Author Correction: Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population.
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ABSTRACT:
SUBMITTER: Slavotinek A
PROVIDER: S-EPMC10593851 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Author Correction: Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population.
Slavotinek Anne A Rego Shannon S Sahin-Hodoglugil Nuriye N Kvale Mark M Lianoglou Billie B Yip Tiffany T Hoban Hannah H Outram Simon S Anguiano Beatrice B Chen Flavia F Michelson Jeremy J Cilio Roberta M RM Curry Cynthia C Gallagher Renata C RC Gardner Marisa M Kuperman Rachel R Mendelsohn Bryce B Sherr Elliott E Shieh Joseph J Strober Jonathan J Tam Allison A Tenney Jessica J Weiss William W Whittle Amy A Chin Garrett G Faubel Amanda A Prasad Hannah H Mavura Yusuph Y Van Ziffle Jessica J Devine W Patrick WP Hodoglugil Ugur U Martin Pierre-Marie PM Sparks Teresa N TN Koenig Barbara B Ackerman Sara S Risch Neil N Kwok Pui-Yan PY Norton Mary E ME
NPJ genomic medicine 20231023 1
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Project description:The diagnostic yield of exome sequencing (ES) has primarily been evaluated in individuals of European ancestry, with less focus on underrepresented minority (URM) and underserved (US) patients. We evaluated the diagnostic yield of ES in a cohort of predominantly US and URM pediatric and prenatal patients suspected to have a genetic disorder. Eligible pediatric patients had multiple congenital anomalies and/or neurocognitive disabilities and prenatal patients had one or more structural anomalies, disorders of fetal growth, or fetal effusions. URM and US patients were prioritized for enrollment and underwent ES at a single academic center. We identified definitive positive or probable positive results in 201/845 (23.8%) patients, with a significantly higher diagnostic rate in pediatric (26.7%) compared to prenatal patients (19.0%) (P = 0.01). For both pediatric and prenatal patients, the diagnostic yield and frequency of inconclusive findings did not differ significantly between URM and non-URM patients or between patients with US status and those without US status. Our results demonstrate a similar diagnostic yield of ES between prenatal and pediatric URM/US patients and non-URM/US patients for positive and inconclusive results. These data support the use of ES to identify clinically relevant variants in patients from diverse populations.
| S-EPMC10220040 | biostudies-literature
Project description:PurposeIt has been hypothesized that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort.MethodsCases (N=845) with suspected genetic disorders underwent ES for diagnosis. Continental genetic ancestry proportions were estimated from the ES data. We compared the distribution of genetic ancestries in positive, negative, and inconclusive cases by Kolmogorov Smirnov tests and linear associations of ancestry with DY by Cochran-Armitage trend tests.ResultsWe observed no reduction in overall DY associated with any continental genetic ancestry (Africa, America, East Asia, Europe, Middle East, South Asia). However, we observed a relative increase in proportion of autosomal recessive homozygous inheritance versus other inheritance patterns associated with Middle Eastern and South Asian ancestry, due to consanguinity.ConclusionsIn this empirical study of ES for undiagnosed pediatric and prenatal genetic conditions, genetic ancestry was not associated with the likelihood of a positive diagnosis, supporting the ethical and equitable use of ES in diagnosis of previously undiagnosed but potentially Mendelian disorders across all ancestral populations.
| S-EPMC10246153 | biostudies-literature
Project description:It has been suggested that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental/subcontinental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. Cases (N = 845) with suspected genetic disorders underwent ES for diagnosis. Continental/subcontinental genetic ancestry proportions were estimated from the ES data. We compared the distribution of genetic ancestries in positive, negative, and inconclusive cases by Kolmogorov-Smirnov tests and linear associations of ancestry with DY by Cochran-Armitage trend tests. We observed no reduction in overall DY associated with any genetic ancestry (African, Native American, East Asian, European, Middle Eastern, South Asian). However, we observed a relative increase in proportion of autosomal recessive homozygous inheritance versus other inheritance patterns associated with Middle Eastern and South Asian ancestry, due to consanguinity. In this empirical study of ES for undiagnosed pediatric and prenatal genetic conditions, genetic ancestry was not associated with the likelihood of a positive diagnosis, supporting the equitable use of ES in diagnosis of previously undiagnosed but potentially Mendelian disorders across all ancestral populations.
