Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/104165
Title: KIAA1109 variants are associated with a severe disorder of brain development and arthrogryposis
Authors: Roechert, Bernd
Van Hasselt, Peter M.
Monroe, Glen R.
Lai, Angeline Hwei Meeng
Ambusaidi Qamariya
Ambrozaitytė, Laima
Preikšaitienė, Eglė
Gueneau, Lucie
Tran-Mau-Them, Frédéric
Fish, Richard J.
Shamseldin, Hanan E.
Voisin, Norine
Allias, Fabienne
Jamuar Saumya Shekhar
Lim, J. Ying
Bonnard, Carine
Wright, Caroline F.
Putoux, Audrey
Cimbalistienė, Loreta
Delafontaine, Julien
Guex, Nicolas
Hashem Mais
Kurdi Wesam
Pradervand, Sylvain
Reversade, Bruno
Xenarios, Ioannis
Lesca, Gaëtan
Pippucci, Tommaso
Wiederkehr, Michaël
Van Haaften, Gijs W.
Shaw-Smith, Charles J.
Schindewolf, Erica M.
Reymond, Alexandre
Sanlaville, Damien
Guibaud, Laurent
Kučinskas, Vaidutis
Chelly, Jamel
Alkuraya, Fowzan S.
Keywords: Brain Malformations
Clubfoot
DRNTU::Science::Medicine
Issue Date: 2017
Source: Gueneau, L., Fish, R. J., Shamseldin, H. E., Voisin, N., Mau-Them, F . T., Preiksaitiene, E., . . . Reymond, A. (2017). KIAA1109 variants are associated with a severe disorder of brain development and arthrogryposis. The American Journal of Human Genetics, 102(1), 116-132. doi:10.1016/j.ajhg.2017.12.002
Series/Report no.: The American Journal of Human Genetics
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.
URI: https://hdl.handle.net/10356/104165
http://hdl.handle.net/10220/47895
ISSN: 0002-9297
DOI: 10.1016/j.ajhg.2017.12.002
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
Rights: © 2017 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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