Pub Date : 2024-10-04DOI: 10.1016/j.gim.2024.101286
Hsiang-Yu Lin , Chung-Lin Lee , Ya-Hui Chang , Yuan-Rong Tu , Yun-Ting Lo , Jun-Yi Wu , Dau-Ming Niu , Mei-Ying Liu , Hsin-Yun Liu , Hsiao-Jan Chen , Shu-Min Kao , Li-Yun Wang , Huey-Jane Ho , Chih-Kuang Chuang , Shuan-Pei Lin
Purpose
Mucopolysaccharidosis IVA (MPS IVA) is a rare lysosomal storage disorder arising from a deficiency in N-acetylgalactosamine-6-sulfatase.
Methods
From September 2019 to October 2023, a total of 264,843 Taiwanese newborns underwent screening for MPS IVA using dried blood spots and tandem mass spectrometry.
Results
Among the 95 referred infants, 9 (9%) were confirmed to have MPS IVA (group 1), 18 (19%) were highly suspected to have MPS IVA (group 2), 61 (64%) were identified as heterozygotes of MPS IVA (group 3), and 7 (7%) were determined not to have MPS IVA (group 4). A total of 34 different GALNS (HGNC:4122) gene variants were identified through our MPS IVA newborn screening program. The most prevalent variant was c.857C>T p.(Thr286Met), found in 33 cases (29%), followed by c.953T>G p.(Met318Arg) in 22 cases (19%). Intravenous enzyme replacement therapy was initiated in 5 patients at ages ranging from 0.3 to 1.7 years. The estimated incidence of MPS IVA in this screening program was 3.4 per 100,000 live births.
Conclusion
Because of the progressive nature of MPS IVA, an early diagnosis facilitated by newborn screening and prompt initiation of enzyme replacement therapy before irreversible organ damage occurs may result in improved clinical outcomes.
{"title":"Implementation of newborn screening for mucopolysaccharidosis type IVA and long-term monitoring in Taiwan","authors":"Hsiang-Yu Lin , Chung-Lin Lee , Ya-Hui Chang , Yuan-Rong Tu , Yun-Ting Lo , Jun-Yi Wu , Dau-Ming Niu , Mei-Ying Liu , Hsin-Yun Liu , Hsiao-Jan Chen , Shu-Min Kao , Li-Yun Wang , Huey-Jane Ho , Chih-Kuang Chuang , Shuan-Pei Lin","doi":"10.1016/j.gim.2024.101286","DOIUrl":"10.1016/j.gim.2024.101286","url":null,"abstract":"<div><h3>Purpose</h3><div>Mucopolysaccharidosis IVA (MPS IVA) is a rare lysosomal storage disorder arising from a deficiency in N-acetylgalactosamine-6-sulfatase.</div></div><div><h3>Methods</h3><div>From September 2019 to October 2023, a total of 264,843 Taiwanese newborns underwent screening for MPS IVA using dried blood spots and tandem mass spectrometry.</div></div><div><h3>Results</h3><div>Among the 95 referred infants, 9 (9%) were confirmed to have MPS IVA (group 1), 18 (19%) were highly suspected to have MPS IVA (group 2), 61 (64%) were identified as heterozygotes of MPS IVA (group 3), and 7 (7%) were determined not to have MPS IVA (group 4). A total of 34 different <em>GALNS</em> (HGNC:4122) gene variants were identified through our MPS IVA newborn screening program. The most prevalent variant was c.857C>T p.(Thr286Met), found in 33 cases (29%), followed by c.953T>G p.(Met318Arg) in 22 cases (19%). Intravenous enzyme replacement therapy was initiated in 5 patients at ages ranging from 0.3 to 1.7 years. The estimated incidence of MPS IVA in this screening program was 3.4 per 100,000 live births.</div></div><div><h3>Conclusion</h3><div>Because of the progressive nature of MPS IVA, an early diagnosis facilitated by newborn screening and prompt initiation of enzyme replacement therapy before irreversible organ damage occurs may result in improved clinical outcomes.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101286"},"PeriodicalIF":6.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389823","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 : 2024-10-02DOI: 10.1016/j.gim.2024.101287
Isaac Wade , Leora Witkowski , Afrida Ahmed , Charlie F. Rowlands , Susana Banerjee , Joseph G. Pressey , Terri P. McVeigh , Marc D. Tischkowitz , William D. Foulkes , Clare Turnbull , SCCOHT-SMARCA4 Registry Consortium
Purpose
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an extremely rare, highly aggressive cancer (mean age of onset, 24 years). Nearly all cases are associated with somatic or germline pathogenic variants (GPVs) in SMARCA4. Early bilateral oophorectomy is recommended for unaffected females with a SMARCA4 GPV. However, the penetrance of SMARCA4 GPVs for SCCOHT is highly uncertain and subject to ascertainment bias.
