uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. (Lars Feuk)ORCID iD: 0000-0001-8367-8391
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Show others and affiliations
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.

Place, publisher, year, edition, pages
2018. Vol. 177, no 1, p. 10-20
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-326280DOI: 10.1002/ajmg.b.32574ISI: 000417876700002PubMedID: 28990276OAI: oai:DiVA.org:uu-326280DiVA, id: diva2:1119768
Funder
EU, European Research Council
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2018-01-17Bibliographically approved
In thesis
1. Sequence based identification of genetic variation associated with intellectual disability
Open this publication in new window or tab >>Sequence based identification of genetic variation associated with intellectual disability
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:nbn:se:uu:diva-326283 (URN)978-91-513-0007-8 (ISBN)
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

Open Access in DiVA

fulltext(525 kB)3 downloads
File information
File name FULLTEXT01.pdfFile size 525 kBChecksum SHA-512
6ef4756776ec68ed7bc5ff69018d0c7490329c08995a64fb07efe2e0d43c203bbaeee324b5c1c676bdeb6f0c7b550639c443ebca47ac1a1d5e7f3be6d0742220
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Halvardson, JonatanZander, CeciliaZaghlool, AmmarFrykholm, CarinaThuresson, Ann-CharlotteFeuk, Lars

Search in DiVA

By author/editor
Zhao, Jin JamesHalvardson, JonatanZander, CeciliaZaghlool, AmmarFrykholm, CarinaThuresson, Ann-CharlotteFeuk, Lars
By organisation
Department of Immunology, Genetics and PathologyScience for Life Laboratory, SciLifeLabMedicinsk genetik och genomik
In the same journal
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 3 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 229 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf