The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing

Abstract Purpose Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. Methods We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). Results We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. Conclusion Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.

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The diagnostic yield of intellectual disability: Combined whole genome low-coverage sequencing and medical exome sequencing

10.21203/rs.2.18388/v3 ◽

2020 ◽

Author(s):

Jun Wang ◽

Yan Wang ◽

Liwen Wang ◽

Wangyang Chen ◽

Min Sheng New

Keyword(s):

Intellectual Disability ◽

Diagnostic Test ◽

Detection Rate ◽

Whole Genome ◽

Single Nucleotide ◽

Detection Scheme ◽

Pathogenic Cnvs ◽

Clinical Detection ◽

Single Nucleotide Variations ◽

Low Coverage

Abstract Background: Intellectual disability (ID) is a heterogeneous neurodevelopmental disorder with a complex genetic underpinning in its etiology. Chromosome microarray (CMA) is recommended as the first-tier diagnostic test for ID due to high detection rate of copy number variation (CNV). Methods: To identify an appropriate clinical detection scheme for ID in Han Chinese patients, whole genome low-coverage sequencing was performed as the first-tier diagnostic test, and medical exome sequencing (MES) as the second-tier diagnostic test for patients with negative results of CNVs. Results: A total of 19 pathogenic CNVs in 16/95(16.84%) ID patients and 10 pathogenic single-nucleotide variations (SNVs), including 6 novel mutations in 8/95(8.42%) ID patients were identified on whom no pathogenic CNVs were discovered. The detection rate of CNVs in ID with multiple congenital anomalies (MCA) subgroup was significantly higher than ID with autism spectrum disorders and other IDs subgroups. And the single-nucleotide variations showed a higher occurrence rate in the other IDs subgroup. Conclusions: There were differences in the diagnostic yields of different variation types among the three ID subgroups. Our findings provided a new perspective on appropriate clinical detection scheme in different ID subgroups based on statistically significant differences among the three ID subgroups. The application of whole genome low-coverage sequencing as the first-tier diagnostic test for ID with MCA subgroup and MES as the first-tier diagnostic test for other ID subgroup was considered as an efficient clinical detection scheme.

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The diagnostic yield of intellectual disability: Combined whole genome low-coverage sequencing and medical exome sequencing

10.21203/rs.2.18388/v4 ◽

2020 ◽

Author(s):

Jun Wang ◽

Yan Wang ◽

Liwen Wang ◽

Wangyang Chen ◽

Min Sheng

Keyword(s):

Intellectual Disability ◽

Diagnostic Test ◽

Detection Rate ◽

Whole Genome ◽

Single Nucleotide ◽

Detection Scheme ◽

Pathogenic Cnvs ◽

Clinical Detection ◽

Single Nucleotide Variations ◽

Low Coverage

Abstract Background: Intellectual disability (ID) is a heterogeneous neurodevelopmental disorder with a complex genetic underpinning in its etiology. Chromosome microarray (CMA) is recommended as the first-tier diagnostic test for ID due to high detection rate of copy number variation (CNV). Methods: To identify an appropriate clinical detection scheme for ID in Han Chinese patients, whole genome low-coverage sequencing was performed as the first-tier diagnostic test, and medical exome sequencing (MES) as the second-tier diagnostic test for patients with negative results of CNVs.Results: A total of 19 pathogenic CNVs in 16/95(16.84%) ID patients and 10 pathogenic single-nucleotide variations (SNVs), including 6 novel mutations in 8/95(8.42%) ID patients were identified on whom no pathogenic CNVs were discovered. The detection rate of CNVs in ID with multiple congenital anomalies (MCA) subgroup was significantly higher than ID with autism spectrum disorders and other IDs subgroups. And the single-nucleotide variations showed a higher occurrence rate in the other IDs subgroup.Conclusions: There were differences in the diagnostic yields of different variation types among the three ID subgroups. Our findings provided a new perspective on appropriate clinical detection scheme in different ID subgroups based on statistically significant differences among the three ID subgroups. The application of whole genome low-coverage sequencing as the first-tier diagnostic test for ID with MCA subgroup and MES as the first-tier diagnostic test for other ID subgroup was considered as an efficient clinical detection scheme.

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The Efficacy of Whole Genome Sequencing and RNA-Seq in the Diagnosis of Whole Exome Sequencing Negative Patients with Complex Neurological Phenotypes

Journal of Pediatric Genetics ◽

10.1055/s-0041-1736610 ◽

2021 ◽

Author(s):

Bianca Blake ◽

Lauren I. Brady ◽

Nicholas A. Rouse ◽

Peter Nagy ◽

Mark A. Tarnopolsky

Keyword(s):

Whole Genome Sequencing ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genome Sequencing ◽

Diagnostic Yield ◽

Whole Genome ◽

Rna Seq ◽

Complete Coverage ◽

Whole Exome ◽

Chromosome Microarray

AbstractWhole-genome sequencing (WGS) is being increasingly utilized for the diagnosis of neurological disease by sequencing both the exome and the remaining 98 to 99% of the genetic code. In addition to more complete coverage, WGS can detect structural variants (SVs) and intronic variants (SNVs) that cannot be identified by whole exome sequencing (WES) or chromosome microarray (CMA). Other multi-omics tools, such as RNA sequencing (RNA-Seq), can be used in conjunction with WGS to functionally validate certain variants by detecting changes in gene expression and splicing. The objective of this retrospective study was to measure the diagnostic yield of duo/trio-based WGS and RNA-Seq in a cohort of 22 patients (20 families) with pediatric onset neurological phenotypes and negative or inconclusive WES results in lieu of reanalysis. WGS with RNA-Seq resulted in a definite diagnosis of an additional 25% of cases. Sixty percent of these solved cases arose from the identification of variants that were missed by WES. Variants that could not be unequivocally proven to be causative of the patients' condition were identified in an additional 5% of cases.

