findings underscore the importance of NGS genetic investigations in patients with PCa, regardless of ethnicity or disease stage.
