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

Abstract

BackgroundMicrocephaly 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.MethodsWe 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.ResultsWe 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.ConclusionsAll 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.

An interphase pool of KIF11 localizes at the basal bodies of primary cilia and a reduction in KIF11 expression alters cilia dynamics

“…Because MCLMR and FEVR patients are reported to have a mutation in only one allele of KIF11, we next created two heterozygous CRISPR/Cas9 clonal lines of RPE1 cells to experimentally represent this genetic state (crKIF11-1 and crKIF11-2). Gene editing via CRISPR/Cas9 more closely reflects the patient mutational state than RNA interference via siRNA, and hence is critical for evaluating the impact of reduced KIF11 on primary cilia [12][13][14]16,41 . Depletion of KIF11 was confirmed by immunoblotting ( Supplementary Fig.…”

“…The mutations are found throughout the gene, and a given mutation is not typically seen in more than one patient unless inherited 11 – 16 . Importantly, all reported patient mutations are heterozygous, with many of the mutations predicted to lead to haploinsufficiency of KIF11 11 , 13 , 16 . These patients share a characteristic collection of phenotypes, but not all patients present with every phenotype, and some are more severe than others.…”

“…of KIF11 11,13,16 . These patients share a characteristic collection of phenotypes, but not all patients present with every phenotype, and some are more severe than others.…”

KIF11 microdeletion is associated with microcephaly, chorioretinopathy and intellectual disability

“…Although KIF11 is primarily associated with MCLMR syndrome, the clinical features are heterogeneous, indicating both variable expressivity and incomplete penetrance. 5 We report on the first microdeletion encompassing the entire KIF11 gene, which cosegregates in a family with true microcephaly ( microcephalia vera ), chorioretinopathy and mild intellectual disability.…”

“…1 Since then, other patients with KIF11 mutations have been identified, confirming the causal association between this gene and MCLMR syndrome. 2–5 KIF11 , which maps at 10q23.33, encodes a spindle motor protein of the kinesin family. Although KIF11 is primarily associated with MCLMR syndrome, the clinical features are heterogeneous, indicating both variable expressivity and incomplete penetrance.…”