Pub Date : 2025-01-01DOI: 10.1016/j.gim.2024.101252
Nicole R. Wong , Alexandra Klomhaus , David J. Adams , Benjamin N. Schneider , Sunil Mehta , Charlotte DiStefano , Rujuta B. Wilson , Julian A. Martinez-Agosto , Shafali S. Jeste , Aaron D. Besterman
Purpose
This study aimed to identify phenotypic factors associated with genetic diagnoses in patients with neurodevelopmental disorders and generate a decision tree to assist clinicians in identifying patients most likely to receive a positive result on genetic testing.
Methods
We retrospectively reviewed the charts of 316 patients evaluated in a neurodevelopmental clinic between 2014 and 2019. Patients were categorized based on genetic test results. Analyses were performed to identify variables that discriminate between patients with and without a genetic diagnosis.
Results
Patients with a genetic diagnosis were more likely to be female and have a history of motor delay, hypotonia, congenital heart disease, and early intervention. Classification and regression tree analysis revealed that 75% of patients with motor delay had a genetic diagnosis. In patients without motor delay, hypotonia, age of walking, and age at initial evaluation were important indicators of a genetic diagnosis.
Conclusion
Our findings suggest that motor delay and hypotonia are associated with genetic diagnoses in children with neurodevelopmental disorders. The decision tree highlights patient subsets at greater risk and suggests possible phenotypic screens. Future studies could develop validated decision trees based on phenotypic data to assist clinicians in stratifying patients for genetic testing.
{"title":"Clinical factors associated with genetic diagnosis in suspected neurogenetic disorders in a tertiary care clinic","authors":"Nicole R. Wong , Alexandra Klomhaus , David J. Adams , Benjamin N. Schneider , Sunil Mehta , Charlotte DiStefano , Rujuta B. Wilson , Julian A. Martinez-Agosto , Shafali S. Jeste , Aaron D. Besterman","doi":"10.1016/j.gim.2024.101252","DOIUrl":"10.1016/j.gim.2024.101252","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to identify phenotypic factors associated with genetic diagnoses in patients with neurodevelopmental disorders and generate a decision tree to assist clinicians in identifying patients most likely to receive a positive result on genetic testing.</div></div><div><h3>Methods</h3><div>We retrospectively reviewed the charts of 316 patients evaluated in a neurodevelopmental clinic between 2014 and 2019. Patients were categorized based on genetic test results. Analyses were performed to identify variables that discriminate between patients with and without a genetic diagnosis.</div></div><div><h3>Results</h3><div>Patients with a genetic diagnosis were more likely to be female and have a history of motor delay, hypotonia, congenital heart disease, and early intervention. Classification and regression tree analysis revealed that 75% of patients with motor delay had a genetic diagnosis. In patients without motor delay, hypotonia, age of walking, and age at initial evaluation were important indicators of a genetic diagnosis.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that motor delay and hypotonia are associated with genetic diagnoses in children with neurodevelopmental disorders. The decision tree highlights patient subsets at greater risk and suggests possible phenotypic screens. Future studies could develop validated decision trees based on phenotypic data to assist clinicians in stratifying patients for genetic testing.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101252"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463191","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 : 2025-01-01DOI: 10.1016/j.gim.2024.101223
Samuel G. Cox , Ashley Acevedo , Anand Ahuja , Heather G. LaBreche , Maria P. Alfaro , Summer Pierson , Thomas Westover , Sarah Ratzel , Susan Hancock , Krista Moyer , Dale Muzzey
Purpose
Advances in fetal fraction amplification in prenatal cell-free DNA screening now allow for high-resolution detection of copy-number variants (CNVs). However, approaches to interpreting CNVs as part of a primary screen are still evolving and require consensus. Here, we present a conservative, patient-centered framework for reporting fetal CNVs.
Methods
Syndromes described in the literature were evaluated for inclusion based on a definable minimal critical region, disease severity, penetrance, and age of onset. The reporting framework required that a CNV overlap a defined minimal critical region and/or that it be ≥5 Mb and contain at least 1 OMIM disease-associated gene. This framework was then applied to CNVs identified from a cohort of 313,544 prenatal cfDNA screening patient samples. Patient-friendly terminology describing syndrome phenotypes was developed by scientists with training in genetic counseling.
