Pub Date : 2024-10-01DOI: 10.1016/j.gim.2024.101208
{"title":"Correspondence on “Comparison of literature mining tools for variant classification: Through the lens of 50 RYR1 variants” by Wermers et al","authors":"","doi":"10.1016/j.gim.2024.101208","DOIUrl":"10.1016/j.gim.2024.101208","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 10","pages":"Article 101208"},"PeriodicalIF":6.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.gim.2024.101229
Laurie H. Seaver , Perry Chan , Lynn D. Fleisher , Samuel J. Huang , Susan D. Klugman , Dena R. Matalon , ACMG Ethical, Legal, and Social Issues Committee
{"title":"Points to consider for providing expert witness testimony for the specialty of medical genetics: A statement of the American College of Medical Genetics and Genomics (ACMG)","authors":"Laurie H. Seaver , Perry Chan , Lynn D. Fleisher , Samuel J. Huang , Susan D. Klugman , Dena R. Matalon , ACMG Ethical, Legal, and Social Issues Committee","doi":"10.1016/j.gim.2024.101229","DOIUrl":"10.1016/j.gim.2024.101229","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 10","pages":"Article 101229"},"PeriodicalIF":6.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.gim.2024.101209
{"title":"Response to Wei et al","authors":"","doi":"10.1016/j.gim.2024.101209","DOIUrl":"10.1016/j.gim.2024.101209","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 10","pages":"Article 101209"},"PeriodicalIF":6.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.gim.2024.101285
Shangqing Jiang, Gregory F Guzauskas, Shawn Garbett, John A Graves, Marc S Williams, Jing Hao, Jinyi Zhu, Gail P Jarvik, Josh J Carlson, Josh F Peterson, David L Veenstra
Purpose: Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize colorectal cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies.
Methods: We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening with standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of no CRC, CRC stages (A-D), and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions.
Results: Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared with SOC. The incremental cost-effectiveness ratio was $124,415 per quality-adjusted life year; screening had a 69% probability of being cost-effective using a willingness-to-pay threshold of $150,000/quality-adjusted life year . Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared with 95th, 85th, and 80th percentiles.
Conclusion: Population-level LS+PRS screening is marginally cost-effective, and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.
{"title":"Cost-effectiveness of population-wide genomic screening for Lynch Syndrome and polygenic risk scores to inform colorectal cancer screening.","authors":"Shangqing Jiang, Gregory F Guzauskas, Shawn Garbett, John A Graves, Marc S Williams, Jing Hao, Jinyi Zhu, Gail P Jarvik, Josh J Carlson, Josh F Peterson, David L Veenstra","doi":"10.1016/j.gim.2024.101285","DOIUrl":"10.1016/j.gim.2024.101285","url":null,"abstract":"<p><strong>Purpose: </strong>Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize colorectal cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies.</p><p><strong>Methods: </strong>We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening with standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of no CRC, CRC stages (A-D), and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions.</p><p><strong>Results: </strong>Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared with SOC. The incremental cost-effectiveness ratio was $124,415 per quality-adjusted life year; screening had a 69% probability of being cost-effective using a willingness-to-pay threshold of $150,000/quality-adjusted life year . Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared with 95th, 85th, and 80th percentiles.</p><p><strong>Conclusion: </strong>Population-level LS+PRS screening is marginally cost-effective, and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101285"},"PeriodicalIF":6.6,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-28DOI: 10.1016/j.gim.2024.101283
Pleuntje J. van der Sluijs , Sébastien Moutton , Alexander J.M. Dingemans , Denisa Weis , Michael A. Levy , Kym M. Boycott , Claudia Arberas , Margherita Baldassarri , Claire Beneteau , Alfredo Brusco , Charles Coutton , Tabib Dabir , Maria L. Dentici , Koenraad Devriendt , Laurence Faivre , Mieke M. van Haelst , Khadije Jizi , Marlies J. Kempers , Jennifer Kerkhof , Mira Kharbanda , Gijs W.E. Santen
Purpose
ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype.
