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Article: The Genetics of Intellectual Disability.

Jansen, Sandra / Vissers, Lisenka E L M / de Vries, Bert B A

2023 Volume 13, Issue 2

Abstract: Intellectual disability (ID) has a prevalence of ~2-3% in the general population, having a large societal impact. The underlying cause of ID is largely of genetic origin; however, identifying this genetic cause has in the past often led to long ... ...

Abstract	Intellectual disability (ID) has a prevalence of ~2-3% in the general population, having a large societal impact. The underlying cause of ID is largely of genetic origin; however, identifying this genetic cause has in the past often led to long diagnostic Odysseys. Over the past decades, improvements in genetic diagnostic technologies and strategies have led to these causes being more and more detectable: from cytogenetic analysis in 1959, we moved in the first decade of the 21st century from genomic microarrays with a diagnostic yield of ~20% to next-generation sequencing platforms with a yield of up to 60%. In this review, we discuss these various developments, as well as their associated challenges and implications for the field of ID, which highlight the revolutionizing shift in clinical practice from a phenotype-first into genotype-first approach.
Language	English
Publishing date	2023-01-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci13020231
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Article ; Online: A complex structural variant near

de Boer, Elke / Marcelis, Carlo / Neveling, Kornelia / van Beusekom, Ellen / Hoischen, Alexander / Klein, Willemijn M / de Leeuw, Nicole / Mantere, Tuomo / Melo, Uirá S / van Reeuwijk, Jeroen / Smeets, Dominique / Spielmann, Malte / Kleefstra, Tjitske / van Bokhoven, Hans / Vissers, Lisenka E L M

HGG advances

2023 Volume 4, Issue 3, Page(s) 100200

Abstract: Split-hand/foot malformation (SHFM) is a congenital limb defect most typically presenting with median clefts in hands and/or feet, that can occur in a syndromic context as well as in isolated form. SHFM is caused by failure to maintain normal apical ... ...

Abstract	Split-hand/foot malformation (SHFM) is a congenital limb defect most typically presenting with median clefts in hands and/or feet, that can occur in a syndromic context as well as in isolated form. SHFM is caused by failure to maintain normal apical ectodermal ridge function during limb development. Although several genes and contiguous gene syndromes are implicated in the monogenic etiology of isolated SHFM, the disorder remains genetically unexplained for many families and associated genetic loci. We describe a family with isolated X-linked SHFM, for which the causative variant could be detected after a diagnostic journey of 20 years. We combined well-established approaches including microarray-based copy number variant analysis and fluorescence
MeSH term(s)	Humans ; In Situ Hybridization, Fluorescence ; Limb Deformities, Congenital/genetics ; Genetic Loci ; SOXB1 Transcription Factors/genetics
Chemical Substances	SOX3 protein, human ; SOXB1 Transcription Factors
Language	English
Publishing date	2023-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-2477
ISSN (online)	2666-2477
DOI	10.1016/j.xhgg.2023.100200
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Article: Lessons learned from rapid exome sequencing for 575 critically ill patients across the broad spectrum of rare disease.

Marouane, Abderrahim / Neveling, Kornelia / Deden, A Chantal / van den Heuvel, Simone / Zafeiropoulou, Dimitra / Castelein, Steven / van de Veerdonk, Frank / Koolen, David A / Simons, Annet / Rodenburg, Richard / Westra, Dineke / Mensenkamp, Arjen R / de Leeuw, Nicole / Ligtenberg, Marjolijn / Matthijsse, Rene / Pfundt, Rolph / Kamsteeg, Erik Jan / Brunner, Han G / Gilissen, Christian /

Feenstra, Ilse / de Boode, Willem P / Yntema, Helger G / van Zelst-Stams, Wendy A G / Nelen, Marcel / Vissers, Lisenka E L M

Frontiers in genetics

2024 Volume 14, Page(s) 1304520

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2024-01-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2023.1304520
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Article ; Online: Refining the 9q34.3 microduplication syndrome reveals mild neurodevelopmental features associated with a distinct global DNA methylation profile.