Methods
Leveraging the early-onset, sex-specific, highly morbid nature of SCCOHT, we hypothesized that the penetrance for SCCOHT could be quantified from the deficit in SMARCA4 GPVs in females compared with males in UK Biobank, a population cohort for which recruitment was restricted to those age 40 to 69. We also analyzed pedigrees ascertained internationally by the Montreal-based SCCOHT-SMARCA4 Registry.
Results
We observed SMARCA4 GPVs in 8/210,182 (0.0038%) female and 18/179,210 (0.0100%) male participants in UK Biobank (P = .028), representing a male:female odds ratio of 2.64 (95% CI 1.09-7.02), implying a penetrance of 62% for SCCOHT (given the absence of other SMARCA4-related female-specific early morbid diseases). A deficit of GPVs in females in UK Biobank was also demonstrated for BRCA1 and TP53.
Conclusion
Our findings support bilateral oophorectomy in early adulthood as a rational choice for at-risk females with SMARCA4 GPVs.
{"title":"Using cancer phenotype sex-specificity to enable unbiased penetrance estimation of SMARCA4 pathogenic variants for small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)","authors":"Isaac Wade , Leora Witkowski , Afrida Ahmed , Charlie F. Rowlands , Susana Banerjee , Joseph G. Pressey , Terri P. McVeigh , Marc D. Tischkowitz , William D. Foulkes , Clare Turnbull , SCCOHT-SMARCA4 Registry Consortium","doi":"10.1016/j.gim.2024.101287","DOIUrl":"10.1016/j.gim.2024.101287","url":null,"abstract":"<div><h3>Purpose</h3><div>Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an extremely rare, highly aggressive cancer (mean age of onset, 24 years). Nearly all cases are associated with somatic or germline pathogenic variants (GPVs) in <em>SMARCA4</em>. Early bilateral oophorectomy is recommended for unaffected females with a <em>SMARCA4</em> GPV. However, the penetrance of <em>SMARCA4</em> GPVs for SCCOHT is highly uncertain and subject to ascertainment bias.</div></div><div><h3>Methods</h3><div>Leveraging the early-onset, sex-specific, highly morbid nature of SCCOHT, we hypothesized that the penetrance for SCCOHT could be quantified from the deficit in <em>SMARCA4</em> GPVs in females compared with males in UK Biobank, a population cohort for which recruitment was restricted to those age 40 to 69. We also analyzed pedigrees ascertained internationally by the Montreal-based SCCOHT-SMARCA4 Registry.</div></div><div><h3>Results</h3><div>We observed <em>SMARCA4</em> GPVs in 8/210,182 (0.0038%) female and 18/179,210 (0.0100%) male participants in UK Biobank (<em>P</em> = .028), representing a male:female odds ratio of 2.64 (95% CI 1.09-7.02), implying a penetrance of 62% for SCCOHT (given the absence of other <em>SMARCA4</em>-related female-specific early morbid diseases). A deficit of GPVs in females in UK Biobank was also demonstrated for <em>BRCA1</em> and <em>TP53</em>.</div></div><div><h3>Conclusion</h3><div>Our findings support bilateral oophorectomy in early adulthood as a rational choice for at-risk females with <em>SMARCA4</em> GPVs.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101287"},"PeriodicalIF":6.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375383","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 : 2024-10-02DOI: 10.1016/j.gim.2024.101288
Irene Valenzuela , Marta Codina-Solà , Elida Vazquez , Anna Cueto-González , Jordi Leno-Colorado , Amaia Lasa-Aranzasti , Laura Trujillano , Bárbara Masotto , Miriam Masas , Mar Escobar , Elena García-Arumí , Eduardo F. Tizzano
Purpose
Despite ever-increasing knowledge of the genetic etiologies of neurodevelopmental disorders, approximately half remain undiagnosed after exome or genome sequencing. Here, we provide a deep clinical characterization of 11 previously unreported patients with a recently described neurodevelopmental disorder (NDD) due to pathogenic variants in RNU4-2.
