Pub Date : 2026-01-01DOI: 10.1016/j.gimo.2025.103476
K. Taylor Wild , Sara L. Reichert , Matthew C. Dulik , Alexandra Heck , Emma C. Bedoukian , Kathleen H. Wood , Katharine P. Callahan , Jennifer A. Hershey , David A. Munson , Kieran B. Pechter , Kelly Regan-Fendt , Anthony M. Gacita , Francis Jeshira Reynoso Santos , Morgan L. McManus , Natalie Burrill , Maria Alejandra Diaz-Miranda , Melissa A. Gilbert , Ian D. Krantz , Ramakrishnan Rajagopalan , Laura K. Conlin , Nancy B. Spinner
Purpose
We developed a genome sequencing-based test (Rapid Targeted Analysis of the Genome for Infants [rTAG-I]) to minimize turnaround time while maximizing diagnostic yield and access to rapid sequencing for critically ill infants. We sought to create a system of predicting which infants would have a molecular finding.
Methods
We performed a prospective observational study of infants referred for genetics consult who received rTAG-I testing, which analyzes 3183 curated genes with phenotype-agnostic prioritization of pathogenic and likely pathogenic variants. Infants were stratified by perceived likelihood of a diagnostic result and divided into “Likely,” “Uncertain,” and “Not Likely.” We also assessed whether reportable findings correlated with patient phenotypes.
Results
We identified reportable findings in 133/400 (33%) infants. Access to rapid testing increased from 1% to 20% of all infants hospitalized in the neonatal/infant intensive care unit and cardiac intensive care unit, with a median turnaround time of 4.9 days. rTAG-I performed as well as exome/genome sequencing. Clinically associated results were identified in 59% of the “Likely” group and 9% of the “Not Likely” group.
Conclusion
rTAG-I produced a high rate of reportable findings with a rapid turnaround time. Our ability to predict infants who would benefit most was imperfect, reinforcing that broad access to genome-based testing is still required.
{"title":"Rapid targeted analysis of the genome: Rapid genomic sequencing in critically ill infants","authors":"K. Taylor Wild , Sara L. Reichert , Matthew C. Dulik , Alexandra Heck , Emma C. Bedoukian , Kathleen H. Wood , Katharine P. Callahan , Jennifer A. Hershey , David A. Munson , Kieran B. Pechter , Kelly Regan-Fendt , Anthony M. Gacita , Francis Jeshira Reynoso Santos , Morgan L. McManus , Natalie Burrill , Maria Alejandra Diaz-Miranda , Melissa A. Gilbert , Ian D. Krantz , Ramakrishnan Rajagopalan , Laura K. Conlin , Nancy B. Spinner","doi":"10.1016/j.gimo.2025.103476","DOIUrl":"10.1016/j.gimo.2025.103476","url":null,"abstract":"<div><h3>Purpose</h3><div>We developed a genome sequencing-based test (Rapid Targeted Analysis of the Genome for Infants [rTAG-I]) to minimize turnaround time while maximizing diagnostic yield and access to rapid sequencing for critically ill infants. We sought to create a system of predicting which infants would have a molecular finding.</div></div><div><h3>Methods</h3><div>We performed a prospective observational study of infants referred for genetics consult who received rTAG-I testing, which analyzes 3183 curated genes with phenotype-agnostic prioritization of pathogenic and likely pathogenic variants. Infants were stratified by perceived likelihood of a diagnostic result and divided into “Likely,” “Uncertain,” and “Not Likely.” We also assessed whether reportable findings correlated with patient phenotypes.</div></div><div><h3>Results</h3><div>We identified reportable findings in 133/400 (33%) infants. Access to rapid testing increased from 1% to 20% of all infants hospitalized in the neonatal/infant intensive care unit and cardiac intensive care unit, with a median turnaround time of 4.9 days. rTAG-I performed as well as exome/genome sequencing. Clinically associated results were identified in 59% of the “Likely” group and 9% of the “Not Likely” group.</div></div><div><h3>Conclusion</h3><div>rTAG-I produced a high rate of reportable findings with a rapid turnaround time. Our ability to predict infants who would benefit most was imperfect, reinforcing that broad access to genome-based testing is still required.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103476"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.gimo.2025.103481
Dominique P. Germain , Fatma Al-Jasmi , Gheona Altarescu , Olga Azevedo , Fellype C. Barreto , Alessandro P. Burlina , Fatih Ezgü , Dawn A. Laney , Ales Linhart , Manish Maski , Sergey Moiseev , Dau-Ming Niu , Kotaro Nochioka , Yan Ouyang , Huseyin Onay , Mary Pavlou , Nicholas Pachter , Juan Politei , Sunbul Rawda , Richard P. Steeds , Irina Maksimova
{"title":"Expert opinion on facilitating intrafamily communication in rare diseases—Lessons from Fabry disease","authors":"Dominique P. Germain , Fatma Al-Jasmi , Gheona Altarescu , Olga Azevedo , Fellype C. Barreto , Alessandro P. Burlina , Fatih Ezgü , Dawn A. Laney , Ales Linhart , Manish Maski , Sergey Moiseev , Dau-Ming Niu , Kotaro Nochioka , Yan Ouyang , Huseyin Onay , Mary Pavlou , Nicholas Pachter , Juan Politei , Sunbul Rawda , Richard P. Steeds , Irina Maksimova","doi":"10.1016/j.gimo.2025.103481","DOIUrl":"10.1016/j.gimo.2025.103481","url":null,"abstract":"","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103481"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.gimo.2025.103490
Siwaar Abouhala , Maya C. del Rosario , Ingrid A. Holm , Monica H. Wojcik
Purpose
Many rare genetic conditions manifest soon after birth and result in admission to the Neonatal Intensive Care Unit (NICU), where prior research suggests that parents experience high levels of stress and uncertainty. However, further insight into parent-reported, longer-term outcomes for these infants and their families is needed.
