Abstract
In patients with neurodevelopmental disorders (NDDs), exome sequencing (ES), the diagnostic gold standard, reveals an underlying monogenic condition in only approximately 40% of cases. We report the case of a female patient with profound NDD who died 30 years ago at the age of 3 years and for whom genome sequencing (GS) now identified a single-exon deletion in TBCK previously missed by ExomeDepth, the copy number variation (CNV) detection algorithm in ES. Deoxyribonucleic acid (DNA) was extracted from frozen muscle tissue of the index patient and the parents' blood. Genome data were analyzed for structural variants and single nucleotide variants (SUVs)/indels as part of the Bavarian Genomes consortium project. Biallelic variants in TBCK, which are linked to the autosomal recessive disorder TBCK syndrome, were detected in the affected individual: a novel frameshift variant and a deletion of exon 23, previously established as common but underrecognized pathogenic variant in individuals with TBCK syndrome. While in the foregoing ES analysis, calling algorithms for (SNVs)/indels were able to identify the frameshift variant, ExomeDepth failed to call the intragenic deletion. Our case illustrates the added value of GS for the detection of single-exon deletions for which calling from ES data remains challenging and confirms that the deletion of exon 23 in TBCK may be underdiagnosed in patients with NDDs. Furthermore, it shows the importance of molecular or genetic autopsy allowing genetic risk counseling for family members as well as the end of a diagnostic odyssey of 30 years.
| Original language | English |
|---|---|
| Journal | Neuropediatrics |
| DOIs | |
| State | Accepted/In press - 2023 |
| Externally published | Yes |
Keywords
- genome sequencing
- molecular autopsy
- neurodevelopmental disorder
- TBCK
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Jacob, M., Brugger, M., Andres, S., Wagner, M., Graf, E., Berutti, R., Tilch, E., Pavlov, M., Mayerhanser, K., Hoefele, J., Meitinger, T., Winkelmann, J., & Brunet, T. (Accepted/In press). Genome Sequencing for Cases Unsolved by Exome Sequencing: Identifying a Single-Exon Deletion in TBCK in a Case from 30 Years Ago. Neuropediatrics. https://doi.org/10.1055/s-0044-1782680
Jacob, Maureen ; Brugger, Melanie ; Andres, Stephanie et al. / Genome Sequencing for Cases Unsolved by Exome Sequencing : Identifying a Single-Exon Deletion in TBCK in a Case from 30 Years Ago. In: Neuropediatrics. 2023.
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title = "Genome Sequencing for Cases Unsolved by Exome Sequencing: Identifying a Single-Exon Deletion in TBCK in a Case from 30 Years Ago",
abstract = "In patients with neurodevelopmental disorders (NDDs), exome sequencing (ES), the diagnostic gold standard, reveals an underlying monogenic condition in only approximately 40% of cases. We report the case of a female patient with profound NDD who died 30 years ago at the age of 3 years and for whom genome sequencing (GS) now identified a single-exon deletion in TBCK previously missed by ExomeDepth, the copy number variation (CNV) detection algorithm in ES. Deoxyribonucleic acid (DNA) was extracted from frozen muscle tissue of the index patient and the parents' blood. Genome data were analyzed for structural variants and single nucleotide variants (SUVs)/indels as part of the Bavarian Genomes consortium project. Biallelic variants in TBCK, which are linked to the autosomal recessive disorder TBCK syndrome, were detected in the affected individual: a novel frameshift variant and a deletion of exon 23, previously established as common but underrecognized pathogenic variant in individuals with TBCK syndrome. While in the foregoing ES analysis, calling algorithms for (SNVs)/indels were able to identify the frameshift variant, ExomeDepth failed to call the intragenic deletion. Our case illustrates the added value of GS for the detection of single-exon deletions for which calling from ES data remains challenging and confirms that the deletion of exon 23 in TBCK may be underdiagnosed in patients with NDDs. Furthermore, it shows the importance of molecular or genetic autopsy allowing genetic risk counseling for family members as well as the end of a diagnostic odyssey of 30 years.",
keywords = "genome sequencing, molecular autopsy, neurodevelopmental disorder, TBCK",
author = "Maureen Jacob and Melanie Brugger and Stephanie Andres and Matias Wagner and Elisabeth Graf and Riccardo Berutti and Erik Tilch and Martin Pavlov and Katharina Mayerhanser and Julia Hoefele and Thomas Meitinger and Juliane Winkelmann and Theresa Brunet",
note = "Publisher Copyright: {\textcopyright} 2023 Georg Thieme Verlag. All rights reserved.",
year = "2023",
doi = "10.1055/s-0044-1782680",
language = "English",
journal = "Neuropediatrics",
issn = "0174-304X",
publisher = "Hippokrates Verlag GmbH",
}
Jacob, M, Brugger, M, Andres, S, Wagner, M, Graf, E, Berutti, R, Tilch, E, Pavlov, M, Mayerhanser, K, Hoefele, J, Meitinger, T, Winkelmann, J & Brunet, T 2023, 'Genome Sequencing for Cases Unsolved by Exome Sequencing: Identifying a Single-Exon Deletion in TBCK in a Case from 30 Years Ago', Neuropediatrics. https://doi.org/10.1055/s-0044-1782680
Genome Sequencing for Cases Unsolved by Exome Sequencing: Identifying a Single-Exon Deletion in TBCK in a Case from 30 Years Ago. / Jacob, Maureen; Brugger, Melanie; Andres, Stephanie et al.
