Mutations in KIF11 Cause Autosomal-Dominant Microcephaly Variably Associated with Congenital Lymphedema and Chorioretinopathy

Abstract

We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures.

New developments in clinical aspects of lymphatic disease

“…The predominant phenotype for mutations of this gene is late-onset fourlimb involvement, but there is a wide diversity in age of onset and extent of limb involvement (20). Additional genes, very recently identified, are GATA2 (21) and KIF11 (22). GATA2 causes Emberger syndrome and is interesting because of the relationship between lymphedema, immunodeficiency, and myelodysplasia, the latter predisposing to acute myeloid leukemia.…”

Microcephaly-Lymphedema-Chorioretinal Dysplasia Syndrome: Two Case Reports

“…Based on the variability of features observed in some families, several authors have argued that autosomal dominant microcephaly with chorioretinopathy and the lymphedema, microcephaly, and chorioretinopathy syndrome may represent variable expressions of the same entity. Ostergaard et al [8] analyzed the KIF11 gene in unrelated chorioretinal dysplasia, microcephaly and mental retardation syndrome (CDMMR) and MLCRD syndrome families identified heterozygous mutations in KIF11 gene. It was concluded that the MLCRD and CDMMR syndromes should be considered a single entity with variable clinical features.…”

An approach to familial lymphoedema

“…Microcephaly-chorioretinopathy-lymphoedema-mental retardation is associated with alterations in the KIF11 gene 15 and follows an autosomal dominant pattern of inheritance. It is included in this section as there is a very high incidence of congenital lower limb lymphoedema (46%).…”