Results
65 syndromes met criteria for inclusion and represented the second most common class of CNVs in a retrospective cohort, more so than an established panel of microdeletions (1p36, 4p, 5p, 15q11.2-q13, and 22q11.2). Frequencies were concordant with reported syndrome incidence rates. The most common CNVs were those ≥5 Mb encompassing an OMIM disease gene(s).
Conclusion
This framework for genome-wide fetal-CNV reporting carefully prioritizes findings with the potential to affect reproductive decision making.
{"title":"Curation and reporting of pathogenic genome-wide copy-number variants in a prenatal cell-free DNA screen","authors":"Samuel G. Cox , Ashley Acevedo , Anand Ahuja , Heather G. LaBreche , Maria P. Alfaro , Summer Pierson , Thomas Westover , Sarah Ratzel , Susan Hancock , Krista Moyer , Dale Muzzey","doi":"10.1016/j.gim.2024.101223","DOIUrl":"10.1016/j.gim.2024.101223","url":null,"abstract":"<div><h3>Purpose</h3><div>Advances in fetal fraction amplification in prenatal cell-free DNA screening now allow for high-resolution detection of copy-number variants (CNVs). However, approaches to interpreting CNVs as part of a primary screen are still evolving and require consensus. Here, we present a conservative, patient-centered framework for reporting fetal CNVs.</div></div><div><h3>Methods</h3><div>Syndromes described in the literature were evaluated for inclusion based on a definable minimal critical region, disease severity, penetrance, and age of onset. The reporting framework required that a CNV overlap a defined minimal critical region and/or that it be ≥5 Mb and contain at least 1 OMIM disease-associated gene. This framework was then applied to CNVs identified from a cohort of 313,544 prenatal cfDNA screening patient samples. Patient-friendly terminology describing syndrome phenotypes was developed by scientists with training in genetic counseling.</div></div><div><h3>Results</h3><div>65 syndromes met criteria for inclusion and represented the second most common class of CNVs in a retrospective cohort, more so than an established panel of microdeletions (1p36, 4p, 5p, 15q11.2-q13, and 22q11.2). Frequencies were concordant with reported syndrome incidence rates. The most common CNVs were those ≥5 Mb encompassing an OMIM disease gene(s).</div></div><div><h3>Conclusion</h3><div>This framework for genome-wide fetal-CNV reporting carefully prioritizes findings with the potential to affect reproductive decision making.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101223"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709858","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 : 2025-01-01DOI: 10.1016/j.gim.2024.101243
Tuya Pal , Katherine R. Schon , Esteban Astiazaran-Symonds , Judith Balmaña , William D. Foulkes , Paul James , Susan Klugman , Alicia A. Livinski , Julie S. Mak , Joanne Ngeow , Nicoleta Voian , Myra J. Wick , Helen Hanson , Douglas R. Stewart , Marc Tischkowitz , ACMG Professional Practice and Guidelines Committee
Purpose
ATM germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer. Resources for managing ATM heterozygotes in clinical practice are limited.
Methods
An international workgroup developed a clinical practice resource to guide management of ATM heterozygotes using peer-reviewed publications and expert opinion.
Results
Although ATM is a moderate (intermediate) penetrance gene, cancer risks may be considered as a continuous variable, influenced by family history and other modifiers. ATM GPV heterozygotes should generally be offered enhanced breast surveillance according to their personalized risk estimate and country-specific guidelines and, generally, risk-reducing mastectomy is not recommended. Prostate cancer surveillance should be considered. Pancreatic cancer surveillance should be considered based on assessment of family history, ideally as part of a clinical trial, with existence of country-specific guidelines. For ATM GPV heterozygotes who develop cancer, radiation therapy decisions should not be influenced by the genetic result. Although poly-adenosine diphosphate ribose polymerase inhibitors are licensed for use in metastatic castration-resistant prostate cancer and ATM GPVs, the evidence-base is currently weak.