Methods
We collected patients with duplications encompassing ARID1A and ARID1B duplications.
Results
16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 10.3 Mb (2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay, and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation reanalysis, resulting in the reclassification of 2 ARID1A and 2 ARID1B duplications as pathogenic.
Conclusion
Our findings reveal that ARID1B duplications manifest a clinical phenotype, and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole-gene duplication rather than haploinsufficiency.
{"title":"Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy","authors":"Pleuntje J. van der Sluijs , Sébastien Moutton , Alexander J.M. Dingemans , Denisa Weis , Michael A. Levy , Kym M. Boycott , Claudia Arberas , Margherita Baldassarri , Claire Beneteau , Alfredo Brusco , Charles Coutton , Tabib Dabir , Maria L. Dentici , Koenraad Devriendt , Laurence Faivre , Mieke M. van Haelst , Khadije Jizi , Marlies J. Kempers , Jennifer Kerkhof , Mira Kharbanda , Gijs W.E. Santen","doi":"10.1016/j.gim.2024.101283","DOIUrl":"10.1016/j.gim.2024.101283","url":null,"abstract":"<div><h3>Purpose</h3><div><em>ARID1A/ARID1B</em> haploinsufficiency leads to Coffin-Siris syndrome, duplications of <em>ARID1A</em> lead to a distinct clinical syndrome, whilst <em>ARID1B</em> duplications have not yet been linked to a phenotype.</div></div><div><h3>Methods</h3><div>We collected patients with duplications encompassing <em>ARID1A</em> and <em>ARID1B</em> duplications.</div></div><div><h3>Results</h3><div>16 <em>ARID1A</em> and 13 <em>ARID1B</em> duplication cases were included with duplication sizes ranging from 0.1 to 1.2 Mb (1-44 genes) for <em>ARID1A</em> and 0.9 to 10.3 Mb (2-101 genes) for <em>ARID1B</em>. Both groups shared features, with <em>ARID1A</em> patients having more severe intellectual disability, growth delay, and congenital anomalies. DNA methylation analysis showed that <em>ARID1A</em> patients had a specific methylation pattern in blood, which differed from controls and from patients with <em>ARID1A</em> or <em>ARID1B</em> loss-of-function variants. <em>ARID1B</em> patients appeared to have a distinct methylation pattern, similar to <em>ARID1A</em> duplication patients, but further research is needed to validate these results. Five cases with duplications including <em>ARID1A</em> or <em>ARID1B</em> initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation reanalysis, resulting in the reclassification of 2 <em>ARID1A</em> and 2 <em>ARID1B</em> duplications as pathogenic.</div></div><div><h3>Conclusion</h3><div>Our findings reveal that <em>ARID1B</em> duplications manifest a clinical phenotype, and <em>ARID1A</em> duplications have a distinct episignature that overlaps with that of <em>ARID1B</em> duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole-gene duplication rather than haploinsufficiency.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101283"},"PeriodicalIF":6.6,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-28DOI: 10.1016/j.gim.2024.101284
Sarah L. Bick , Aparna Nathan , Hannah Park , Robert C. Green , Monica H. Wojcik , Nina B. Gold
Purpose
Over 30 research groups and companies are exploring newborn screening using genomic sequencing (NBSeq), but the sensitivity of this approach is not well understood.
Methods
We identified individuals with treatable inherited metabolic disorders (IMDs) and ascertained the proportion whose DNA analysis revealed explanatory deleterious variants (EDVs). We examined variables associated with EDV detection and estimated the sensitivity of DNA-first NBSeq. We further predicted the annual rate of true-positive and false-negative NBSeq results in the United States for several conditions on the Recommended Uniform Screening Panel.
Results
We identified 635 individuals with 80 unique IMDs. In univariate analyses, Black race (OR = 0.37, 95% CI: 0.16-0.89, P = .02) and public insurance (OR = 0.60, 95% CI: 0.39-0.91, P = .02) were less likely to be associated with finding EDVs. Had all individuals been screened with NBSeq, the sensitivity would have been 80.3%. We estimated that between 0 and 649.9 cases of Recommended Uniform Screening Panel IMDs would be missed annually by NBSeq in the United States.