Methods
We undertook a qualitative analysis of parent-reported experiences with genomic care over the course of their NICU admission and beyond, after an initial quantitative study of 110 families who received genetic evaluation in the NICU, in a mixed-methods approach. Twenty families participated in individual semistructured interviews eliciting the impact of the NICU experience and genetic diagnostic odyssey on the infant and family.
Results
We identified 4 main themes: (1) Rare Disease as “Culture Shock,” (2) Parental Trauma and Stressors, (3) Family Resiliency, and (4) Hospital System Recommendations. Early, rapid, and broad genomic testing was appreciated by parents, although additional genomic- and nongenomic supports after NICU discharge were desired. Stressors in the NICU related to uncertainty and critical illness occurred independent of genetic testing applications or results. Parents reported adapting their expectations regarding the benefits of a genetic diagnosis over time, ultimately focusing on day-to-day care and finding pride in medical and social resilience.
Conclusion
The NICU experience, particularly for infants with rare conditions, has long-lasting impact on the family. Enhanced attention to longitudinal supports from NICU to home may be beneficial for families undergoing genetic diagnostic odysseys.
{"title":"Rare and resilient: Longer-term experiences of families after genetic evaluation in the neonatal intensive care unit","authors":"Siwaar Abouhala , Maya C. del Rosario , Ingrid A. Holm , Monica H. Wojcik","doi":"10.1016/j.gimo.2025.103490","DOIUrl":"10.1016/j.gimo.2025.103490","url":null,"abstract":"<div><h3>Purpose</h3><div>Many rare genetic conditions manifest soon after birth and result in admission to the Neonatal Intensive Care Unit (NICU), where prior research suggests that parents experience high levels of stress and uncertainty. However, further insight into parent-reported, longer-term outcomes for these infants and their families is needed.</div></div><div><h3>Methods</h3><div>We undertook a qualitative analysis of parent-reported experiences with genomic care over the course of their NICU admission and beyond, after an initial quantitative study of 110 families who received genetic evaluation in the NICU, in a mixed-methods approach. Twenty families participated in individual semistructured interviews eliciting the impact of the NICU experience and genetic diagnostic odyssey on the infant and family.</div></div><div><h3>Results</h3><div>We identified 4 main themes: (1) Rare Disease as “Culture Shock,” (2) Parental Trauma and Stressors, (3) Family Resiliency, and (4) Hospital System Recommendations. Early, rapid, and broad genomic testing was appreciated by parents, although additional genomic- and nongenomic supports after NICU discharge were desired. Stressors in the NICU related to uncertainty and critical illness occurred independent of genetic testing applications or results. Parents reported adapting their expectations regarding the benefits of a genetic diagnosis over time, ultimately focusing on day-to-day care and finding pride in medical and social resilience.</div></div><div><h3>Conclusion</h3><div>The NICU experience, particularly for infants with rare conditions, has long-lasting impact on the family. Enhanced attention to longitudinal supports from NICU to home may be beneficial for families undergoing genetic diagnostic odysseys.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103490"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.gimo.2025.103482
Laura M. Amendola , Alison J. Coffey , Josh Lowry , James Avecilla , Alka Malhotra , Aditi Chawla , Stetson Thacker , Julie P. Taylor , Revathi Rajkumar , Carolyn M. Brown , Katie Golden-Grant , Rueben Hejja , Tasha Kalista , Jennifer A. Lee , Phillip Medrano , Becky Milewski , Felipe Mullen , Andrew Walker , Adriana Huertas-Vazquez , Mauro Longoni , Ryan J. Taft
Purpose
Despite monogenic and polygenic contributions to cardiovascular disease (CVD), genetic testing is not widely adopted, and current tests are limited by the breadth of surveyed conditions and variant interpretation burden. To address these limitations, a comprehensive clinical genome CVD test with semiautomated interpretation was developed.