Conclusion
Systematic prospective data collection is needed to establish the spectrum of ATM-associated cancer and determine the outlines of surveillance, response to cancer treatment, and survival.
{"title":"Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)","authors":"Tuya Pal , Katherine R. Schon , Esteban Astiazaran-Symonds , Judith Balmaña , William D. Foulkes , Paul James , Susan Klugman , Alicia A. Livinski , Julie S. Mak , Joanne Ngeow , Nicoleta Voian , Myra J. Wick , Helen Hanson , Douglas R. Stewart , Marc Tischkowitz , ACMG Professional Practice and Guidelines Committee","doi":"10.1016/j.gim.2024.101243","DOIUrl":"10.1016/j.gim.2024.101243","url":null,"abstract":"<div><h3>Purpose</h3><div><em>ATM</em> germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer. Resources for managing <em>ATM</em> heterozygotes in clinical practice are limited.</div></div><div><h3>Methods</h3><div>An international workgroup developed a clinical practice resource to guide management of <em>ATM</em> heterozygotes using peer-reviewed publications and expert opinion.</div></div><div><h3>Results</h3><div>Although <em>ATM</em> is a moderate (intermediate) penetrance gene, cancer risks may be considered as a continuous variable, influenced by family history and other modifiers. <em>ATM</em> GPV heterozygotes should generally be offered enhanced breast surveillance according to their personalized risk estimate and country-specific guidelines and, generally, risk-reducing mastectomy is not recommended. Prostate cancer surveillance should be considered. Pancreatic cancer surveillance should be considered based on assessment of family history, ideally as part of a clinical trial, with existence of country-specific guidelines. For <em>ATM</em> GPV heterozygotes who develop cancer, radiation therapy decisions should not be influenced by the genetic result. Although poly-adenosine diphosphate ribose polymerase inhibitors are licensed for use in metastatic castration-resistant prostate cancer and <em>ATM</em> GPVs, the evidence-base is currently weak.</div></div><div><h3>Conclusion</h3><div>Systematic prospective data collection is needed to establish the spectrum of <em>ATM</em>-associated cancer and determine the outlines of surveillance, response to cancer treatment, and survival.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101243"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785032","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 : 2025-01-01DOI: 10.1016/j.gim.2024.101228
The ClinGen Consortium
The Clinical Genome Resource (ClinGen) is a National Institutes of Health-funded program founded 10 years ago that defines the clinical relevance of genes and variants for medical and research use. ClinGen working groups develop standards for data sharing and curating genomic knowledge. Expert panels, with >2500 active members from 67 countries, curate the validity of monogenic disease relationships, pathogenicity of genetic variation, dosage sensitivity of genes, and actionability of gene-disease interventions using ClinGen standards, infrastructure, and curation interfaces. Results are available on clinicalgenome.org and classified variants are also submitted to ClinVar, a publicly available database hosted by the National Institutes of Health. As of January 2024, over 2700 genes have been curated (2420 gene-disease relationships for validity, 1557 genes for dosage sensitivity, and 447 gene-condition pairs for actionability), and 5161 unique variants have been classified for pathogenicity. New efforts are underway in somatic cancer, complex disease and pharmacogenomics, and a systematic approach to addressing justice, equity, diversity, and inclusion. ClinGen’s knowledge can be used to build evidence-based genetic testing panels, interpret copy-number variation, resolve discrepancies in variant classification, guide disclosure of genomic findings to patients, and assess new predictive algorithms. To get involved in ClinGen activities go to https://www.clinicalgenome.org/start.