Conclusion
The overall sensitivity of NBSeq for treatable IMDs is estimated at 80.3%. That sensitivity will likely be lower for Black infants and those who are on public insurance.
{"title":"Estimating the sensitivity of genomic newborn screening for treatable inherited metabolic disorders","authors":"Sarah L. Bick , Aparna Nathan , Hannah Park , Robert C. Green , Monica H. Wojcik , Nina B. Gold","doi":"10.1016/j.gim.2024.101284","DOIUrl":"10.1016/j.gim.2024.101284","url":null,"abstract":"<div><h3>Purpose</h3><div>Over 30 research groups and companies are exploring newborn screening using genomic sequencing (NBSeq), but the sensitivity of this approach is not well understood.</div></div><div><h3>Methods</h3><div>We identified individuals with treatable inherited metabolic disorders (IMDs) and ascertained the proportion whose DNA analysis revealed explanatory deleterious variants (EDVs). We examined variables associated with EDV detection and estimated the sensitivity of DNA-first NBSeq. We further predicted the annual rate of true-positive and false-negative NBSeq results in the United States for several conditions on the Recommended Uniform Screening Panel.</div></div><div><h3>Results</h3><div>We identified 635 individuals with 80 unique IMDs. In univariate analyses, Black race (OR = 0.37, 95% CI: 0.16-0.89, <em>P</em> = .02) and public insurance (OR = 0.60, 95% CI: 0.39-0.91, <em>P</em> = .02) were less likely to be associated with finding EDVs. Had all individuals been screened with NBSeq, the sensitivity would have been 80.3%. We estimated that between 0 and 649.9 cases of Recommended Uniform Screening Panel IMDs would be missed annually by NBSeq in the United States.</div></div><div><h3>Conclusion</h3><div>The overall sensitivity of NBSeq for treatable IMDs is estimated at 80.3%. That sensitivity will likely be lower for Black infants and those who are on public insurance.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101284"},"PeriodicalIF":6.6,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.gim.2024.101282
Hosneara Akter , Md. Atikur Rahaman , Tamannyat Binte Eshaque , Nesrin Mohamed , Amirul Islam , Mehzabin Morshed , Zaha Shahin , Al Muhaimin , Arif Md. Foyzullah , Rabeya Akter Mim , Farjana Binta Omar , Md. Nahid Hasan , Dharana Satsangi , Nahid Ahmed , Abdullah Al Saba , Nargis Jahan , Md. Arif Hossen , Md.Ashadujjaman Mondol , Ahammad Sharif Sakib , Rezwana Kabir , Mohammed Uddin
Purpose
The genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from 576 well-phenotyped and highly consanguineous (16%) NDD cohort.
Methods
We used chromosomal microarray (CMA; N:247), exome sequencing (ES; N:127), combined CMA and ES (N:202), and long-read genome sequencing to identify genetic etiology. Deep clinical multivariate data were coupled with genomic variants for stratification analysis.
Results
Genetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (P < .01) compared to those from nonconsanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded FMR1 trinucleotide repeats. Additionally, we identified 2 recurrent X-linked variants in the G6PD in 3.65% (12/329) of NDD participants. These variants were absent in large-population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift.
Conclusion
This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort, highlighting a strong association of G6PD with NDD in this population.