| S-EPMC10764913 | biostudies-literature
Project description:Exome sequencing is the current standard for diagnosing Mendelian disorders; however, it is generally not considered the first-line test for detecting copy number variants (CNVs). We retrospectively investigated the additional diagnostic yield by performing concurrent CNV analysis using exome data in a large and diverse pediatric cohort. Patients were referred from various sources with variable phenotypes. Human Phenotype Ontology terms were used to prioritize variants for analysis. Ancestry and CNV analyses were performed using Somalier and NxClinical, respectively. A total of 1538 patients were tested, with the majority being Admixed Americans. Diagnostic CNVs were identified in 70 patients (4.6%), ranging from exonic deletions to large, unbalanced rearrangements, aneuploidies, and mosaic findings. While no significant differences were identified in diagnostic yield, or rates of negative or uncertain diagnoses, between ancestries, our study demonstrates the feasibility and increased yield of CNV analysis of exome data, across multiple phenotypes, referral sources, and ancestries.
| S-EPMC11845629 | biostudies-literature
Project description:Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. DCM typically remains clinically silent until adulthood, yet symptomatic disease can develop in childhood. We sought to identify the genetic basis of pediatric DCM in 15 sporadic and three affected-siblings cases, comprised of 21 affected children (mean age, five years) whose parents had normal echocardiograms (mean age, 39 years). Twelve underwent cardiac transplantation and five died with severe heart failure. Parent-offspring whole exome sequencing (WES) data were filtered for rare, deleterious, de novo and recessive variants. In prior work, we reported de novo mutations in TNNT2 and RRAGC and compound heterozygous mutations in ALMS1 and TAF1A among four cases in our cohort. Here, de novo mutations in established DCM genes-RBM20, LMNA, TNNT2, and PRDM16-were identified among five additional cases. The RBM20 mutation was previously reported in familial DCM. An identical unreported LMNA mutation was identified in two unrelated cases, both harboring gene-specific defects in cardiomyocyte nuclear morphology. Collectively, WES had a 50% diagnostic yield in our cohort, providing an explanation for pediatric heart failure and enabling informed family planning. Research is ongoing to discover novel DCM genes among the remaining families.
| S-EPMC5715713 | biostudies-literature
Project description:PurposePrevious studies have reported that prenatal exome sequencing (pES) can detect monogenic diseases in fetuses with congenital anomalies with diagnostic yields ranging from 6% to 81%, but there are few reports of its clinical utility.MethodsWe conducted a retrospective chart review of patients who had pES to determine whether results led to clinical management changes.ResultsOf 20 patients, 8 (40%) received a definitive diagnosis. Seven patients (35%) had medical management changes based on the pES results, including alterations to their delivery plan and neonatal management (such as use of targeted medications, subspecialty referrals, additional imaging and/or procedures). All patients who received a definitive diagnosis and one who received a likely pathogenic variant (n = 9; 45%) received specific counseling about recurrence risk and the medical/developmental prognosis for the baby. In five (25%) cases, the result facilitated a diagnosis in parents and/or siblings.ConclusionpES results can have significant impacts on clinical management, some of which would not be possible if testing is deferred until after birth. To maximize the clinical utility, pES should be prioritized in cases where multiple care options are available and the imaging findings alone are not sufficient to guide parental decision-making, or where postnatal testing will not be feasible.