Methods
Monogenic conditions and risk alleles were selected based on the strength of disease association and evidence for increased disease risk, respectively. Non-CVD secondary findings genes, pharmacogenomic (PGx) variants, and CVD-associated polygenic risk scores (PRS) were also assessed for inclusion. Test performance was modeled using 2594 genomes from the 1000 Genomes Project and further investigated in 20 previously tested individuals.
Results
The CVD genome test comprises a panel of 215 high-confidence CVD gene-disease pairs, 35 non-CVD secondary findings genes, 4 risk alleles or genotypes, 10 PGx genes, and a PRS for coronary artery disease. Modeling of test performance using samples from the 1000 Genomes Project revealed approximately 6% of individuals with a monogenic finding in a CVD-associated gene, 6% with a risk allele finding, 1% with a non-CVD secondary finding, and 93% with CVD-associated PGx variants. Assessment of blinded clinical samples showed concordance with prior testing. An average of 4 variants were reviewed per case, with interpretation and reporting time ranging from 9 to 96 minutes.
Conclusion
A genome-sequencing-based CVD genetic risk assessment test can provide comprehensive genetic disease and genetic risk information to patients with CVD. The semiautomated and limited interpretation burden suggest that this testing approach can be scaled to support population-level initiatives in phenotypically enriched populations.
{"title":"Development of a comprehensive cardiovascular disease genetic risk assessment test","authors":"Laura M. Amendola , Alison J. Coffey , Josh Lowry , James Avecilla , Alka Malhotra , Aditi Chawla , Stetson Thacker , Julie P. Taylor , Revathi Rajkumar , Carolyn M. Brown , Katie Golden-Grant , Rueben Hejja , Tasha Kalista , Jennifer A. Lee , Phillip Medrano , Becky Milewski , Felipe Mullen , Andrew Walker , Adriana Huertas-Vazquez , Mauro Longoni , Ryan J. Taft","doi":"10.1016/j.gimo.2025.103482","DOIUrl":"10.1016/j.gimo.2025.103482","url":null,"abstract":"<div><h3>Purpose</h3><div>Despite monogenic and polygenic contributions to cardiovascular disease (CVD), genetic testing is not widely adopted, and current tests are limited by the breadth of surveyed conditions and variant interpretation burden. To address these limitations, a comprehensive clinical genome CVD test with semiautomated interpretation was developed.</div></div><div><h3>Methods</h3><div>Monogenic conditions and risk alleles were selected based on the strength of disease association and evidence for increased disease risk, respectively. Non-CVD secondary findings genes, pharmacogenomic (PGx) variants, and CVD-associated polygenic risk scores (PRS) were also assessed for inclusion. Test performance was modeled using 2594 genomes from the 1000 Genomes Project and further investigated in 20 previously tested individuals.</div></div><div><h3>Results</h3><div>The CVD genome test comprises a panel of 215 high-confidence CVD gene-disease pairs, 35 non-CVD secondary findings genes, 4 risk alleles or genotypes, 10 PGx genes, and a PRS for coronary artery disease. Modeling of test performance using samples from the 1000 Genomes Project revealed approximately 6% of individuals with a monogenic finding in a CVD-associated gene, 6% with a risk allele finding, 1% with a non-CVD secondary finding, and 93% with CVD-associated PGx variants. Assessment of blinded clinical samples showed concordance with prior testing. An average of 4 variants were reviewed per case, with interpretation and reporting time ranging from 9 to 96 minutes.</div></div><div><h3>Conclusion</h3><div>A genome-sequencing-based CVD genetic risk assessment test can provide comprehensive genetic disease and genetic risk information to patients with CVD. The semiautomated and limited interpretation burden suggest that this testing approach can be scaled to support population-level initiatives in phenotypically enriched populations.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103482"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.gimo.2025.103479
Rhandi Christensen , Chaini Konwar , Beryl C. Zhuang , Michael S. Kobor , Vann Chau , Anne Synnes , Ting Guo , Julia MacIsaac , Ruth E. Grunau , Steven P. Miller
Purpose
The objective of this study was to identify predictors of epigenetic age and its association with neurodevelopmental outcomes in children born preterm.
