KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620592
Title:
KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.
Authors:
Gueneau, L. [et al]; Shaw-Smith, Charles
Abstract:
Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.
Citation:
KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis. 2018, 102 (1):116-132 Am. J. Hum. Genet.
Publisher:
Cell Press
Journal:
American journal of human genetics
Issue Date:
4-Jan-2018
URI:
http://hdl.handle.net/11287/620592
DOI:
10.1016/j.ajhg.2017.12.002
PubMed ID:
29290337
Additional Links:
http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(17)30491-3
Note:
This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.
Type:
Journal Article
Language:
en
ISSN:
1537-6605
Appears in Collections:
Clinical Genetics (Peninsula Genetics); 2018 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorGueneau, L. [et al]en
dc.contributor.authorShaw-Smith, Charlesen
dc.date.accessioned2018-01-10T16:33:46Z-
dc.date.available2018-01-10T16:33:46Z-
dc.date.issued2018-01-04-
dc.identifier.citationKIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis. 2018, 102 (1):116-132 Am. J. Hum. Genet.en
dc.identifier.issn1537-6605-
dc.identifier.pmid29290337-
dc.identifier.doi10.1016/j.ajhg.2017.12.002-
dc.identifier.urihttp://hdl.handle.net/11287/620592-
dc.description.abstractWhole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.en
dc.language.isoenen
dc.publisherCell Pressen
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0002-9297(17)30491-3en
dc.rightsArchived with thanks to American Journal of Human Genetics. This is an Open Access article under the CC-BY licence (http://creativecommons.org/licenses/by/4.0/).en
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleKIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.en
dc.typeJournal Articleen
dc.identifier.journalAmerican journal of human geneticsen
dc.description.noteThis article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.en
dc.type.versionPublisheden

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