{"title":"The Clinical Genome Resource (ClinGen): Advancing genomic knowledge through global curation","authors":"The ClinGen Consortium","doi":"10.1016/j.gim.2024.101228","DOIUrl":"10.1016/j.gim.2024.101228","url":null,"abstract":"<div><div>The Clinical Genome Resource (ClinGen) is a National Institutes of Health-funded program founded 10 years ago that defines the clinical relevance of genes and variants for medical and research use. ClinGen working groups develop standards for data sharing and curating genomic knowledge. Expert panels, with >2500 active members from 67 countries, curate the validity of monogenic disease relationships, pathogenicity of genetic variation, dosage sensitivity of genes, and actionability of gene-disease interventions using ClinGen standards, infrastructure, and curation interfaces. Results are available on <span><span>clinicalgenome.org</span><svg><path></path></svg></span> and classified variants are also submitted to ClinVar, a publicly available database hosted by the National Institutes of Health. As of January 2024, over 2700 genes have been curated (2420 gene-disease relationships for validity, 1557 genes for dosage sensitivity, and 447 gene-condition pairs for actionability), and 5161 unique variants have been classified for pathogenicity. New efforts are underway in somatic cancer, complex disease and pharmacogenomics, and a systematic approach to addressing justice, equity, diversity, and inclusion. ClinGen’s knowledge can be used to build evidence-based genetic testing panels, interpret copy-number variation, resolve discrepancies in variant classification, guide disclosure of genomic findings to patients, and assess new predictive algorithms. To get involved in ClinGen activities go to <span><span>https://www.clinicalgenome.org/start</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101228"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463209","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 : 2025-01-01DOI: 10.1016/j.gim.2024.101269
Ashley Acevedo , Oyang Teng , Heather G. LaBreche , Alison Nguyen , Luis Jazo , Sun Hae Hong , John Suk , Summer Pierson , Thomas Westover , Sarah Ratzel , Kevin R. Haas , Dale Muzzey
Purpose
Clinically significant copy-number variants (CNVs) occur in 1% to 2% of pregnancies and are difficult to detect via prenatal cell-free DNA (cfDNA) screening because of the low fraction of fetal-derived cfDNA in maternal plasma. Here, we use fetal fraction amplification (FFA) and improved computational algorithms to enhance the resolution and sensitivity of CNV detection.
Methods
We implemented and characterized the performance of a hidden Markov model that identifies fetal CNVs. This CNV caller was analytically validated on 117 FFA samples, including 57 fetal-CNV-containing samples, and applied retrospectively to a cohort of more than 300k patient samples.
Results
Our assay was concordant with orthogonal testing and detected fetal CNVs ≥5 Mb with estimated aggregate sensitivity and specificity of >95.1% and >99.7%, respectively. The resolution of CNV detection was fetal fraction dependent, but 97.2% of samples reached ≥5-Mb resolution. Overall, CNVs ≥5 Mb were found in 1 in 500 pregnancies.
Conclusion
FFA improves the sensitivity and resolution of CNV detection in prenatal cfDNA screening, allowing accurate detection of fetal CNVs as small as 1 Mb. Using our approach, we found that clinically significant fetal CNVs were detected more frequently than the common trisomies 13 and 18 that are recommended as part of guideline-based screening.