Methods
A prospective cohort of children born 24-to-32-weeks gestation, well characterized with clinical data, brain imaging, and neurodevelopmental assessments at 3 years (Bayley-III cognitive and motor composite), were included. Epigenetic age (in weeks) was determined using the Pediatric Buccal Epigenetic Clock and corrected for chronological age to give epigenetic age difference (EAD). The associations between EAD, clinical risk factors and neurodevelopmental outcomes were examined using multivariable linear regression.
Results
A total of 102 study participants (47% males) were included. Epigenetic age showed a positive association with chronological age at term-equivalent age and 3 years. Neonatal morbidity was associated with a lower EAD (epigenetic age deceleration) at 3 years (β = −10.1, P = .03). Sex modified the association between EAD and extreme prematurity (P = .08), retinopathy of prematurity (P = .04), and infection (P = .06), with males having a higher EAD (epigenetic age acceleration). EAD at 3 years was associated with cognitive (β = 0.1, P = .004) and motor (β = 0.2, P = .001) scores at 3 years, with a higher EAD (epigenetic age acceleration) being associated with better outcomes.
Conclusion
Epigenetic age acceleration was associated with better cognitive and motor outcomes in children born preterm. Epigenetic modification is an important biological mechanism that contributes to the variability in neurodevelopmental outcomes in the preterm population.
目的本研究的目的是确定表观遗传年龄的预测因素及其与早产儿神经发育结局的关系。方法纳入一个前瞻性队列研究，研究对象为妊娠24- 32周出生的儿童，具有临床资料、脑成像和3岁时神经发育评估（Bayley-III认知和运动综合）。表观遗传年龄（以周为单位）使用儿科颊表观遗传时钟确定，并根据实足年龄进行校正，得出表观遗传年龄差异（EAD）。使用多变量线性回归检查EAD、临床危险因素和神经发育结局之间的关系。结果共纳入102例研究对象，其中男性占47%。表观遗传年龄与足月年龄和3岁时的实足年龄呈正相关。新生儿发病率与3岁时较低的EAD（表观遗传年龄减速）相关（β = - 10.1, P = .03）。性别改变了EAD与极端早产（P = 0.08）、早产儿视网膜病变（P = 0.04）和感染（P = 0.06）之间的关系，男性的EAD更高（表观遗传年龄加速）。3岁时的EAD与3岁时的认知评分（β = 0.1, P = 0.004）和运动评分（β = 0.2, P = 0.001）相关，较高的EAD（表观遗传年龄加速）与较好的结果相关。结论表观遗传年龄加速与早产儿更好的认知和运动预后有关。表观遗传修饰是一种重要的生物学机制，有助于早产儿神经发育结果的变异性。
{"title":"Epigenetic age and neurodevelopmental outcomes in children born preterm","authors":"Rhandi Christensen , Chaini Konwar , Beryl C. Zhuang , Michael S. Kobor , Vann Chau , Anne Synnes , Ting Guo , Julia MacIsaac , Ruth E. Grunau , Steven P. Miller","doi":"10.1016/j.gimo.2025.103479","DOIUrl":"10.1016/j.gimo.2025.103479","url":null,"abstract":"<div><h3>Purpose</h3><div>The objective of this study was to identify predictors of epigenetic age and its association with neurodevelopmental outcomes in children born preterm.</div></div><div><h3>Methods</h3><div>A prospective cohort of children born 24-to-32-weeks gestation, well characterized with clinical data, brain imaging, and neurodevelopmental assessments at 3 years (Bayley-III cognitive and motor composite), were included. Epigenetic age (in weeks) was determined using the Pediatric Buccal Epigenetic Clock and corrected for chronological age to give epigenetic age difference (EAD). The associations between EAD, clinical risk factors and neurodevelopmental outcomes were examined using multivariable linear regression.</div></div><div><h3>Results</h3><div>A total of 102 study participants (47% males) were included. Epigenetic age showed a positive association with chronological age at term-equivalent age and 3 years. Neonatal morbidity was associated with a lower EAD (epigenetic age deceleration) at 3 years (β = −10.1, <em>P</em> = .03). Sex modified the association between EAD and extreme prematurity (<em>P</em> = .08), retinopathy of prematurity (<em>P</em> = .04), and infection (<em>P</em> = .06), with males having a higher EAD (epigenetic age acceleration). EAD at 3 years was associated with cognitive (β = 0.1, <em>P</em> = .004) and motor (β = 0.2, <em>P</em> = .001) scores at 3 years, with a higher EAD (epigenetic age acceleration) being associated with better outcomes.</div></div><div><h3>Conclusion</h3><div>Epigenetic age acceleration was associated with better cognitive and motor outcomes in children born preterm. Epigenetic modification is an important biological mechanism that contributes to the variability in neurodevelopmental outcomes in the preterm population.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103479"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145926807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.gimo.2025.103478
Ankit K. Desai , Eleanor Rodriguez-Rassi , Suhag Parikh , Rossana Sanchez Russo , David Kronn , J. Austin Hamm , Irene J. Chang , Damara Ortiz , Molly McPheron , Holly Lydigsen , Stephanie DeArmey , Sarah P. Young , Priya S. Kishnani
Purpose
To assess the benefits of early enzyme replacement therapy (ERT) in patients with infantile-onset Pompe disease (IOPD).
