Gueneau, L., Fish, R. J., Shamseldin, H. E., Voisin, N., Tran Mau-Them, F., Preiksaitiene, E., … Reymond, A. (2018). 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
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.
License type:
Attribution 4.0 International (CC BY 4.0)
Funding Info:
We thank the affected individuals and their families for their contribution to this study. We are grateful to Keith Joung for reagents. This work was supported by grants from the Swiss National Science Foundation ( 31003A_160203 ) to A.R., the Lithuanian-Swiss cooperation program to reduce economic and social disparities within the enlarged European Union ( CH-3-ŠMM-0104 , Unigene project) to V.K. and A.R., and King Abdulaziz City for Science and Technology grant 13BIO-1113-20 to F.S.A. We also acknowledge the support of the Saudi Human Genome Program . The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003 ), a parallel funding partnership between the Wellcome Trust and the Department of Health , and the Wellcome Trust Sanger Institute (grant number WT098051 ). The study has UK Research Ethics Committee approval ( 10/H0305/83 , granted by the Cambridge South REC , and GEN/284/12 granted by the Republic of Ireland REC ). The research team acknowledges the support of the National Institute for Health Research , through the Comprehensive Clinical Research Network. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.