Methods
The 11 patients were identified in a pool of 70 patients selected for targeted RNU4-2 sequencing on the basis of their clinical phenotypes from a cohort of 1032 individuals with a NDD and without a prior genetic diagnosis.
Results
The 11 patients were aged between 13 months and 36 years. All patients showed moderate to severe developmental delay and/or intellectual disability. Height and weight were below 10th percentile and most showed microcephaly. In almost 50% of the patients, intrauterine growth retardation was detected. All patients showed a distinctive pattern of dysmorphic features, including hooded upper eyelid and epicanthus, full cheeks, tented philtrum, mouth constantly slightly open with an everted lower lip vermilion, high palate, and profuse drooling. Of 11 patients, 64% also presented with ophthalmological problems (mainly strabismus, nystagmus, and refraction errors) and 64% had musculoskeletal features (joint hypermobility, mild scoliosis, and easy fractures).
Conclusion
This work provides an improved characterization of the phenotypic spectrum of RNU4-2 syndrome across different age groups and demonstrates that thorough clinical assessment of patients with an NDD can be enhanced significantly for this novel syndrome.
{"title":"Deep phenotyping of 11 individuals with pathogenic variants in RNU4-2 reveals a clinically recognizable syndrome","authors":"Irene Valenzuela , Marta Codina-Solà , Elida Vazquez , Anna Cueto-González , Jordi Leno-Colorado , Amaia Lasa-Aranzasti , Laura Trujillano , Bárbara Masotto , Miriam Masas , Mar Escobar , Elena García-Arumí , Eduardo F. Tizzano","doi":"10.1016/j.gim.2024.101288","DOIUrl":"10.1016/j.gim.2024.101288","url":null,"abstract":"<div><h3>Purpose</h3><div>Despite ever-increasing knowledge of the genetic etiologies of neurodevelopmental disorders, approximately half remain undiagnosed after exome or genome sequencing. Here, we provide a deep clinical characterization of 11 previously unreported patients with a recently described neurodevelopmental disorder (NDD) due to pathogenic variants in <em>RNU4-2</em>.</div></div><div><h3>Methods</h3><div>The 11 patients were identified in a pool of 70 patients selected for targeted <em>RNU4-2</em> sequencing on the basis of their clinical phenotypes from a cohort of 1032 individuals with a NDD and without a prior genetic diagnosis.</div></div><div><h3>Results</h3><div>The 11 patients were aged between 13 months and 36 years. All patients showed moderate to severe developmental delay and/or intellectual disability. Height and weight were below 10th percentile and most showed microcephaly. In almost 50% of the patients, intrauterine growth retardation was detected. All patients showed a distinctive pattern of dysmorphic features, including hooded upper eyelid and epicanthus, full cheeks, tented philtrum, mouth constantly slightly open with an everted lower lip vermilion, high palate, and profuse drooling. Of 11 patients, 64% also presented with ophthalmological problems (mainly strabismus, nystagmus, and refraction errors) and 64% had musculoskeletal features (joint hypermobility, mild scoliosis, and easy fractures).</div></div><div><h3>Conclusion</h3><div>This work provides an improved characterization of the phenotypic spectrum of <em>RNU4-2</em> syndrome across different age groups and demonstrates that thorough clinical assessment of patients with an NDD can be enhanced significantly for this novel syndrome.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"26 12","pages":"Article 101288"},"PeriodicalIF":6.6,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377758","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.2024.101208
{"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 : 2024-09-28DOI: 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.2024.101281
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}
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