{"title":"Fetal fraction amplification within prenatal cfDNA screening enables detection of genome-wide copy-number variants at enhanced resolution","authors":"Ashley Acevedo , Oyang Teng , Heather G. LaBreche , Alison Nguyen , Luis Jazo , Sun Hae Hong , John Suk , Summer Pierson , Thomas Westover , Sarah Ratzel , Kevin R. Haas , Dale Muzzey","doi":"10.1016/j.gim.2024.101269","DOIUrl":"10.1016/j.gim.2024.101269","url":null,"abstract":"<div><h3>Purpose</h3><div>Clinically significant copy-number variants (CNVs) occur in 1% to 2% of pregnancies and are difficult to detect via prenatal cell-free DNA (cfDNA) screening because of the low fraction of fetal-derived cfDNA in maternal plasma. Here, we use fetal fraction amplification (FFA) and improved computational algorithms to enhance the resolution and sensitivity of CNV detection.</div></div><div><h3>Methods</h3><div>We implemented and characterized the performance of a hidden Markov model that identifies fetal CNVs. This CNV caller was analytically validated on 117 FFA samples, including 57 fetal-CNV-containing samples, and applied retrospectively to a cohort of more than 300k patient samples.</div></div><div><h3>Results</h3><div>Our assay was concordant with orthogonal testing and detected fetal CNVs ≥5 Mb with estimated aggregate sensitivity and specificity of >95.1% and >99.7%, respectively. The resolution of CNV detection was fetal fraction dependent, but 97.2% of samples reached ≥5-Mb resolution. Overall, CNVs ≥5 Mb were found in 1 in 500 pregnancies.</div></div><div><h3>Conclusion</h3><div>FFA improves the sensitivity and resolution of CNV detection in prenatal cfDNA screening, allowing accurate detection of fetal CNVs as small as 1 Mb. Using our approach, we found that clinically significant fetal CNVs were detected more frequently than the common trisomies 13 and 18 that are recommended as part of guideline-based screening.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101269"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709909","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 : 2025-01-01DOI: 10.1016/j.gim.2024.101253
Lachlan De Hayr , Laura E.R. Blok , Kerith-Rae Dias , Jingyi Long , Anaïs Begemann , Robyn D. Moir , Ian M. Willis , Martina Mocera , Gabriele Siegel , Katharina Steindl , Carey-Anne Evans , Ying Zhu , Futao Zhang , Michael Field , Alan Ma , Lesley Adès , Sarah Josephi-Taylor , Rolph Pfundt , Maha S. Zaki , Hoda Tomoum , Robert J. Harvey
Purpose
This study details a novel syndromic form of autosomal recessive intellectual disability resulting from recessive variants in GTF3C3, encoding a key component of the DNA-binding transcription factor IIIC, which has a conserved role in RNA polymerase III-mediated transcription.
Methods
Exome sequencing, minigene analysis, molecular modeling, RNA polymerase III reporter gene assays, and Drosophila knockdown models were utilized to characterize GTF3C3 variants.
Results
Twelve affected individuals from 7 unrelated families were identified with homozygous or compound heterozygous missense variants in GTF3C3 including c.503C>T p.(Ala168Val), c.1268T>C p.(Leu423Pro), c.1436A>G p.(Tyr479Cys), c.2419C>T p.(Arg807Cys), and c.2420G>A p.(Arg807His). The cohort presented with intellectual disability, variable nonfamilial facial features, motor impairments, seizures, and cerebellar/corpus callosum malformations. Consistent with disruptions in intra- and intermolecular interactions observed in molecular modeling, RNA polymerase III reporter assays confirmed that the majority of missense variants resulted in a loss of function. Minigene analysis of the recurrent c.503C>T p.(Ala168Val) variant confirmed the introduction of a cryptic donor site into exon 4, resulting in mRNA missplicing. Consistent with the clinical features of this cohort, neuronal loss of Gtf3c3 in Drosophila induced seizure-like behavior, motor impairment, and learning deficits.
Conclusion
These findings confirm that GTF3C3 variants result in an autosomal recessive form of syndromic intellectual disability.
