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

Authors :
Gueneau L
Fish RJ
Shamseldin HE
Voisin N
Tran Mau-Them F
Preiksaitiene E
Monroe GR
Lai A
Putoux A
Allias F
Ambusaidi Q
Ambrozaityte L
Cimbalistienė L
Delafontaine J
Guex N
Hashem M
Kurdi W
Jamuar SS
Ying LJ
Bonnard C
Pippucci T
Pradervand S
Roechert B
van Hasselt PM
Wiederkehr M
Wright CF
Xenarios I
van Haaften G
Shaw-Smith C
Schindewolf EM
Neerman-Arbez M
Sanlaville D
Lesca G
Guibaud L
Reversade B
Chelly J
Kučinskas V
Alkuraya FS
Reymond A
Source :
American journal of human genetics [Am J Hum Genet] 2018 Jan 04; Vol. 102 (1), pp. 116-132. Date of Electronic Publication: 2017 Dec 28.
Publication Year :
2018

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 <superscript>nd</superscript> and 3 <superscript>rd</superscript> 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.<br /> (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1537-6605
Volume :
102
Issue :
1
Database :
MEDLINE
Journal :
American journal of human genetics
Publication Type :
Academic Journal
Accession number :
29290337
Full Text :
https://doi.org/10.1016/j.ajhg.2017.12.002