KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis
Lucie Gueneau
(1)
,
Richard Fish
(2)
,
Hanan Shamseldin
(3)
,
Norine Voisin
(1)
,
Frédéric Tran Mau-Them
(4, 5)
,
Egle Preiksaitiene
(6)
,
Glen Monroe
(7)
,
Angeline Lai
(8, 9)
,
Audrey Putoux
(10, 11)
,
Fabienne Allias
(10)
,
Qamariya Ambusaidi
(3)
,
Laima Ambrozaityte
(6)
,
Loreta Cimbalistiene
(6)
,
Julien Delafontaine
(12)
,
Nicolas Guex
(12)
,
Mais Hashem
(3)
,
Wesam Kurdi
(3)
,
Saumya Jamuar
(9)
,
Lim Ying
(9)
,
Carine Bonnard
(13)
,
Tommaso Pippucci
(14)
,
Sylvain Pradervand
(12)
,
Bernd Roechert
(12)
,
Peter van Hasselt
(7)
,
Michaël Wiederkehr
(1)
,
Caroline Wright
(15)
,
Ioannis Xenarios
(12)
,
Gijs van Haaften
(7)
,
Charles Shaw-Smith
(16)
,
Erica Schindewolf
(17)
,
Marguerite Neerman-Arbez
(2)
,
Damien Sanlaville
(10, 11)
,
Gaëtan Lesca
(10, 11)
,
Laurent Guibaud
(11, 18)
,
Bruno Reversade
(13, 19, 20)
,
Jameleddine Chelly
(4, 5)
,
Vaidutis Kucinskas
(6)
,
Fowzan Alkuraya
(3, 21)
,
Alexandre Reymond
(1)
1
UNIL -
Université de Lausanne = University of Lausanne
2 UNIGE - Université de Genève = University of Geneva
3 King Faisal Specialist Hospital and Research Center
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 HUS - Les Hôpitaux Universitaires de Strasbourg
6 Vilnius University [Vilnius]
7 University Medical Center [Utrecht]
8 Imperial College London
9 KK Women's and Children's Hospital [Singapore]
10 HCL - Hospices Civils de Lyon
11 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
12 SIB - Swiss Institute of Bioinformatics [Lausanne]
13 A*STAR - Agency for science, technology and research [Singapore]
14 Sant'Orsola-Malpighi Hospital [Bologna, Italy]
15 The Wellcome Trust Sanger Institute [Cambridge]
16 Royal Devon and Exeter NHS Foundation Trust [UK]
17 CHOP - Children’s Hospital of Philadelphia
18 HFME - Hôpital Femme Mère Enfant [CHU - HCL]
19 NUS - National University of Singapore
20 VU University Medical Center [Amsterdam]
21 Alfaisal University
2 UNIGE - Université de Genève = University of Geneva
3 King Faisal Specialist Hospital and Research Center
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 HUS - Les Hôpitaux Universitaires de Strasbourg
6 Vilnius University [Vilnius]
7 University Medical Center [Utrecht]
8 Imperial College London
9 KK Women's and Children's Hospital [Singapore]
10 HCL - Hospices Civils de Lyon
11 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
12 SIB - Swiss Institute of Bioinformatics [Lausanne]
13 A*STAR - Agency for science, technology and research [Singapore]
14 Sant'Orsola-Malpighi Hospital [Bologna, Italy]
15 The Wellcome Trust Sanger Institute [Cambridge]
16 Royal Devon and Exeter NHS Foundation Trust [UK]
17 CHOP - Children’s Hospital of Philadelphia
18 HFME - Hôpital Femme Mère Enfant [CHU - HCL]
19 NUS - National University of Singapore
20 VU University Medical Center [Amsterdam]
21 Alfaisal University
Ioannis Xenarios
- Fonction : Auteur
- PersonId : 761984
- ORCID : 0000-0002-3413-6841
- IdRef : 195639707
Damien Sanlaville
- Fonction : Auteur
- PersonId : 760022
- ORCID : 0000-0001-9939-2849
- IdRef : 059247878
Laurent Guibaud
- Fonction : Auteur
- PersonId : 940989
Bruno Reversade
- Fonction : Auteur
- PersonId : 758347
- ORCID : 0000-0002-4070-7997
- IdRef : 109134621
Jameleddine Chelly
- Fonction : Auteur
- PersonId : 1054990
Résumé
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-Kucinskas 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(nd) and 3(rd) 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.