{"title":"Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort","authors":"Hosneara Akter , Md. Atikur Rahaman , Tamannyat Binte Eshaque , Nesrin Mohamed , Amirul Islam , Mehzabin Morshed , Zaha Shahin , Al Muhaimin , Arif Md. Foyzullah , Rabeya Akter Mim , Farjana Binta Omar , Md. Nahid Hasan , Dharana Satsangi , Nahid Ahmed , Abdullah Al Saba , Nargis Jahan , Md. Arif Hossen , Md.Ashadujjaman Mondol , Ahammad Sharif Sakib , Rezwana Kabir , Mohammed Uddin","doi":"10.1016/j.gim.2024.101282","DOIUrl":"10.1016/j.gim.2024.101282","url":null,"abstract":"<div><h3>Purpose</h3><div>The genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from 576 well-phenotyped and highly consanguineous (16%) NDD cohort.</div></div><div><h3>Methods</h3><div>We used chromosomal microarray (CMA; N:247), exome sequencing (ES; N:127), combined CMA and ES (N:202), and long-read genome sequencing to identify genetic etiology. Deep clinical multivariate data were coupled with genomic variants for stratification analysis.</div></div><div><h3>Results</h3><div>Genetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (<em>P</em> < .01) compared to those from nonconsanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded <em>FMR1</em> trinucleotide repeats. Additionally, we identified 2 recurrent X-linked variants in the <em>G6PD</em> in 3.65% (12/329) of NDD participants. These variants were absent in large-population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift.</div></div><div><h3>Conclusion</h3><div>This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort, highlighting a strong association of <em>G6PD</em> with NDD in this population.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101282"},"PeriodicalIF":6.6,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-21DOI: 10.1016/j.gim.2024.101278
Lettie E Rawlins, Reza Maroofian, Stuart J Cannon, Muhannad Daana, Mina Zamani, Shamsul Ghani, Joseph S Leslie, Nishanka Ubeyratna, Nasar Khan, Hamid Khan, Annarita Scardamaglia, Robin Cloarec, Shujaat Ali Khan, Muhammad Umair, Saeid Sadeghian, Hamid Galehdari, Almundher Al-Maawali, Adila Al-Kindi, Reza Azizimalamiri, Gholamreza Shariati, Faraz Ahmad, Amna Al-Futaisi, Pedro M Rodriguez Cruz, Ainara Salazar-Villacorta, Moustapha Ndiaye, Amadou G Diop, Alireza Sedaghat, Alihossein Saberi, Mohammad Hamid, Maha S Zaki, Barbara Vona, Daniel Owrang, Abdullah M Alhashem, Makram Obeid, Amjad Khan, Ahmad Beydoun, Marwan Najjar, Homa Tajsharghi, Giovanni Zifarelli, Peter Bauer, Wejdan S Hakami, Amal M Al Hashem, Rose-Mary N Boustany, Lydie Burglen, Shahryar Alavi, Adam C Gunning, Martina Owens, Ehsan G Karimiani, Joseph G Gleeson, Mathieu Milh, Somaya Salah, Jahangir Khan, Volker Haucke, Caroline F Wright, Lucy McGavin, Orly Elpeleg, Muhammad I Shabbir, Henry Houlden, Michael Ebner, Emma L Baple, Andrew H Crosby
Purpose: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single-case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations.
Methods: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies.
Results: We characterize a clinically variable disorder with cardinal features, including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a-/- mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition.
Conclusion: Our studies comprehensively characterize INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose that the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.