| S-EPMC7804210 | biostudies-literature
Project description:BackgroundCongenital vertical talus (CVT), also known as "rocker-bottom foot", is a rare foot deformity associated with a dislocation of the talonavicular joint. Although genetic causes of CVT have been described in single isolated and syndromic families, whole-exome sequencing (WES) of large cohorts have not yet been reported.MethodsIn this study, 62 probands with CVT were evaluated for likely causative single nucleotide variants (SNVs) and copy number variants (CNVs) using WES. Segregation of variants within families was determined by Sanger sequencing.ResultsIn this cohort, CVT occurred as an isolated anomaly in 75.8% (47/62) and was familial in 19.3% (12/62) of cases. Analysis of WES data led to the identification of likely causative variants in known disease genes in 30.6% (19/62) of all CVT probands. More than one proband had likely causative SNVs in TSHZ1, GDF5, and LMX1B. Only two probands had likely causative CNVs: a chromosome 12q13.13 deletion of the 5' HOXC gene cluster, and a chromosome 18q22.3q23 deletion involving TSHZ1. Familial CVT was strongly predictive of identifying a molecular diagnosis [75% (9/12) of familial cases compared to 20% (10/50) of non-familial cases (Chi-square test, P-value = 0.0002)]. There was no difference in the solved rate based on isolated or syndromic presentation, unilateral or bilateral affectation, or sex.ConclusionsCVT is genetically heterogeneous and more often caused by SNVs than CNVs. There is a high yield of WES in familial CVT cases (∼75%). Additional research is needed to identify the causes of sporadic CVT, which had much lower solved rates.
| S-EPMC10039454 | biostudies-literature
Project description:ObjectivesWe conducted a systematic review and meta-analysis to determine the diagnostic yield of exome sequencing (ES) for prenatal diagnosis of fetal structural anomalies, where karyotype/chromosomal microarray (CMA) is normal.MethodsFollowing electronic searches of four databases, we included studies with ≥10 structurally abnormal fetuses undergoing ES or whole genome sequencing. The incremental diagnostic yield of ES over CMA/karyotype was calculated and pooled in a meta-analysis. Sub-group analyses investigated effects of case selection and fetal phenotype on diagnostic yield.ResultsWe identified 72 reports from 66 studies, representing 4350 fetuses. The pooled incremental yield of ES was 31% (95% confidence interval (CI) 26%-36%, p < 0.0001). Diagnostic yield was significantly higher for cases pre-selected for likelihood of monogenic aetiology compared to unselected cases (42% vs. 15%, p < 0.0001). Diagnostic yield differed significantly between phenotypic sub-groups, ranging from 53% (95% CI 42%-63%, p < 0.0001) for isolated skeletal abnormalities, to 2% (95% CI 0%-5%, p = 0.04) for isolated increased nuchal translucency.ConclusionPrenatal ES provides a diagnosis in an additional 31% of structurally abnormal fetuses when CMA/karyotype is non-diagnostic. The expected diagnostic yield depends on the body system(s) affected and can be optimised by pre-selection of cases following multi-disciplinary review to determine that a monogenic cause is likely.
| S-EPMC9325531 | biostudies-literature
Project description:ObjectiveWe aimed to determine the frequency of accepting secondary findings in families undergoing exome sequencing in prenatal and pediatric settings.MethodsThis was a secondary analysis of prospectively enrolled patients undergoing trio exome sequencing for congenital anomalies or developmental disorders in prenatal and pediatric settings, in which families were offered receiving secondary findings (initially assessed in the proband and, if identified, then in the parents). The primary outcome was frequency of accepting secondary findings. Secondary outcomes included frequency of acceptance in prenatal versus pediatric settings, and sociodemographic differences between those who accepted versus declined secondary findings.ResultsThere were 682 families included in the cohort (289 prenatal and 393 pediatric). Overall, 84% (576/682) of families accepted secondary findings: 86.2% (249/289) of families undergoing prenatal versus 83.2% (327/393) pediatric (p = 0.30) testing. Secondary findings were identified in 2.6% (15/576) of cases, with no difference between prenatal and pediatric settings. There were no differences in sociodemographics between families that accepted versus declined secondary findings.ConclusionThe majority of families undergoing exome sequencing accepted secondary findings; this did not differ in prenatal versus pediatric settings. This highlights the need for guidance surrounding the offer of secondary findings in the prenatal setting.
| S-EPMC8630094 | biostudies-literature
Project description: Not available
| S-EPMC8116337 | biostudies-literature