Methods
A retrospective chart review of 17 IOPD (7 cross-reactive immunologic material [CRIM]-negative and 10 CRIM positive) who initiated ERT (alglucosidase alfa) ≤4 weeks of age and had ≥18 months follow-up was performed.
Results
Patients received starting doses of 20 mg/kg/every other week (n = 11), 20 mg/kg/week (n = 3), or 40 mg/kg/week (n = 3). Six CRIM-negative and 2 patients who were CRIM positive received immune tolerance induction (ITI) with Rituximab+Methotrexate+intravenous immunoglobulin. Five patients who were CRIM positive received transient low-dose methotrexate. All CRIM-negative patients were immune tolerant. Three patients who were CRIM positive developed high-sustained antibody titers (HSAT); 2 were immune tolerant after bortezomib-based ITI. One patient who was CRIM positive developed HSAT, was invasively ventilated, and succumbed at age 5.2 years. At the most recent follow-up (MRFU; 3.1-18.4 years), 16 patients were alive, ambulatory, feeding orally, invasive ventilator-free, and receiving high-dose ERT (median lifelong dose 2.76X; 1.36-4.00). All patients experienced left ventricular mass index and Glc4 reductions and for a subset, biomarkers were within normal limits at MRFU (left ventricular mass index:16/17, AST:9/17, CK:5/17, and Glc4:5/16).
Conclusion
These data highlight the benefits of early ERT initiation and ITI, along with high-dose ERT. Despite early treatment, patients with IOPD remain at risk of developing HSAT.
{"title":"Early initiation of enzyme replacement therapy as facilitated by newborn screening improves health outcomes among patients with infantile-onset Pompe disease","authors":"Ankit K. Desai , Eleanor Rodriguez-Rassi , Suhag Parikh , Rossana Sanchez Russo , David Kronn , J. Austin Hamm , Irene J. Chang , Damara Ortiz , Molly McPheron , Holly Lydigsen , Stephanie DeArmey , Sarah P. Young , Priya S. Kishnani","doi":"10.1016/j.gimo.2025.103478","DOIUrl":"10.1016/j.gimo.2025.103478","url":null,"abstract":"<div><h3>Purpose</h3><div>To assess the benefits of early enzyme replacement therapy (ERT) in patients with infantile-onset Pompe disease (IOPD).</div></div><div><h3>Methods</h3><div>A retrospective chart review of 17 IOPD (7 cross-reactive immunologic material [CRIM]-negative and 10 CRIM positive) who initiated ERT (alglucosidase alfa) ≤4 weeks of age and had ≥18 months follow-up was performed.</div></div><div><h3>Results</h3><div>Patients received starting doses of 20 mg/kg/every other week (<em>n</em> = 11), 20 mg/kg/week (<em>n</em> = 3), or 40 mg/kg/week (<em>n</em> = 3). Six CRIM-negative and 2 patients who were CRIM positive received immune tolerance induction (ITI) with Rituximab+Methotrexate+intravenous immunoglobulin. Five patients who were CRIM positive received transient low-dose methotrexate. All CRIM-negative patients were immune tolerant. Three patients who were CRIM positive developed high-sustained antibody titers (HSAT); 2 were immune tolerant after bortezomib-based ITI. One patient who was CRIM positive developed HSAT, was invasively ventilated, and succumbed at age 5.2 years. At the most recent follow-up (MRFU; 3.1-18.4 years), 16 patients were alive, ambulatory, feeding orally, invasive ventilator-free, and receiving high-dose ERT (median lifelong dose 2.76X; 1.36-4.00). All patients experienced left ventricular mass index and Glc<sub>4</sub> reductions and for a subset, biomarkers were within normal limits at MRFU (left ventricular mass index:16/17, AST:9/17, CK:5/17, and Glc<sub>4</sub>:5/16).</div></div><div><h3>Conclusion</h3><div>These data highlight the benefits of early ERT initiation and ITI, along with high-dose ERT. Despite early treatment, patients with IOPD remain at risk of developing HSAT.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103478"},"PeriodicalIF":0.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.gimo.2025.103480
Jasmine Saunders , Veda N. Giri , Susan Vadaparampil , Adrian Rivera , Tatiana Sanchez Nolasco , Mariana Rangel Camacho , Nataliya Byrne , Kellie Owens , Michele Santacatterina , Stacy Loeb
Purpose
Underutilization of genetic testing among Hispanic males results in higher rates of variants of uncertain significance (VUS). We examined the impact of VUS on decision making and behavioral intentions.