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Diagnostic yield of whole‐exome sequencing in non‐syndromic intellectual disability

Journal of Intellectual Disability Research ◽

10.1111/jir.12835 ◽

2021 ◽

Author(s):

E. Z. Taşkıran ◽

B. Karaosmanoğlu ◽

C. Koşukcu ◽

G. Ürel‐Demir ◽

Ö. Akgün‐Doğan ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Whole Exome

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Identification of a Rare Case With Nagashima-Type Palmoplantar Keratoderma and 18q Deletion Syndrome via Exome Sequencing and Low-Coverage Whole-Genome Sequencing

Frontiers in Genetics ◽

10.3389/fgene.2021.707411 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qianqian Li ◽

Xiaofan Zhu ◽

Conghui Wang ◽

Jingjing Meng ◽

Duo Chen ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Exome Sequencing ◽

Genome Sequencing ◽

Deletion Syndrome ◽

Compound Heterozygous Mutation ◽

Compound Heterozygous ◽

Whole Genome ◽

Palmoplantar Keratoderma ◽

18Q Deletion Syndrome ◽

Low Coverage

Nagashima-type palmoplantar keratoderma (NPPK) is characterized by non-progressive, diffuse, and cross-gradient hyperkeratosis caused by mutations in the SERPINB7 gene on chromosome 18q21.33. Chromosome 18q deletion syndrome (18q- syndrome) is a terminal deletion or microdeletion syndrome characterized by intellectual disability and congenital malformations. This paper describes an 18-year-old man with palmoplantar keratoderma and diffuse white matter abnormalities in the brain. Trio-based exome sequencing (ES) revealed a suspected mosaic compound heterozygous mutation for c.796C>T (p.Arg266∗) in exon 8 inherited from the mother and a de novo exons 4–6 deletion of SERPINB7. Additional copy number variant (CNV) analysis of the ES data indicated a heterozygous gross deletion of 18q22.3-q23. The two SERPINB7 gene variants were verified by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). Finally, low-coverage whole-genome sequencing (WGS) confirmed the 18q22.3-q23 deletion and additionally detected a mosaic 18q21.33-q22.3 deletion, together explaining NPPK and the neurological phenotypes of the proband. The gross deletion of all exons of SERPINB7 was revealed for the first time. More rarely, c.796C>T (p.Arg266∗) was likely to be mosaic, while the exon deletion was mosaic. In conclusion, the combination of multiple molecular genetic testing methods provides comprehensive informative molecular findings and promotes the diagnosis of complex diseases, as in this case.

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Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies

Neurology ◽

10.1212/wnl.0000000000011655 ◽

2021 ◽

Vol 96 (13) ◽

pp. e1770-e1782

Author(s):

Elizabeth Emma Palmer ◽

Rani Sachdev ◽

Rebecca Macintosh ◽

Uirá Souto Melo ◽

Stefan Mundlos ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Exome Sequencing ◽

Genome Sequencing ◽

Diagnostic Yield ◽

Chromosomal Microarray ◽

Whole Genome ◽

Structural Variants ◽

Epileptic Encephalopathies ◽

Complex Structural ◽

Made In

ObjectiveTo assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE).MethodsWe performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15).ResultsEight diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants, which now had additional evidence for pathogenicity. Eleven diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n = 10) involved genes not included in the panel, particularly in individuals with postneonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features, or multiorgan involvement. A total of 42% of diagnoses were autosomal recessive or X-chromosome linked.ConclusionWGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.

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Diagnostic and Clinical Utility of Clinical Exome Sequencing in Children With Moderate and Severe Global Developmental Delay / Intellectual Disability

Journal of Child Neurology ◽

10.1177/0883073819879835 ◽

2019 ◽

Vol 35 (2) ◽

pp. 116-131 ◽

Cited By ~ 3

Author(s):

Jelena Ruml Stojanovic ◽

Aleksandra Miletic ◽

Borut Peterlin ◽

Ales Maver ◽

Marija Mijovic ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Developmental Delay ◽

Clinical Utility ◽

Diagnostic Yield ◽

Genetic Disorders ◽

Significant Proportion ◽

Global Developmental Delay ◽

Clinical Exome Sequencing ◽

The Impact

Clinical exome sequencing is currently being used in diagnostics of various genetic disorders, but studies supporting its application in clinical setting are scarce. The aim of this study was to establish diagnostic and clinical utility of clinical exome sequencing in patients with moderate and severe global developmental delay/intellectual disability. Clinical diagnosis was made in 49 of 88 investigated patients, with overall diagnostic yield of 55.7%. Molecular findings are characterized in detail, including the impact of newly made diagnosis on clinical management. Several previously unreported genotype-phenotype correlations and 33 novel variants are described. Genetic and clinical data were shared through publicly available database. In conclusion, clinical exome sequencing allows identification of causative variants in a significant proportion of patients in investigated clinical subgroup. Compared to whole exome sequencing, it shows similar diagnostic and clinical utility with reduced costs, which could be of particular importance for institutions with limited resources.

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