{"title":"Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.","authors":"Lettie E Rawlins, Reza Maroofian, Stuart J Cannon, Muhannad Daana, Mina Zamani, Shamsul Ghani, Joseph S Leslie, Nishanka Ubeyratna, Nasar Khan, Hamid Khan, Annarita Scardamaglia, Robin Cloarec, Shujaat Ali Khan, Muhammad Umair, Saeid Sadeghian, Hamid Galehdari, Almundher Al-Maawali, Adila Al-Kindi, Reza Azizimalamiri, Gholamreza Shariati, Faraz Ahmad, Amna Al-Futaisi, Pedro M Rodriguez Cruz, Ainara Salazar-Villacorta, Moustapha Ndiaye, Amadou G Diop, Alireza Sedaghat, Alihossein Saberi, Mohammad Hamid, Maha S Zaki, Barbara Vona, Daniel Owrang, Abdullah M Alhashem, Makram Obeid, Amjad Khan, Ahmad Beydoun, Marwan Najjar, Homa Tajsharghi, Giovanni Zifarelli, Peter Bauer, Wejdan S Hakami, Amal M Al Hashem, Rose-Mary N Boustany, Lydie Burglen, Shahryar Alavi, Adam C Gunning, Martina Owens, Ehsan G Karimiani, Joseph G Gleeson, Mathieu Milh, Somaya Salah, Jahangir Khan, Volker Haucke, Caroline F Wright, Lucy McGavin, Orly Elpeleg, Muhammad I Shabbir, Henry Houlden, Michael Ebner, Emma L Baple, Andrew H Crosby","doi":"10.1016/j.gim.2024.101278","DOIUrl":"10.1016/j.gim.2024.101278","url":null,"abstract":"<p><strong>Purpose: </strong>Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single-case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations.</p><p><strong>Methods: </strong>Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies.</p><p><strong>Results: </strong>We characterize a clinically variable disorder with cardinal features, including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a<sup>-/-</sup> mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition.</p><p><strong>Conclusion: </strong>Our studies comprehensively characterize INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose that the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101278"},"PeriodicalIF":6.6,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-21DOI: 10.1016/j.gim.2024.101281
Chen-Han Wilfred Wu , Ishita Patel , Katreya Lovrenert , Brian Eisner , Naomi Meeks , Anne Chun-Hui Tsai , Michelle Baum , Gerard Berry , Fredrick R. Schumacher
Purpose
Cystine stones, an autosomal recessive disorder caused by cystinuria, result from pathogenic variants of SLC3A1 and SLC7A9. Previous publications revealed that clinical prevalence is higher than genetically predicted prevalence. Heterozygotes in either gene are not stone formers. However, double heterozygotes (DH), individuals with 2 heterozygous pathogenic variants in both genes, were never evaluated and may explain the gap between clinical and genetic prevalence.
Methods
Because of the rarity of the condition, direct clinical observation is impractical. We perform this population study as a surrogate by identifying the observed DH, deriving the theoretical/expected DH, and testing the null hypothesis (NH) that the observed DH frequency is equal or greater than expected. This NH biologically correlate to that DH are asymptomatic and do not have cystine stone.
Results
Using the 1000 Genome Database, we identified 0 DH. We derived the theoretical/expected DH with Hardy-Weinberg Equilibrium and Mendel’s law of independent assortment as 4.94 × 10−s. Population proportion test revealed z = −0.353, and P = .362, the NH cannot be rejected.
Conclusion
Statistical testing does not support that DH are symptomatic, ie, DH of SLC3A1 and SLC7A9 may not present with cystine stone, and other factors responsible for the gap that current genetics knowledge cannot explain.
{"title":"The role of double heterozygotes of SLC3A1 and SLC7A9 in the prevalence of cystine stones","authors":"Chen-Han Wilfred Wu , Ishita Patel , Katreya Lovrenert , Brian Eisner , Naomi Meeks , Anne Chun-Hui Tsai , Michelle Baum , Gerard Berry , Fredrick R. Schumacher","doi":"10.1016/j.gim.2024.101281","DOIUrl":"10.1016/j.gim.2024.101281","url":null,"abstract":"<div><h3>Purpose</h3><div>Cystine stones, an autosomal recessive disorder caused by cystinuria, result from pathogenic variants of <em>SLC3A1</em> and <em>SLC7A9</em>. Previous publications revealed that clinical prevalence is higher than genetically predicted prevalence. Heterozygotes in either gene are not stone formers. However, double heterozygotes (DH), individuals with 2 heterozygous pathogenic variants in both genes, were never evaluated and may explain the gap between clinical and genetic prevalence.</div></div><div><h3>Methods</h3><div>Because of the rarity of the condition, direct clinical observation is impractical. We perform this population study as a surrogate by identifying the observed DH, deriving the theoretical/expected DH, and testing the null hypothesis (NH) that the observed DH frequency is equal or greater than expected. This NH biologically correlate to that DH are asymptomatic and do not have cystine stone.</div></div><div><h3>Results</h3><div>Using the 1000 Genome Database, we identified 0 DH. We derived the theoretical/expected DH with Hardy-Weinberg Equilibrium and Mendel’s law of independent assortment as 4.94 × 10−s. Population proportion test revealed <em>z</em> = −0.353, and <em>P</em> = .362, the NH cannot be rejected.</div></div><div><h3>Conclusion</h3><div>Statistical testing does not support that DH are symptomatic, ie, DH of <em>SLC3A1</em> and <em>SLC7A9</em> may not present with cystine stone, and other factors responsible for the gap that current genetics knowledge cannot explain.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101281"},"PeriodicalIF":6.6,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-21DOI: 10.1016/j.gim.2024.101279
Frank Angelo , Margaret Waltz , Haoyang Yan , Jonathan S. Berg , Ann Katherine M. Foreman , Julianne O’Daniel , Christine Rini
Purpose
Investigating associations between group-based medical mistrust (GBMM) and perceptions of patient-provider encounters can identify one mechanism through which GBMM may influence health outcomes and serve as a barrier to equitable health care. This study investigated associations between GBMM reported by caregivers of children with a possible genetic condition and caregivers’ and providers’ perceptions of a specialty care appointment discussing diagnostic plans.