{"title":"Biallelic variants in GTF3C3 result in an autosomal recessive disorder with intellectual disability","authors":"Lachlan De Hayr , Laura E.R. Blok , Kerith-Rae Dias , Jingyi Long , Anaïs Begemann , Robyn D. Moir , Ian M. Willis , Martina Mocera , Gabriele Siegel , Katharina Steindl , Carey-Anne Evans , Ying Zhu , Futao Zhang , Michael Field , Alan Ma , Lesley Adès , Sarah Josephi-Taylor , Rolph Pfundt , Maha S. Zaki , Hoda Tomoum , Robert J. Harvey","doi":"10.1016/j.gim.2024.101253","DOIUrl":"10.1016/j.gim.2024.101253","url":null,"abstract":"<div><h3>Purpose</h3><div>This study details a novel syndromic form of autosomal recessive intellectual disability resulting from recessive variants in <em>GTF3C3</em>, encoding a key component of the DNA-binding transcription factor IIIC, which has a conserved role in RNA polymerase III-mediated transcription.</div></div><div><h3>Methods</h3><div>Exome sequencing, minigene analysis, molecular modeling, RNA polymerase III reporter gene assays, and <em>Drosophila</em> knockdown models were utilized to characterize <em>GTF3C3</em> variants.</div></div><div><h3>Results</h3><div>Twelve affected individuals from 7 unrelated families were identified with homozygous or compound heterozygous missense variants in <em>GTF3C3</em> including c.503C>T p.(Ala168Val), c.1268T>C p.(Leu423Pro), c.1436A>G p.(Tyr479Cys), c.2419C>T p.(Arg807Cys), and c.2420G>A p.(Arg807His). The cohort presented with intellectual disability, variable nonfamilial facial features, motor impairments, seizures, and cerebellar/corpus callosum malformations. Consistent with disruptions in intra- and intermolecular interactions observed in molecular modeling, RNA polymerase III reporter assays confirmed that the majority of missense variants resulted in a loss of function. Minigene analysis of the recurrent c.503C>T p.(Ala168Val) variant confirmed the introduction of a cryptic donor site into exon 4, resulting in mRNA missplicing. Consistent with the clinical features of this cohort, neuronal loss of <em>Gtf3c3</em> in <em>Drosophila</em> induced seizure-like behavior, motor impairment, and learning deficits.</div></div><div><h3>Conclusion</h3><div>These findings confirm that <em>GTF3C3</em> variants result in an autosomal recessive form of syndromic intellectual disability.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101253"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785029","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 : 2025-01-01DOI: 10.1016/j.gim.2024.101271
Rocio Rius , Alison G. Compton , Naomi L. Baker , Shanti Balasubramaniam , Stephanie Best , Kaustuv Bhattacharya , Kirsten Boggs , Tiffany Boughtwood , Jeffrey Braithwaite , Drago Bratkovic , Alessandra Bray , Marie-Jo Brion , Jo Burke , Sarah Casauria , Belinda Chong , David Coman , Shannon Cowie , Mark Cowley , Michelle G. de Silva , Martin B. Delatycki , David R. Thorburn
Purpose
Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.
Methods
A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing.
Results
Diagnostic yield was 55% (n = 77) with variants in nuclear (n = 37) and mtDNA (n = 18) MD genes, as well as phenocopy genes (n = 22). A nuclear gene etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases and comparable in children with non-European (78%) vs European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, 3 adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified in blood.
Conclusion
Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.
{"title":"The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses","authors":"Rocio Rius , Alison G. Compton , Naomi L. Baker , Shanti Balasubramaniam , Stephanie Best , Kaustuv Bhattacharya , Kirsten Boggs , Tiffany Boughtwood , Jeffrey Braithwaite , Drago Bratkovic , Alessandra Bray , Marie-Jo Brion , Jo Burke , Sarah Casauria , Belinda Chong , David Coman , Shannon Cowie , Mark Cowley , Michelle G. de Silva , Martin B. Delatycki , David R. Thorburn","doi":"10.1016/j.gim.2024.101271","DOIUrl":"10.1016/j.gim.2024.101271","url":null,"abstract":"<div><h3>Purpose</h3><div>Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.</div></div><div><h3>Methods</h3><div>A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing.</div></div><div><h3>Results</h3><div>Diagnostic yield was 55% (<em>n</em> = 77) with variants in nuclear (<em>n</em> = 37) and mtDNA (<em>n</em> = 18) MD genes, as well as phenocopy genes (<em>n</em> = 22). A nuclear gene etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases and comparable in children with non-European (78%) vs European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, 3 adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified in blood.</div></div><div><h3>Conclusion</h3><div>Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101271"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284364","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 : 2025-01-01DOI: 10.1016/j.gim.2024.101293
Megan Ball , Sophie E. Bouffler , Christopher B. Barnett , Mary-Louise Freckmann , Matthew F. Hunter , Benjamin Kamien , Karin S. Kassahn , Sebastian Lunke , Chirag V. Patel , Jason Pinner , Tony Roscioli , Sarah A. Sandaradura , Hamish S. Scott , Tiong Y. Tan , Mathew Wallis , Alison G. Compton , David R. Thorburn , Zornitza Stark , John Christodoulou
Purpose
To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program.
