KIF11 – Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability

Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability (MCLMR) is an autosomal dominant neurodevelopmental syndrome linked to heterozygous variants in KIF11. KIF11 encodes the kinesin motor protein EG5, essential for mitotic spindle assembly and microtubule dynamics in neural, retinal, and lymphatic tissues. Initial whole-exome and targeted sequencing identified heterozygous KIF11 variants in 18 unrelated probands across 15 families, including two nonsense, two splice-site, four missense, and six frameshift mutations, with de novo events in multiple cases (15 probands; [PMID:22284827]) and additional de novo missense and synonymous variants in singletons ([PMID:30733662]; [PMID:34965526]).

Genetic evidence includes 18 probands with KIF11 mutations, comprising missense (e.g., c.1402T>G (p.Leu468Val)), canonical splice (c.574-1G>A), and loss-of-function variants ([PMID:22284827]; [PMID:30733662]). De novo status was demonstrated in three singletons ([PMID:30733662]; [PMID:34965526]) and co-segregation was observed in familial cases, supporting high penetrance. Variant spectrum spans missense, splice, and null alleles with no founder effect reported.

Case reports detail a de novo c.1402T>G (p.Leu468Val) variant in a child with microcephaly, ventricular septal defect, congenital lymphedema, and chorioretinal lacunae ([PMID:30733662]), and a c.2922G>T (p.Pro974=) synonymous change affecting exon 20 splicing, yielding a dominant-negative truncated protein ([PMID:34965526]).

Functional studies demonstrate that KIF11 loss-of-function and dominant-negative variants disrupt spindle assembly. Patient-derived cell assays and minigene splicing experiments confirm aberrant pre-mRNA processing for c.2922G>T, leading to exon 20 skipping and shortened EG5 that competes with wild-type protein ([PMID:34965526]). In vitro loss of EG5 impairs microtubule sliding and spindle bipolarity, consistent with neural progenitor proliferation defects ([PMID:22284827]).

The mechanism of pathogenicity is haploinsufficiency and dominant-negative interference with EG5 function, resulting in impaired mitosis in neuroepithelial and vascular progenitors. Experimental concordance across cellular models and phenotypic overlap with mouse spindle assembly deficits reinforce causality.

In summary, heterozygous KIF11 variants cause autosomal dominant MCLMR via disrupted spindle dynamics, yielding microcephaly, chorioretinal dysplasia, and lymphedema. Clinical KIF11 sequencing should be considered in patients with this phenotype.

Key take-home: KIF11 genetic testing provides a definitive diagnosis for MCLMR and informs management of neuro-ophthalmic and lymphatic complications.

References

• American journal of human genetics • 2012 • Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy PMID:22284827
• Molecular syndromology • 2019 • A Novel Mutation of KIF11 in a Child with 22q11.2 Deletion Syndrome Associated with MCLMR PMID:30733662
• Developmental neuroscience • 2022 • A Novel Variant of the KIF11 Gene, c.2922G>T, Is Associated with Microcephaly by Affecting RNA Splicing PMID:34965526

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