Methods
Caregivers (N = 177) completed the GBMM scale and other measures before their child’s initial specialty clinic visit. After the visit, caregivers reported their perceptions of the visit, including patient centeredness and satisfaction with care. Providers (N = 6) reported their perceptions of patient engagement.
Results
Multivariable linear regression showed that higher caregiver GBMM was associated with caregivers’ lower satisfaction with care (P < .01) and more negative perceptions of every domain of patient centeredness (P = .001-.04). Multilevel modeling showed that higher caregiver GBMM was associated with more negative provider perceptions of caregivers’ preparedness to participate in care (P = .03), likely treatment compliance (P = .03), and relevance of questions asked during visit (P = .04).
Conclusion
Our findings extend evidence for detrimental effects of GBMM on patient satisfaction to caregivers of pediatric patients and offer new evidence for associations with health care providers’ perceptions of caregivers’ engagement with care.
{"title":"Group-based medical mistrust in genomic medicine: Associations with patient and provider perceptions of a specialty clinical encounter","authors":"Frank Angelo , Margaret Waltz , Haoyang Yan , Jonathan S. Berg , Ann Katherine M. Foreman , Julianne O’Daniel , Christine Rini","doi":"10.1016/j.gim.2024.101279","DOIUrl":"10.1016/j.gim.2024.101279","url":null,"abstract":"<div><h3>Purpose</h3><div>Investigating associations between group-based medical mistrust (GBMM) and perceptions of patient-provider encounters can identify one mechanism through which GBMM may influence health outcomes and serve as a barrier to equitable health care. This study investigated associations between GBMM reported by caregivers of children with a possible genetic condition and caregivers’ and providers’ perceptions of a specialty care appointment discussing diagnostic plans.</div></div><div><h3>Methods</h3><div>Caregivers (<em>N</em> = 177) completed the GBMM scale and other measures before their child’s initial specialty clinic visit. After the visit, caregivers reported their perceptions of the visit, including patient centeredness and satisfaction with care. Providers (<em>N</em> = 6) reported their perceptions of patient engagement.</div></div><div><h3>Results</h3><div>Multivariable linear regression showed that higher caregiver GBMM was associated with caregivers’ lower satisfaction with care (<em>P</em> < .01) and more negative perceptions of every domain of patient centeredness (<em>P</em> = .001-.04). Multilevel modeling showed that higher caregiver GBMM was associated with more negative provider perceptions of caregivers’ preparedness to participate in care (<em>P</em> = .03), likely treatment compliance (<em>P</em> = .03), and relevance of questions asked during visit (<em>P</em> = .04).</div></div><div><h3>Conclusion</h3><div>Our findings extend evidence for detrimental effects of GBMM on patient satisfaction to caregivers of pediatric patients and offer new evidence for associations with health care providers’ perceptions of caregivers’ engagement with care.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101279"},"PeriodicalIF":6.6,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号