Rots, Dmitrijs / Rooney, Kathleen / Relator, Raissa / Kerkhof, Jennifer / McConkey, Haley / Pfundt, Rolph / Marcelis, Carlo / Willemsen, Marjolein H / van Hagen, Johanna M / Zwijnenburg, Petra / Alders, Marielle / Õunap, Katrin / Reimand, Tiia / Fjodorova, Olga / Berland, Siren / Liahjell, Eva Benedicte / Bojovic, Ognjen / Kriek, Marjolein / Ruivenkamp, Claudia /

Bonati, Maria Teresa / Brunner, Han G / Vissers, Lisenka E L M / Sadikovic, Bekim / Kleefstra, Tjitske

Clinical genetics

2024

Abstract: Precise regulation of gene expression is important for correct neurodevelopment. 9q34.3 deletions affecting the EHMT1 gene result in a syndromic neurodevelopmental disorder named Kleefstra syndrome. In contrast, duplications of the 9q34.3 locus ... ...

Abstract	Precise regulation of gene expression is important for correct neurodevelopment. 9q34.3 deletions affecting the EHMT1 gene result in a syndromic neurodevelopmental disorder named Kleefstra syndrome. In contrast, duplications of the 9q34.3 locus encompassing EHMT1 have been suggested to cause developmental disorders, but only limited information has been available. We have identified 15 individuals from 10 unrelated families, with 9q34.3 duplications <1.5 Mb in size, encompassing EHMT1 entirely. Clinical features included mild developmental delay, mild intellectual disability or learning problems, autism spectrum disorder, and behavior problems. The individuals did not consistently display dysmorphic features, congenital anomalies, or growth abnormalities. DNA methylation analysis revealed a weak DNAm profile for the cases with 9q34.3 duplication encompassing EHMT1, which could segregate the majority of the affected cases from controls. This study shows that individuals with 9q34.3 duplications including EHMT1 gene present with mild non-syndromic neurodevelopmental disorders and DNA methylation changes different from Kleefstra syndrome.
Language	English
Publishing date	2024-02-21
Publishing country	Denmark
Document type	Journal Article
ZDB-ID	221209-2
ISSN	1399-0004 ; 0009-9163
ISSN (online)	1399-0004
ISSN	0009-9163
DOI	10.1111/cge.14498
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Article ; Online: Reanalysis of whole-exome sequencing (WES) data of children with neurodevelopmental disorders in a standard patient care context.

van Slobbe, Michelle / van Haeringen, Arie / Vissers, Lisenka E L M / Bijlsma, Emilia K / Rutten, Julie W / Suerink, Manon / Nibbeling, Esther A R / Ruivenkamp, Claudia A L / Koene, Saskia

European journal of pediatrics

2023 Volume 183, Issue 1, Page(s) 345–355

Abstract: This study aims to inform future genetic reanalysis management by evaluating the yield of whole-exome sequencing (WES) reanalysis in standard patient care in the Netherlands. Single-center data of 159 patients with a neurodevelopmental disorder (NDD), in ...