In: Neuropediatrics, 2023.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Genome Sequencing for Cases Unsolved by Exome Sequencing
T2 - Identifying a Single-Exon Deletion in TBCK in a Case from 30 Years Ago
AU - Jacob, Maureen
AU - Brugger, Melanie
AU - Andres, Stephanie
AU - Wagner, Matias
AU - Graf, Elisabeth
AU - Berutti, Riccardo
AU - Tilch, Erik
AU - Pavlov, Martin
AU - Mayerhanser, Katharina
AU - Hoefele, Julia
AU - Meitinger, Thomas
AU - Winkelmann, Juliane
AU - Brunet, Theresa
N1 - Publisher Copyright:© 2023 Georg Thieme Verlag. All rights reserved.
PY - 2023
Y1 - 2023
N2 - In patients with neurodevelopmental disorders (NDDs), exome sequencing (ES), the diagnostic gold standard, reveals an underlying monogenic condition in only approximately 40% of cases. We report the case of a female patient with profound NDD who died 30 years ago at the age of 3 years and for whom genome sequencing (GS) now identified a single-exon deletion in TBCK previously missed by ExomeDepth, the copy number variation (CNV) detection algorithm in ES. Deoxyribonucleic acid (DNA) was extracted from frozen muscle tissue of the index patient and the parents' blood. Genome data were analyzed for structural variants and single nucleotide variants (SUVs)/indels as part of the Bavarian Genomes consortium project. Biallelic variants in TBCK, which are linked to the autosomal recessive disorder TBCK syndrome, were detected in the affected individual: a novel frameshift variant and a deletion of exon 23, previously established as common but underrecognized pathogenic variant in individuals with TBCK syndrome. While in the foregoing ES analysis, calling algorithms for (SNVs)/indels were able to identify the frameshift variant, ExomeDepth failed to call the intragenic deletion. Our case illustrates the added value of GS for the detection of single-exon deletions for which calling from ES data remains challenging and confirms that the deletion of exon 23 in TBCK may be underdiagnosed in patients with NDDs. Furthermore, it shows the importance of molecular or genetic autopsy allowing genetic risk counseling for family members as well as the end of a diagnostic odyssey of 30 years.
AB - In patients with neurodevelopmental disorders (NDDs), exome sequencing (ES), the diagnostic gold standard, reveals an underlying monogenic condition in only approximately 40% of cases. We report the case of a female patient with profound NDD who died 30 years ago at the age of 3 years and for whom genome sequencing (GS) now identified a single-exon deletion in TBCK previously missed by ExomeDepth, the copy number variation (CNV) detection algorithm in ES. Deoxyribonucleic acid (DNA) was extracted from frozen muscle tissue of the index patient and the parents' blood. Genome data were analyzed for structural variants and single nucleotide variants (SUVs)/indels as part of the Bavarian Genomes consortium project. Biallelic variants in TBCK, which are linked to the autosomal recessive disorder TBCK syndrome, were detected in the affected individual: a novel frameshift variant and a deletion of exon 23, previously established as common but underrecognized pathogenic variant in individuals with TBCK syndrome. While in the foregoing ES analysis, calling algorithms for (SNVs)/indels were able to identify the frameshift variant, ExomeDepth failed to call the intragenic deletion. Our case illustrates the added value of GS for the detection of single-exon deletions for which calling from ES data remains challenging and confirms that the deletion of exon 23 in TBCK may be underdiagnosed in patients with NDDs. Furthermore, it shows the importance of molecular or genetic autopsy allowing genetic risk counseling for family members as well as the end of a diagnostic odyssey of 30 years.
KW - genome sequencing
KW - molecular autopsy
KW - neurodevelopmental disorder
KW - TBCK
UR - http://www.scopus.com/inward/record.url?scp=85189108540&partnerID=8YFLogxK
U2 - 10.1055/s-0044-1782680
DO - 10.1055/s-0044-1782680
M3 - Article
AN - SCOPUS:85189108540
SN - 0174-304X
JO - Neuropediatrics
JF - Neuropediatrics
ER -
Jacob M, Brugger M, Andres S, Wagner M, Graf E, Berutti R et al. Genome Sequencing for Cases Unsolved by Exome Sequencing: Identifying a Single-Exon Deletion in TBCK in a Case from 30 Years Ago. Neuropediatrics. 2023. doi: 10.1055/s-0044-1782680
