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

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State: Public
Version: Final published version
Serval ID
serval:BIB_D335250BB897
Type
Article: article from journal or magazin.
Collection
Publications
Title
KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.
Journal
American journal of human genetics
Author(s)
Gueneau L., Fish R.J., Shamseldin H.E., Voisin N., Tran Mau-Them F., Preiksaitiene E., Monroe G.R., Lai A., Putoux A., Allias F., Ambusaidi Q., Ambrozaityte L., Cimbalistienė L., Delafontaine J., Guex N., Hashem M., Kurdi W., Jamuar S.S., Ying L.J., Bonnard C., Pippucci T., Pradervand S., Roechert B., van Hasselt P.M., Wiederkehr M., Wright C.F., Xenarios I., van Haaften G., Shaw-Smith C., Schindewolf E.M., Neerman-Arbez M., Sanlaville D., Lesca G., Guibaud L., Reversade B., Chelly J., Kučinskas V., Alkuraya F.S., Reymond A.
Working group(s)
DDD Study
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Publication state
Published
Issued date
04/01/2018
Peer-reviewed
Oui
Volume
102
Number
1
Pages
116-132
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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 2 <sup>nd</sup> and 3 <sup>rd</sup> 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.
Keywords
Adolescent, Animals, Arthrogryposis/genetics, Brain/diagnostic imaging, Brain/embryology, Brain/pathology, Child, Female, Gene Knockdown Techniques, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Mutation/genetics, Pedigree, Proteins/genetics, Zebrafish, Zebrafish Proteins/genetics, arthrogryposis, brain malformations, cerebellar hypoplasia, clubfoot, hydrocephaly, whole-exome sequencing
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2018 19:23
Last modification date
20/08/2019 16:53
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