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Sequence based identification of genetic variation associated with intellectual disability
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Lars Feuk)ORCID iD: 0000-0001-8367-8391
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Intellectual disability (ID) is a common neurodevelopmental condition, often caused by genetic defects. De novo variation (DNV) is an important cause of ID, especially in severe or syndromic forms of the disorder. Next generation sequencing has been a successful application for finding pathogenic variation in ID patients. The main focus of this thesis is to use whole exome sequencing (WES) and whole genome sequencing (WGS) to identify pathogenic variants in undiagnosed ID patients. In Paper I, WES was used in family trios to identify pathogenic DNVs in patients diagnosed with ID in combination with epilepsy. This work led to the identification of several DNVs in both new and known disease genes, including the first report of variation in the HECW2 gene in association with neurodevelopmental disorder and epilepsy. Paper II is the first independent validation of PIGG as a disease-causing gene in patients with developmental disorder. We used WES to identify the homozygous variation in PIGG, and transcriptome analysis as well as flow-cytometry studies were used to validate the pathogenicity of the PIGG variation. We discovered that PIGG variation give different effects in different cell types, contributing new insights into the disease mechanism. Paper III is also an application of WES in trio families with patients diagnosed with ID in order to identify causal variants, a strategy similar to that of Paper I. Several pathogenic variants were identified in this study; in particular, the gene NAA15 is highlighted as a new disease gene, and was recently confirmed in independent studies. This study also adds evidence to support that variation in the PUF60 gene is causing the symptoms in patients with Verheij syndrome. In Paper IV, WGS was used to analyze families with consanguineous marriages. All families in this study had been previously analyzed with WES without finding a disease cause. A number of new disease-causing variants were identified in the study, including a first validation of FRMD4A as a disease-associated gene. This study also shows that WGS performs better than WES in finding variants, even for variants in coding parts of the genome.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , p. 35
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1343
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-326283ISBN: 978-91-513-0007-8 (print)OAI: oai:DiVA.org:uu-326283DiVA, id: diva2:1119774
Public defence
2017-09-13, B7 111:a, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2017-08-21 Created: 2017-07-04 Last updated: 2017-09-08
List of papers
1. Mutations in HECW2 are associated with intellectual disability and epilepsy
Open this publication in new window or tab >>Mutations in HECW2 are associated with intellectual disability and epilepsy
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2016 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 53, no 10, p. 697-704Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: De novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions.

METHODS: Exome sequencing was performed on 39 patient-parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders.

RESULTS: In 39 patient-parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy.

CONCLUSIONS: Our results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders.

Keywords
Intellectual disability; Epilepsy; Exome sequencing; HECW2; ERC2
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-301393 (URN)10.1136/jmedgenet-2016-103814 (DOI)000385958500008 ()27334371 (PubMedID)
Funder
EU, European Research Council, 282330Swedish Society for Medical Research (SSMF)
Available from: 2016-08-31 Created: 2016-08-22 Last updated: 2018-01-10Bibliographically approved
2. Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function
Open this publication in new window or tab >>Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function
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2017 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 38, no 10, p. 1394-1401Article in journal (Refereed) Published
Abstract [en]

Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism. Here, we present two siblings with ID, cerebellar hypoplasia, cerebellar ataxia, early-onset seizures, and minor facial dysmorphology. Using exome sequencing, we identified a homozygous nonsense variant (NM_001127178.1:c.1640G>A, p.Trp547*) in the gene Phosphatidylinositol Glycan Anchor Biosynthesis, Class G (PIGG) in both the patients. Variants in several other GPI anchor synthesis genes lead to a reduced expression of GPI-anchored proteins (GPI-APs) that can be measured by flow cytometry. No significant differences in GPI-APs could be detected in patient granulocytes, consistent with recent findings. However, fibroblasts showed a reduced global level of GPI anchors and of specific GPI-linked markers. These findings suggest that fibroblasts might be more sensitive to pathogenic variants in GPI synthesis pathway and are well suited to screen for GPI-anchor deficiencies. Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an ID syndrome, and we find that loss of function of PIGG is associated with GPI deficiency.

Keywords
PIGG, GPI deficiency, Intellectual disability, Exome sequencing
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-326282 (URN)10.1002/humu.23268 (DOI)000411740400013 ()
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2018-02-02Bibliographically approved
3. Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability
Open this publication in new window or tab >>Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability
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2018 (English)In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 177, no 1, p. 10-20Article in journal (Refereed) Published
Abstract [en]

Intellectual Disability (ID) is a clinically heterogeneous condition that affects 2-3% of population worldwide. In recent years, exome sequencing has been a successful strategy for studies of genetic causes of ID, providing a growing list of both candidate and validated ID genes. In this study, exome sequencing was performed on 28 ID patients in 27 patient-parent trios with the aim to identify de novo variants (DNVs) in known and novel ID associated genes. We report the identification of 25 DNVs out of which five were classified as pathogenic or likely pathogenic. Among these, a two base pair deletion was identified in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome (Verheij syndrome). Our result adds to the growing evidence that PUF60 is responsible for the majority of the symptoms reported for carriers of a microdeletion across this region. We also report variants in several genes previously not associated with ID, including a de novo missense variant in NAA15. We highlight NAA15 as a novel candidate ID gene based on the vital role of NAA15 in the generation and differentiation of neurons in neonatal brain, the fact that the gene is highly intolerant to loss of function and coding variation, and previously reported DNVs in neurodevelopmental disorders.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-326280 (URN)10.1002/ajmg.b.32574 (DOI)000417876700002 ()28990276 (PubMedID)
Funder
EU, European Research Council
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2018-01-17Bibliographically approved
4. Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability
Open this publication in new window or tab >>Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability
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2019 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 95, no 3, p. 436-439Article in journal, Letter (Refereed) Published
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-326281 (URN)10.1111/cge.13470 (DOI)000458956100013 ()30525197 (PubMedID)
Funder
EU, European Research Council, 282330
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2019-03-14Bibliographically approved

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