2. Academic Validation
  3. KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis

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

  • Am J Hum Genet. 2018 Jan 4;102(1):116-132. doi: 10.1016/j.ajhg.2017.12.002.
Lucie Gueneau 1,  Richard J Fish 2,  Hanan E Shamseldin 3,  Norine Voisin 1,  Frédéric Tran Mau-Them 4,  Egle Preiksaitiene 5,  Glen R Monroe 6,  Angeline Lai 7,  Audrey Putoux 8,  Fabienne Allias 9,  Qamariya Ambusaidi 10,  Laima Ambrozaityte 5,  Loreta Cimbalistienė 5,  Julien Delafontaine 11,  Nicolas Guex 11,  Mais Hashem 3,  Wesam Kurdi 10,  Saumya Shekhar Jamuar 12,  Lim J Ying 13,  Carine Bonnard 14,  Tommaso Pippucci 15,  Sylvain Pradervand 16,  Bernd Roechert 11,  Peter M van Hasselt 6,  Michaël Wiederkehr 1,  Caroline F Wright 17,  DDD Study,  Ioannis Xenarios 16,  Gijs van Haaften 6,  Charles Shaw-Smith 18,  Erica M Schindewolf 19,  Marguerite Neerman-Arbez 2,  Damien Sanlaville 8,  Gaëtan Lesca 8,  Laurent Guibaud 20,  Bruno Reversade 21,  Jamel Chelly 4,  Vaidutis Kučinskas 5,  Fowzan S Alkuraya 22,  Alexandre Reymond 23
Affiliations

Affiliations

  • 1 Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
  • 2 Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
  • 3 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 4 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, INSERM Unité 964, 67404 Illkirch Cedex, France; Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
  • 5 Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania.
  • 6 Department of Genetics and Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
  • 7 KK Women's and Children's Hospital, Singapore 229899, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University-Imperial College London, Singapore 639798, Singapore.
  • 8 Service de Génétique, Hospices Civils de Lyon, 69002 Lyon, France; Centre de Recherche en Neurosciences de Lyon, INSERM U1028, UMR CNRS 5292, Université Claude Bernard Lyon 1, 69675 Bron Cedex, France.
  • 9 Département de Pathologie, Hospices Civils de Lyon, 69002 Lyon, France.
  • 10 Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 11 Swiss Institute of Bioinformatics (SIB), 1015 Lausanne, Switzerland.
  • 12 KK Women's and Children's Hospital, Singapore 229899, Singapore; Duke-NUS Medical School, Singapore 169857, Singapore.
  • 13 KK Women's and Children's Hospital, Singapore 229899, Singapore.
  • 14 Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore.
  • 15 Sant'Orsola-Malpighi Hospital, Medical Genetics Unit, Pavillon 11, 2nd floor, Via Massarenti 9, 40138 Bologna, Italy.
  • 16 Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), 1015 Lausanne, Switzerland.
  • 17 Deciphering Developmental Disorders (DDD) Study, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • 18 Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter EX1 2ED, UK.
  • 19 Center for Fetal Diagnosis and Treatment, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 20 Centre de Recherche en Neurosciences de Lyon, INSERM U1028, UMR CNRS 5292, Université Claude Bernard Lyon 1, 69675 Bron Cedex, France; Département d'imagerie pédiatrique et fœtale, Centre Pluridisciplinaire de Diagnostic Prénatal, Hôpital Femme Mère Enfant, Université Claude Bernard Lyon 1, 69677 Bron Cedex, France.
  • 21 Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore; Institute of Molecular and Cell Biology (IMCB), A(∗)STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Singapore 138673, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Amsterdam Reproduction & Development, Academic Medical Centre & VU University Medical Center, 1105 AZ Amsterdam, the Netherlands.
  • 22 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12371, Saudi Arabia. Electronic address: [email protected].
  • 23 Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address: [email protected].
PMID: 29290337 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.

Keywords

arthrogryposis; brain malformations; cerebellar hypoplasia; clubfoot; hydrocephaly; whole-exome sequencing.

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