Methods
Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: n = 290, exome sequencing +/− mitochondrial DNA sequencing: n = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria.
Results
A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation.
Conclusion
Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.
{"title":"Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing","authors":"Megan Ball , Sophie E. Bouffler , Christopher B. Barnett , Mary-Louise Freckmann , Matthew F. Hunter , Benjamin Kamien , Karin S. Kassahn , Sebastian Lunke , Chirag V. Patel , Jason Pinner , Tony Roscioli , Sarah A. Sandaradura , Hamish S. Scott , Tiong Y. Tan , Mathew Wallis , Alison G. Compton , David R. Thorburn , Zornitza Stark , John Christodoulou","doi":"10.1016/j.gim.2024.101293","DOIUrl":"10.1016/j.gim.2024.101293","url":null,"abstract":"<div><h3>Purpose</h3><div>To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program.</div></div><div><h3>Methods</h3><div>Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: <em>n</em> = 290, exome sequencing +/− mitochondrial DNA sequencing: <em>n</em> = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria.</div></div><div><h3>Results</h3><div>A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (<em>CRLS1</em> and <em>MRPL39</em>). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation.</div></div><div><h3>Conclusion</h3><div>Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101293"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463205","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 : 2025-01-01DOI: 10.1016/j.gim.2024.101242
Ashlee R. Stiles , Taraka R. Donti , Patricia L. Hall , William R. Wilcox , ACMG Laboratory Quality Assurance Committee
Measurement of lysosomal disease (LD) biomarkers can reveal valuable information about disease status. Lyso-globotriaosylceramide (lyso-Gb3), glucosylsphingosine (lyso-Gb1), galactosylsphingosine (psychosine), and glucose tetrasaccharide (Glca1-6Glca1-4Glca1-4Glc, Glc4) are biomarkers associated with Fabry, Gaucher, Krabbe, and Pompe disease, respectively. Clinical biomarker testing is performed to guide patient management, including monitoring disease progression and initiating treatment, and in diagnostic evaluations of either symptomatic patients or asymptomatic individuals with a positive family history or abnormal newborn screen. Biomarker analysis can be performed through independent analysis of a single analyte or as a multiplex assay measuring analytes for more than one disorder utilizing liquid chromatographic separation and tandem mass spectrometric detection. These guidelines were developed to provide technical standards for biomarker analysis, results interpretation, and results reporting, highlighting Fabry, Gaucher, Krabbe, and Pompe diseases as examples.
{"title":"Biomarker testing for lysosomal diseases: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","authors":"Ashlee R. Stiles , Taraka R. Donti , Patricia L. Hall , William R. Wilcox , ACMG Laboratory Quality Assurance Committee","doi":"10.1016/j.gim.2024.101242","DOIUrl":"10.1016/j.gim.2024.101242","url":null,"abstract":"<div><div>Measurement of lysosomal disease (LD) biomarkers can reveal valuable information about disease status. Lyso-globotriaosylceramide (lyso-Gb<sub>3</sub>), glucosylsphingosine (lyso-Gb<sub>1</sub>), galactosylsphingosine (psychosine), and glucose tetrasaccharide (Glca1-6Glca1-4Glca1-4Glc, Glc<sub>4</sub>) are biomarkers associated with Fabry, Gaucher, Krabbe, and Pompe disease, respectively. Clinical biomarker testing is performed to guide patient management, including monitoring disease progression and initiating treatment, and in diagnostic evaluations of either symptomatic patients or asymptomatic individuals with a positive family history or abnormal newborn screen. Biomarker analysis can be performed through independent analysis of a single analyte or as a multiplex assay measuring analytes for more than one disorder utilizing liquid chromatographic separation and tandem mass spectrometric detection. These guidelines were developed to provide technical standards for biomarker analysis, results interpretation, and results reporting, highlighting Fabry, Gaucher, Krabbe, and Pompe diseases as examples.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 1","pages":"Article 101242"},"PeriodicalIF":6.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582845","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 : 2024-12-27DOI: 10.1016/j.gim.2024.101348
Nour Elkhateeb , Renarta Crookes , Michael Spiller , Lisa Pavinato , Flavia Palermo , Alfredo Brusco , Michael Parker , Soo-Mi Park , Ariana Costa Mendes , Jorge M. Saraiva , Trine Bjørg Hammer , Lusine Nazaryan-Petersen , Tahsin Stefan Barakat , Martina Wilke , Elizabeth Bhoj , Rebecca C. Ahrens-Nicklas , Dong Li , Tomoki Nomakuchi , Eva H. Brilstra , David Hunt , Meena Balasubramanian
Purpose
The thousand and one kinase (TAOK) proteins are a group of serine/threonine-protein kinases involved in signaling pathways, cytoskeleton regulation, and neuronal development. TAOK1 variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia, and feeding difficulties. TAOK2 variants have been reported to be associated with autism and early-onset obesity. However, a distinct TAOK2-NDD has not yet been delineated.