Methods
We conducted a nationwide survey of 807 US Hispanic males aged ≥40 in English and Spanish on perspectives about genetic testing results. Logistic regression was used to examine predictors of worry and behavior change with a hypothetical VUS result.
Results
Over half of Hispanic male participants would still participate in genetic testing with a 1 in 5 chance of VUS. However, 36% were at least somewhat likely to regret testing and 49.9% would worry about cancer risk with VUS results. In addition, 56.3% were somewhat or very likely to change behavior due to a VUS, such as getting checked by the doctor more often or telling family members to get checked. Younger age and college education were associated with more worry and intended behavior change.
Conclusion
Although many Hispanic males are interested in genetic testing despite the higher likelihood of VUS, potential consequences include decisional regret, anxiety, and even changes in behavior. Effective counseling and support are important for minoritized groups undergoing genetic evaluation to avoid the potential to exacerbate health disparities.
{"title":"Impact of variants of uncertain significance on decision making about genetic testing for Hispanic males","authors":"Jasmine Saunders , Veda N. Giri , Susan Vadaparampil , Adrian Rivera , Tatiana Sanchez Nolasco , Mariana Rangel Camacho , Nataliya Byrne , Kellie Owens , Michele Santacatterina , Stacy Loeb","doi":"10.1016/j.gimo.2025.103480","DOIUrl":"10.1016/j.gimo.2025.103480","url":null,"abstract":"<div><h3>Purpose</h3><div>Underutilization of genetic testing among Hispanic males results in higher rates of variants of uncertain significance (VUS). We examined the impact of VUS on decision making and behavioral intentions.</div></div><div><h3>Methods</h3><div>We conducted a nationwide survey of 807 US Hispanic males aged ≥40 in English and Spanish on perspectives about genetic testing results. Logistic regression was used to examine predictors of worry and behavior change with a hypothetical VUS result.</div></div><div><h3>Results</h3><div>Over half of Hispanic male participants would still participate in genetic testing with a 1 in 5 chance of VUS. However, 36% were at least somewhat likely to regret testing and 49.9% would worry about cancer risk with VUS results. In addition, 56.3% were somewhat or very likely to change behavior due to a VUS, such as getting checked by the doctor more often or telling family members to get checked. Younger age and college education were associated with more worry and intended behavior change.</div></div><div><h3>Conclusion</h3><div>Although many Hispanic males are interested in genetic testing despite the higher likelihood of VUS, potential consequences include decisional regret, anxiety, and even changes in behavior. Effective counseling and support are important for minoritized groups undergoing genetic evaluation to avoid the potential to exacerbate health disparities.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103480"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1016/j.gimo.2025.103477
Pratiksha Gyawali , Binaya Shrestha , Kelly Beharry , Gareema Agarwal , Shane C. Quinonez
Purpose
Medical genetic services remain limited in low- and middle- income countries, such as Nepal, leading to poor health outcomes for individuals affected by genetic disorders. This study aimed to assess perspective and characterize current practices and attitudes toward genetic services among health care providers in Nepal.
Methods
A web-based survey was completed by 131 clinicians across multiple disciplines, exploring participant demographics, experience with genetic services, and perceived barriers to genetic testing and counseling.
Results
Although 42% of respondents reported regularly caring for patients with suspected genetic disorders, 77% of providers reported difficulties with obtaining genetic testing. The most frequently cited barriers included limited laboratory availability (28%), cost (26%), and logistical challenges (19%). Many respondents reported confidence in discussing disease recurrence risk (63%), treating genetic disorders (40%), and providing genetic counseling (48%), and the majority (86%) expressed interest in furthering their genetic education because only 19% felt their current genetics knowledge was sufficient.
Conclusion
This study highlights a clear demand for accessible, affordable, in-country genetic services in Nepal and underscores the need for investment in clinical training and capacity building to improve access and outcomes for patients with genetic disorders.