Abstract	This study aims to inform future genetic reanalysis management by evaluating the yield of whole-exome sequencing (WES) reanalysis in standard patient care in the Netherlands. Single-center data of 159 patients with a neurodevelopmental disorder (NDD), in which WES analysis and reanalysis were performed between January 1, 2014, and December 31, 2021, was retrospectively collected. Patients were included if they were under the age of 18 years at initial analysis and if this initial analysis did not result in a diagnosis. Demographic, phenotypic, and genotypic characteristics of patients were collected and analyzed. The primary outcomes of our study were (i) diagnostic yield at reanalysis, (ii) reasons for detecting a new possibly causal variant at reanalysis, (iii) unsolicited findings, and (iv) factors associated with positive result of reanalysis. In addition, we conducted a questionnaire study amongst the 7 genetic department in the Netherlands creating an overview of used techniques, yield, and organization of WES reanalysis. The single-center data show that in most cases, WES reanalysis was initiated by the clinical geneticist (65%) or treating physician (30%). The mean time between initial WES analysis and reanalysis was 3.7 years. A new (likely) pathogenic variant or VUS with a clear link to the phenotype was found in 20 initially negative cases, resulting in a diagnostic yield of 12.6%. In 75% of these patients, the diagnosis had clinical consequences, as for example, a screening plan for associated signs and symptoms could be devised. Most (32%) of the (likely) causal variants identified at WES reanalysis were discovered due to a newly described gene-disease association. In addition to the 12.6% diagnostic yield based on new diagnoses, reclassification of a variant of uncertain significance found at initial analysis led to a definite diagnosis in three patients. Diagnostic yield was higher in patients with dysmorphic features compared to patients without clear dysmorphic features (yield 27% vs. 6%; p = 0.001). Conclusions: Our results show that WES reanalysis in patients with NDD in standard patient care leads to a substantial increase in genetic diagnoses. In the majority of newly diagnosed patients, the diagnosis had clinical consequences. Knowledge about the clinical impact of WES reanalysis, clinical characteristics associated with higher yield, and the yield per year after a negative WES in larger clinical cohorts is warranted to inform guidelines for genetic reanalysis. These guidelines will be of great value for pediatricians, pediatric rehabilitation specialists, and pediatric neurologists in daily care of patients with NDD. What is known: • Whole exome sequencing can cost-effectively identify a genetic cause of intellectual disability in about 30-40% of patients. • WES reanalysis in a research setting can lead to a definitive diagnosis in 10-20% of previously exome negative cases. What is new: • WES reanalysis in standard patient care resulted in a diagnostic yield of 13% in previously exome negative children with NDD. • The presence of dysmorphic features is associated with an increased diagnostic yield of WES reanalysis.
MeSH term(s)	Child ; Humans ; Adolescent ; Exome Sequencing ; Retrospective Studies ; Phenotype ; Exome/genetics ; Intellectual Disability/diagnosis ; Genetic Testing/methods
Language	English
Publishing date	2023-10-27
Publishing country	Germany
Document type	Journal Article
ZDB-ID	194196-3
ISSN	1432-1076 ; 0340-6199 ; 0943-9676
ISSN (online)	1432-1076
ISSN	0340-6199 ; 0943-9676
DOI	10.1007/s00431-023-05279-4
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Article ; Online: Correction: Long-read trio sequencing of individuals with unsolved intellectual disability.

Pauper, Marc / Kucuk, Erdi / Wenger, Aaron M / Chakraborty, Shreyasee / Baybayan, Primo / Kwint, Michael / van der Sanden, Bart / Nelen, Marcel R / Derks, Ronny / Brunner, Han G / Hoischen, Alexander / Vissers, Lisenka E L M / Gilissen, Christian

European journal of human genetics : EJHG

2021 Volume 29, Issue 4, Page(s) 720

Language	English
Publishing date	2021-03-23
Publishing country	England
Document type	Published Erratum
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-021-00868-z
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Article ; Online: Diagnostic analysis of the highly complex OPN1LW/OPN1MW gene cluster using long-read sequencing and MLPA

Lonneke Haer-Wigman / Amber den Ouden / Maria M. van Genderen / Hester Y. Kroes / Joke Verheij / Dzenita Smailhodzic / Attje S. Hoekstra / Raymon Vijzelaar / Jan Blom / Ronny Derks / Menno Tjon-Pon-Fong / Helger G. Yntema / Marcel R. Nelen / Lisenka E.L.M. Vissers / Dorien Lugtenberg / Kornelia Neveling

npj Genomic Medicine, Vol 7, Iss 1, Pp 1-

2022 Volume 10

Abstract: Abstract Pathogenic variants in the OPN1LW/OPN1MW gene cluster are causal for a range of mild to severe visual impairments with color deficiencies. The widely utilized short-read next-generation sequencing (NGS) is inappropriate for the analysis of the ... ...