Methods
We retrospectively studied the clinical and genetic data of individuals recruited from several centers with TAOK1 and TAOK2 variants that were detected through exome and genome sequencing.
Results
We report 50 individuals with TAOK1 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (83%), and hypotonia (58%). We report male genital anomalies and hypoglycemia as novel phenotypes. Thirty-seven unique TAOK1 variants were identified. Most of the missense variants clustered in the protein kinase domain at residues that are intolerant to missense variation. We report 10 patients with TAOK2 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and obesity (70%).
Conclusion
We describe the largest cohort of TAOK1-NDD to date, to our knowledge, expanding its phenotype and genotype spectrum with 30 novel variants. We delineated the phenotype of a novel TAOK2-NDD associated with neurodevelopmental abnormalities, autism, macrocephaly, and obesity.
{"title":"Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder","authors":"Nour Elkhateeb , Renarta Crookes , Michael Spiller , Lisa Pavinato , Flavia Palermo , Alfredo Brusco , Michael Parker , Soo-Mi Park , Ariana Costa Mendes , Jorge M. Saraiva , Trine Bjørg Hammer , Lusine Nazaryan-Petersen , Tahsin Stefan Barakat , Martina Wilke , Elizabeth Bhoj , Rebecca C. Ahrens-Nicklas , Dong Li , Tomoki Nomakuchi , Eva H. Brilstra , David Hunt , Meena Balasubramanian","doi":"10.1016/j.gim.2024.101348","DOIUrl":"10.1016/j.gim.2024.101348","url":null,"abstract":"<div><h3>Purpose</h3><div>The thousand and one kinase (TAOK) proteins are a group of serine/threonine-protein kinases involved in signaling pathways, cytoskeleton regulation, and neuronal development. <em>TAOK1</em> variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia, and feeding difficulties. <em>TAOK2</em> variants have been reported to be associated with autism and early-onset obesity. However, a distinct <em>TAOK2</em>-NDD has not yet been delineated.</div></div><div><h3>Methods</h3><div>We retrospectively studied the clinical and genetic data of individuals recruited from several centers with <em>TAOK1</em> and <em>TAOK2</em> variants that were detected through exome and genome sequencing.</div></div><div><h3>Results</h3><div>We report 50 individuals with <em>TAOK1</em> variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (83%), and hypotonia (58%). We report male genital anomalies and hypoglycemia as novel phenotypes. Thirty-seven unique <em>TAOK1</em> variants were identified. Most of the missense variants clustered in the protein kinase domain at residues that are intolerant to missense variation. We report 10 patients with <em>TAOK2</em> variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and obesity (70%).</div></div><div><h3>Conclusion</h3><div>We describe the largest cohort of <em>TAOK1</em>-NDD to date, to our knowledge, expanding its phenotype and genotype spectrum with 30 novel variants. We delineated the phenotype of a novel <em>TAOK2</em>-NDD associated with neurodevelopmental abnormalities, autism, macrocephaly, and obesity.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 3","pages":"Article 101348"},"PeriodicalIF":6.6,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907000","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}
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