{"title":"Medical genetics needs assessment: An online cross-sectional survey from Nepal","authors":"Pratiksha Gyawali , Binaya Shrestha , Kelly Beharry , Gareema Agarwal , Shane C. Quinonez","doi":"10.1016/j.gimo.2025.103477","DOIUrl":"10.1016/j.gimo.2025.103477","url":null,"abstract":"<div><h3>Purpose</h3><div>Medical genetic services remain limited in low- and middle- income countries, such as Nepal, leading to poor health outcomes for individuals affected by genetic disorders. This study aimed to assess perspective and characterize current practices and attitudes toward genetic services among health care providers in Nepal.</div></div><div><h3>Methods</h3><div>A web-based survey was completed by 131 clinicians across multiple disciplines, exploring participant demographics, experience with genetic services, and perceived barriers to genetic testing and counseling.</div></div><div><h3>Results</h3><div>Although 42% of respondents reported regularly caring for patients with suspected genetic disorders, 77% of providers reported difficulties with obtaining genetic testing. The most frequently cited barriers included limited laboratory availability (28%), cost (26%), and logistical challenges (19%). Many respondents reported confidence in discussing disease recurrence risk (63%), treating genetic disorders (40%), and providing genetic counseling (48%), and the majority (86%) expressed interest in furthering their genetic education because only 19% felt their current genetics knowledge was sufficient.</div></div><div><h3>Conclusion</h3><div>This study highlights a clear demand for accessible, affordable, in-country genetic services in Nepal and underscores the need for investment in clinical training and capacity building to improve access and outcomes for patients with genetic disorders.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103477"},"PeriodicalIF":0.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-18DOI: 10.1016/j.gimo.2025.103473
Flavie Ader , Céline Guilbeau-Frugier , Emeline Lhuillier , Frédéric Martins , Anne Alicia Gonzalez , Anne Rollin , Maxime Beneyto , Céline Gales , Filipe Pires , Jean-José Maoret , Jean-Michel Sénard , Jean Timnou-Bekouti , Eric Villard , Laetitia Duboscq-Bidot , Estelle Gandjbakhch , Philippe Maury
Purpose
We present here the technical feasibility of percutaneously retrieving cardiomyocytes (CMs) through the lumen of irrigated ablation catheters, with the aim of obtaining DNA of sufficient quality/quantity for allowing DNA amplification, screening, and derived genetic analysis.
Methods
Irrigated conventional catheters for ablation were used for creating endocardial right ventricular voltage maps in 38 patients with suspected or proved arrhythmogenic right ventricular cardiomyopathy. Blood material was collected from scar areas by aspiration and filtered, CMs detected by light microscopy were aspirated, centrifugated, and freezed.
DNA was extracted, amplified, and sequenced, and variants were compared with variants obtained from leukocyte DNA.
Results
At least 1 CM was obtained in 95% of patients (median 11 CM/patient). After refinements of the technique, a total of 136 samples (22 patients) allowed DNA extraction and amplification, successful in 60% of samples (16 patients). DNA capture sequencing of a panel of cardiomyopathy-associated genes was successfully performed in 14 patients and compared with blood sequencing in 11. After controlled by Sanger, an additional variant, not present in blood, has been confirmed in CM in one patient.
Conclusion
This new mini-invasive technique of sampling allows to perform genetic analysis on CMs. Pending future improvements, this technique could provide new sources of human cells for research and potential mosaicism detection.
{"title":"Methodology of DNA extraction and sequencing from living cardiomyocytes collected by catheter in humans","authors":"Flavie Ader , Céline Guilbeau-Frugier , Emeline Lhuillier , Frédéric Martins , Anne Alicia Gonzalez , Anne Rollin , Maxime Beneyto , Céline Gales , Filipe Pires , Jean-José Maoret , Jean-Michel Sénard , Jean Timnou-Bekouti , Eric Villard , Laetitia Duboscq-Bidot , Estelle Gandjbakhch , Philippe Maury","doi":"10.1016/j.gimo.2025.103473","DOIUrl":"10.1016/j.gimo.2025.103473","url":null,"abstract":"<div><h3>Purpose</h3><div>We present here the technical feasibility of percutaneously retrieving cardiomyocytes (CMs) through the lumen of irrigated ablation catheters, with the aim of obtaining DNA of sufficient quality/quantity for allowing DNA amplification, screening, and derived genetic analysis.</div></div><div><h3>Methods</h3><div>Irrigated conventional catheters for ablation were used for creating endocardial right ventricular voltage maps in 38 patients with suspected or proved arrhythmogenic right ventricular cardiomyopathy. Blood material was collected from scar areas by aspiration and filtered, CMs detected by light microscopy were aspirated, centrifugated, and freezed.</div><div>DNA was extracted, amplified, and sequenced, and variants were compared with variants obtained from leukocyte DNA.</div></div><div><h3>Results</h3><div>At least 1 CM was obtained in 95% of patients (median 11 CM/patient). After refinements of the technique, a total of 136 samples (22 patients) allowed DNA extraction and amplification, successful in 60% of samples (16 patients). DNA capture sequencing of a panel of cardiomyopathy-associated genes was successfully performed in 14 patients and compared with blood sequencing in 11. After controlled by Sanger, an additional variant, not present in blood, has been confirmed in CM in one patient.</div></div><div><h3>Conclusion</h3><div>This new mini-invasive technique of sampling allows to perform genetic analysis on CMs. Pending future improvements, this technique could provide new sources of human cells for research and potential mosaicism detection.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103473"},"PeriodicalIF":0.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-17DOI: 10.1016/j.gimo.2025.103472
Riccardo Perriera , Anabela S. Ramalho , Francois Vermeulen , Emanuele Vitale , Ivana Pibiri , Andrea Pace , Laura Lentini
Purpose
Pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in dysfunctions of the CFTR protein, leading to cystic fibrosis (CF). This genetic disorder is characterized by severe symptoms in the respiratory and digestive systems.