Abstract	Abstract Pathogenic variants in the OPN1LW/OPN1MW gene cluster are causal for a range of mild to severe visual impairments with color deficiencies. The widely utilized short-read next-generation sequencing (NGS) is inappropriate for the analysis of the OPN1LW/OPN1MW gene cluster and many patients with pathogenic variants stay underdiagnosed. A diagnostic genetic assay was developed for the OPN1LW/OPN1MW gene cluster, consisting of copy number analysis via multiplex ligation-dependent probe amplification and sequence analysis via long-read circular consensus sequencing. Performance was determined on 50 clinical samples referred for genetic confirmation of the clinical diagnosis (n = 43) or carrier status analysis (n = 7). A broad range of pathogenic haplotypes were detected, including deletions, hybrid genes, single variants and combinations of variants. The developed genetic assay for the OPN1LW/OPN1MW gene cluster is a diagnostic test that can detect both structural and nucleotide variants with a straightforward analysis, improving diagnostic care of patients with visual impairment.
Keywords	Medicine ; R ; Genetics ; QH426-470
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Economic evaluations of exome and genome sequencing in pediatric genetics: considerations towards a consensus strategy.

Olde Keizer, Richelle A C M / Henneman, Lidewij / Ploos van Amstel, Johannes Kristian / Vissers, Lisenka E L M / Frederix, Gerardus W J

Journal of medical economics

2021 Volume 24, Issue sup1, Page(s) 60–70

Abstract: ... economic evaluations of NGS applications in pediatric diagnostics, i.e. exome sequencing (ES) and/or ...

Abstract	Objective: Next Generation Sequencing (NGS) is increasingly used for the diagnosis of rare genetic disorders. The aim of this study is to review the different approaches for economic evaluations of Next Generation Sequencing (NGS) in pediatric care used to date, to identify all costs, effects, and time horizons taken into account. Methods: A systematic literature review was conducted to identify published economic evaluations of NGS applications in pediatric diagnostics, i.e. exome sequencing (ES) and/or genome sequencing (GS). Information regarding methodological approach, costs, effects, and time horizon was abstracted from these publications. Results: Twenty-eight economic evaluations of ES/GS within pediatrics were identified. Costs included were mainly restricted to direct in-hospital healthcare costs and varied widely in inclusion of sort of costs and time-horizon. Nineteen studies included diagnostic yield and eight studies included cost-effectiveness as outcome measures. Studies varied greatly in terms of included sort of costs data, effects, and time horizon. Conclusion: Large differences in inclusion of cost and effect parameters were identified between studies. Validity of outcomes can therefore be questioned, which hinders valid comparison and widespread generalization of conclusions. In addition to current health economic guidance, specific guidance for evaluations in pediatric care is therefore necessary to improve the validity of outcomes and furthermore facilitate comparable decision-making for implementing novel NGS-based diagnostic modalities in pediatric genetics and beyond.
MeSH term(s)	Child ; Cost-Benefit Analysis ; Delivery of Health Care ; Exome ; Hospital Costs ; Humans ; Pediatrics
Language	English
Publishing date	2021-12-17
Publishing country	England
Document type	Journal Article ; Systematic Review
ZDB-ID	2270945-9
ISSN	1941-837X ; 1369-6998
ISSN (online)	1941-837X
ISSN	1369-6998
DOI	10.1080/13696998.2021.2009725
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Article ; Online: Comprehensive de novo mutation discovery with HiFi long-read sequencing.

Kucuk, Erdi / van der Sanden, Bart P G H / O'Gorman, Luke / Kwint, Michael / Derks, Ronny / Wenger, Aaron M / Lambert, Christine / Chakraborty, Shreyasee / Baybayan, Primo / Rowell, William J / Brunner, Han G / Vissers, Lisenka E L M / Hoischen, Alexander / Gilissen, Christian

Genome medicine

2023 Volume 15, Issue 1, Page(s) 34

Abstract: Background: Long-read sequencing (LRS) techniques have been very successful in identifying structural variants (SVs). However, the high error rate of LRS made the detection of small variants (substitutions and short indels < 20 bp) more challenging. The ...

