2. Academic Validation
  3. No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome

No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome

  • Orphanet J Rare Dis. 2015 May 2;10:52. doi: 10.1186/s13023-015-0271-4.
Matthieu J Schlögel 1,  Antonella Mendola 2,  Elodie Fastré 3,  Pradeep Vasudevan 4,  Koen Devriendt 5,  Thomy J L de Ravel 6,  Hilde Van Esch 7,  Ingele Casteels 8,  Ignacio Arroyo Carrera 9,  Francesca Cristofoli 10,  Karen Fieggen 11,  Katheryn Jones 12,  Mark Lipson 13,  Irina Balikova 14,  Ami Singer 15,  Maria Soller 16,  María Mercedes Villanueva 17,  Nicole Revencu 18 19,  Laurence M Boon 20 21,  Pascal Brouillard 22,  Miikka Vikkula 23 24 25
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 Department of Clinical Genetics, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, LE1 5WW, UK. pradeep.vasudevan@uhl-tr.nhs.uk.
  • 5 Center for Human Genetics, University Hospitals Leuven, KU Leuven, 3000, Leuven, Belgium. koenraad.devriendt@uzleuven.be.
  • 6 Center for Human Genetics, University Hospitals Leuven, KU Leuven, 3000, Leuven, Belgium. thomy.deravel@uzleuven.be.
  • 7 Center for Human Genetics, University Hospitals Leuven, KU Leuven, 3000, Leuven, Belgium. Hilde.Vanesch@uzleuven.be.
  • 8 Department of Ophthalmology, St Rafael University Hospitals, 3000, Leuven, Belgium. ingele.casteels@uzleuven.be.
  • 9 Servicio de Pediatría, Hospital San Pedro de Alcántara, Cáceres, Spain. IARROY@telefonica.net.
  • 10 Center for Human Genetics, University Hospitals Leuven, KU Leuven, 3000, Leuven, Belgium. francesca.cristofoli@med.kuleuven.be.
  • 11 Division of Human Genetics, University of Cape Town, 7700, Cape Town, South Africa. Karen.Fieggen@uct.ac.za.
  • 12 Medical Genetics, Kaiser Permanente, Sacramento, CA, 95815, USA. Katheryn.Jones@kp.org.
  • 13 Medical Genetics, Kaiser Permanente, Sacramento, CA, 95815, USA. Mark.Lipson@kp.org.
  • 14 Department of Ophthalmology, Queen Fabiola Children's University Hospital (HUDERF), 1020, Brussels, Belgium. Irina.Balikova@ulb.ac.be.
  • 15 Pediatrics and Medical Genetics, Barzilai Medical Center, 78306, Ashkelon, Israel. amihood@netvision.net.il.
  • 16 Department of Clinical Genetics, Lund University Hospital, 221 85, Lund, Sweden. maria.soller@med.lu.se.
  • 17 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.
  • 18 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.
  • 19 Center for Human Genetics, Cliniques universitaires Saint-Luc, Université catholique de Louvain, 1200, Brussels, Belgium. nicole.revencu@uclouvain.be.
  • 20 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.
  • 21 Center for Vascular Anomalies, Cliniques universitaires Saint-Luc, Université catholique de Louvain, 1200, Brussels, Belgium. laurence.boon@uclouvain.be.
  • 22 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.
  • 23 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.
  • 24 Center for Vascular Anomalies, Cliniques universitaires Saint-Luc, Université catholique de Louvain, 1200, Brussels, Belgium. miikka.vikkula@uclouvain.be.
  • 25 Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Université catholique de Louvain, 1200, Brussels, Belgium. miikka.vikkula@uclouvain.be.
PMID: 25934493 DOI: 10.1186/s13023-015-0271-4
Abstract

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.

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