No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome.
BACKGROUND
Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome (MCLMR) is a rare autosomal dominant disorder with variable expressivity. It is characterized by mild-to-severe microcephaly, often associated with intellectual disability, ocular defects and lymphedema. It can be sporadic or inherited. Eighty-seven patients have been described to carry a mutation in KIF11, which encodes a homotetrameric motor kinesin, EG5.


METHODS
We tested 23 unreported MCLMR index patients for KIF11. We also reviewed the clinical phenotypes of all our patients as well as of those described in previously published studies.


RESULTS
We identified 14 mutations, 12 of which are novel. We detected mutations in 12 affected individuals, from 6 out of 6 familial cases, and in 8 out of 17 sporadic patients. Phenotypic evaluation of patients (our 26 + 61 earlier published = 87) revealed microcephaly in 91%, eye anomalies in 72%, intellectual disability in 67% and lymphedema in 47% of the patients. Unaffected carriers were rare (4 out of 87: 5%). Family history is not a requisite for diagnosis; 31% (16 out of 52) were de novo cases.


CONCLUSIONS
All inherited cases, and 50% of sporadic cases of MCLMR are due to germline KIF11 mutations. It is possible that mosaic KIF11 mutations cause the remainder of sporadic cases, which the methods employed here were not designed to detect. On the other hand, some of them might have another mimicking disorder and genetic defect, as microcephaly is highly heterogeneous. In aggregate, KIF11 mutations likely cause the majority, if not all, of MCLMR.
Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, bte B1.74.06, B-1200, Brussels, Belgium. matthieu.schlogel@uclouvain.be.
Matthieu J
MJ
Schlögel
Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, bte B1.74.06, B-1200, Brussels, Belgium. antonella.mendola@uclouvain.be.
Antonella
A
Mendola
Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, bte B1.74.06, B-1200, Brussels, Belgium. elodie.fastre@uclouvain.be.
Elodie
E
Fastré
Department of Clinical Genetics, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, LE1 5WW, UK. pradeep.vasudevan@uhl-tr.nhs.uk.
Pradeep
P
Vasudevan
Center for Human Genetics, University Hospitals Leuven, KU Leuven, 3000, Leuven, Belgium. koenraad.devriendt@uzleuven.be.
Koen
K
Devriendt
Center for Human Genetics, University Hospitals Leuven, KU Leuven, 3000, Leuven, Belgium. thomy.deravel@uzleuven.be.
Thomy J L
TJ
de Ravel
Center for Human Genetics, University Hospitals Leuven, KU Leuven, 3000, Leuven, Belgium. Hilde.Vanesch@uzleuven.be.
Hilde
H
Van Esch
Department of Ophthalmology, St Rafael University Hospitals, 3000, Leuven, Belgium. ingele.casteels@uzleuven.be.
Ingele
I
Casteels
Servicio de Pediatría, Hospital San Pedro de Alcántara, Cáceres, Spain. IARROY@telefonica.net.
Ignacio
I
Arroyo Carrera
Center for Human Genetics, University Hospitals Leuven, KU Leuven, 3000, Leuven, Belgium. francesca.cristofoli@med.kuleuven.be.
Francesca
F
Cristofoli
Division of Human Genetics, University of Cape Town, 7700, Cape Town, South Africa. Karen.Fieggen@uct.ac.za.
Karen
K
Fieggen
Medical Genetics, Kaiser Permanente, Sacramento, CA, 95815, USA. Katheryn.Jones@kp.org.
Katheryn
K
Jones
Medical Genetics, Kaiser Permanente, Sacramento, CA, 95815, USA. Mark.Lipson@kp.org.
Mark
M
Lipson
Department of Ophthalmology, Queen Fabiola Children's University Hospital (HUDERF), 1020, Brussels, Belgium. Irina.Balikova@ulb.ac.be.
Irina
I
Balikova
Pediatrics and Medical Genetics, Barzilai Medical Center, 78306, Ashkelon, Israel. amihood@netvision.net.il.
Ami
A
Singer
Department of Clinical Genetics, Lund University Hospital, 221 85, Lund, Sweden. maria.soller@med.lu.se.
Maria
M
Soller
General Hospital of Florencio Varela, Children's Hospital Dr. Pedro Elizalde and Foundation for Neurological Diseases of Childhood (FLENI), C1270AAN, Buenos Aires, Capital Federal, Argentina. mervi3178@yahoo.com.ar.
María
M
Mercedes Villanueva
Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, bte B1.74.06, B-1200, Brussels, Belgium. nicole.revencu@uclouvain.be.|Center for Human Genetics, Cliniques universitaires Saint-Luc, Université catholique de Louvain, 1200, Brussels, Belgium. nicole.revencu@uclouvain.be.
Nicole
N
Revencu
Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, bte B1.74.06, B-1200, Brussels, Belgium. laurence.boon@uclouvain.be.|Center for Vascular Anomalies, Cliniques universitaires Saint-Luc, Université catholique de Louvain, 1200, Brussels, Belgium. laurence.boon@uclouvain.be.
Laurence M
LM
Boon
Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, bte B1.74.06, B-1200, Brussels, Belgium. pascal.brouillard@uclouvain.be.
Pascal
P
Brouillard
Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, bte B1.74.06, B-1200, Brussels, Belgium. miikka.vikkula@uclouvain.be.|Center for Vascular Anomalies, Cliniques universitaires Saint-Luc, Université catholique de Louvain, 1200, Brussels, Belgium. miikka.vikkula@uclouvain.be.|Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Université catholique de Louvain, 1200, Brussels, Belgium. miikka.vikkula@uclouvain.be.
Miikka
M
Vikkula
D000328:Adult; D019066:Facies; D005260:Female; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D016547:Kinesins / Q000235:genetics; D008209:Lymphedema / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D015792:Retinal Dysplasia / Q000235:genetics; D055815:Young Adult
C470243:KIF11 protein, human; D016547:Kinesins