Abstract	Background: Long-read sequencing (LRS) techniques have been very successful in identifying structural variants (SVs). However, the high error rate of LRS made the detection of small variants (substitutions and short indels < 20 bp) more challenging. The introduction of PacBio HiFi sequencing makes LRS also suited for detecting small variation. Here we evaluate the ability of HiFi reads to detect de novo mutations (DNMs) of all types, which are technically challenging variant types and a major cause of sporadic, severe, early-onset disease. Methods: We sequenced the genomes of eight parent-child trios using high coverage PacBio HiFi LRS (~ 30-fold coverage) and Illumina short-read sequencing (SRS) (~ 50-fold coverage). De novo substitutions, small indels, short tandem repeats (STRs) and SVs were called in both datasets and compared to each other to assess the accuracy of HiFi LRS. In addition, we determined the parent-of-origin of the small DNMs using phasing. Results: We identified a total of 672 and 859 de novo substitutions/indels, 28 and 126 de novo STRs, and 24 and 1 de novo SVs in LRS and SRS respectively. For the small variants, there was a 92 and 85% concordance between the platforms. For the STRs and SVs, the concordance was 3.6 and 0.8%, and 4 and 100% respectively. We successfully validated 27/54 LRS-unique small variants, of which 11 (41%) were confirmed as true de novo events. For the SRS-unique small variants, we validated 42/133 DNMs and 8 (19%) were confirmed as true de novo event. Validation of 18 LRS-unique de novo STR calls confirmed none of the repeat expansions as true DNM. Confirmation of the 23 LRS-unique SVs was possible for 19 candidate SVs of which 10 (52.6%) were true de novo events. Furthermore, we were able to assign 96% of DNMs to their parental allele with LRS data, as opposed to just 20% with SRS data. Conclusions: HiFi LRS can now produce the most comprehensive variant dataset obtainable by a single technology in a single laboratory, allowing accurate calling of substitutions, indels, STRs and SVs. The accuracy even allows sensitive calling of DNMs on all variant levels, and also allows for phasing, which helps to distinguish true positive from false positive DNMs.
MeSH term(s)	Humans ; High-Throughput Nucleotide Sequencing ; Alleles ; INDEL Mutation ; Microsatellite Repeats
Language	English
Publishing date	2023-05-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-023-01183-6
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Article ; Online: De novo mutation hotspots in homologous protein domains identify function-altering mutations in neurodevelopmental disorders.

Wiel, Laurens / Hampstead, Juliet E / Venselaar, Hanka / Vissers, Lisenka E L M / Brunner, Han G / Pfundt, Rolph / Vriend, Gerrit / Veltman, Joris A / Gilissen, Christian

American journal of human genetics

2022 Volume 110, Issue 1, Page(s) 92–104

Abstract: Variant interpretation remains a major challenge in medical genetics. We developed Meta-Domain HotSpot (MDHS) to identify mutational hotspots across homologous protein domains. We applied MDHS to a dataset of 45,221 de novo mutations (DNMs) from 31,058 ... ...

Abstract	Variant interpretation remains a major challenge in medical genetics. We developed Meta-Domain HotSpot (MDHS) to identify mutational hotspots across homologous protein domains. We applied MDHS to a dataset of 45,221 de novo mutations (DNMs) from 31,058 individuals with neurodevelopmental disorders (NDDs) and identified three significantly enriched missense DNM hotspots in the ion transport protein domain family (PF00520). The 37 unique missense DNMs that drive enrichment affect 25 genes, 19 of which were previously associated with NDDs. 3D protein structure modeling supports the hypothesis of function-altering effects of these mutations. Hotspot genes have a unique expression pattern in tissue, and we used this pattern alongside in silico predictors and population constraint information to identify candidate NDD-associated genes. We also propose a lenient version of our method, which identifies 32 hotspot positions across 16 different protein domains. These positions are enriched for likely pathogenic variation in clinical databases and DNMs in other genetic disorders.
MeSH term(s)	Humans ; Protein Domains/genetics ; Mutation/genetics ; Neurodevelopmental Disorders/genetics
Language	English
Publishing date	2022-12-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2022.12.001
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