Currently, highly effective CFTR modulator treatments, such as the Elexacaftor-Tezacaftor-Ivacaftor combination, may represent the primary therapeutic option for approximately 82% of people with cystic fibrosis who have at least 1 F508del variant. However, the remaining 18% with rare CFTR variants, including nonsense variants, often lack access to these therapies. Nonsense variants lead to nonfunctional CFTR proteins and contribute to more severe CF symptoms. Research efforts focus on understanding the effects of these variants on disease severity and response to treatment.
Methods
This study utilizes patient-derived intestinal organoids to evaluate the recovery of CFTR function in cells with nonsense variants.
Results
Specifically, we tested 3 translational readthrough-inducing molecules: NV848, NV914, and NV930. Our studies highlighted the positive effect of NV848 on patient organoid swelling, improving CFTR channel function, whereas NV914 and NV930 did not induce organoid swelling, similar to PTC124 treatment.
Conclusion
In conclusion, this study highlights the potential of translational readthrough-inducing molecules to restore CFTR function in cells with nonsense variants. By leveraging patient-derived intestinal organoids, our findings showed that NV848, in combination with Elexacaftor-Tezacaftor-Ivacaftor and the nonsense-mediated mRNA decay inhibitor NMDI14, enhances CFTR activity. This contributes to the development of personalized therapies for individuals with rare CFTR variants, addressing a critical unmet need in cystic fibrosis treatment.
{"title":"CFTR rescue in W1282X cystic fibrosis patient-derived intestinal organoids (PDIOs) mediated by translational readthrough-inducing drugs (TRIDs)","authors":"Riccardo Perriera , Anabela S. Ramalho , Francois Vermeulen , Emanuele Vitale , Ivana Pibiri , Andrea Pace , Laura Lentini","doi":"10.1016/j.gimo.2025.103472","DOIUrl":"10.1016/j.gimo.2025.103472","url":null,"abstract":"<div><h3>Purpose</h3><div>Pathogenic variants in the cystic fibrosis transmembrane conductance regulator (<em>CFTR</em>) gene result in dysfunctions of the CFTR protein, leading to cystic fibrosis (CF). This genetic disorder is characterized by severe symptoms in the respiratory and digestive systems.</div><div>Currently, highly effective CFTR modulator treatments, such as the Elexacaftor-Tezacaftor-Ivacaftor combination, may represent the primary therapeutic option for approximately 82% of people with cystic fibrosis who have at least 1 F508del variant. However, the remaining 18% with rare <em>CFTR</em> variants, including nonsense variants, often lack access to these therapies. Nonsense variants lead to nonfunctional CFTR proteins and contribute to more severe CF symptoms. Research efforts focus on understanding the effects of these variants on disease severity and response to treatment.</div></div><div><h3>Methods</h3><div>This study utilizes patient-derived intestinal organoids to evaluate the recovery of CFTR function in cells with nonsense variants.</div></div><div><h3>Results</h3><div>Specifically, we tested 3 translational readthrough-inducing molecules: NV848, NV914, and NV930. Our studies highlighted the positive effect of NV848 on patient organoid swelling, improving CFTR channel function, whereas NV914 and NV930 did not induce organoid swelling, similar to PTC124 treatment.</div></div><div><h3>Conclusion</h3><div>In conclusion, this study highlights the potential of translational readthrough-inducing molecules to restore CFTR function in cells with nonsense variants. By leveraging patient-derived intestinal organoids, our findings showed that NV848, in combination with Elexacaftor-Tezacaftor-Ivacaftor and the nonsense-mediated mRNA decay inhibitor NMDI14, enhances CFTR activity. This contributes to the development of personalized therapies for individuals with rare <em>CFTR</em> variants, addressing a critical unmet need in cystic fibrosis treatment.</div></div>","PeriodicalId":100576,"journal":{"name":"Genetics in Medicine Open","volume":"4 ","pages":"Article 103472"},"PeriodicalIF":0.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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