Expanding the KIF4A-associated phenotype

Abstract

Kinesin super family (KIF) genes encode motor kinesins, a family of evolutionary conserved proteins, involved in intracellular trafficking of various cargoes. These proteins are critical for various physiological processes including neuron function and survival, ciliary function and ciliogenesis, and cell-cycle progression. Recent evidence suggests that alterations in motor kinesin genes can lead to a variety of human diseases, including monogenic disorders. Neuropathies, impaired higher brain functions, structural brain abnormalities and multiple congenital anomalies (i.e., renal, urogenital, and limb anomalies) can result from pathogenic variants in many KIF genes. We expand the phenotype associated with KIF4A variants from developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of phenotypic manifestations. Additional anomalies of the kidneys and urinary tract, congenital lymphedema, eye, and dental anomalies seem to be variably associated and overlap with clinical signs observed in other kinesinopathies. Caution still applies to missense variants, but hopefully, future work will further establish genotype-phenotype correlations in a larger number of patients and functional studies may give further insights into the complex function of KIF4A.

Keywords: KIF4A; brain anomalies; hydrocephalus; intellectual disability; kinesinopathies; kinesins.

FIGURE 1

KIF4A protein is characterized by a N‐terminal motor domain (aa 9‐336), a coiled coil domain (aa 350‐999), and a C‐terminal globular domain. A C‐terminal region, overlapping the latter two, is responsible for interaction with PRC1 protein. A nuclear localization signal is found between aa 793 and 798 (The UniProt Consortium, 2019). In the lower part of the image, all the missense variants described in this series and by Gowans et al. (2019) are displayed (Gowans et al., 2019). Patient 4 splicing variant from our cohort (c.1674+1G>A) falls in intron 15, within exons coding for the coiled coil domain. The variant published by Willemsen et al. (2014), c.1489‐8_1490delins10, is a splicing variant falling in the intron–exon junction between intron 14 and exon 15, which was predicted to disrupt the acceptor splice site of exon 15, leading to skipping of exon 15 (within the coiled coil domain; Willemsen et al., 2014)

FIGURE 2

Brain prenatal US imaging of patient 1 at 22 wGA, when hydrocephalus internus was apparent. The enlarged ventricles are highlighted by asterisks. The cerebellar size was described as being at the lower end of normal range, corpus callosum was normal (as shown by the Doppler US scan in the lower left corner)

FIGURE 3

Brain CT scan of patient 4 at 6 months of age, from upper to lower panel: (a) Axial image showing hydranencephaly (white asterisk); (b) midsagittal image showing nonvisualized corpus callosum; (c) lower axial image showing relatively intact cerebellum and brainstem (arrowhead)

FIGURE 4

Patient 4 family tree, showing the other likely affected brother and extensive consanguinity in the family

FIGURE 5

Axial, coronal and sagittal T2‐weighted imaging (T2WI) of Patients 5 and 6 brain MRI. (a) Patient 5 brain MRI at 18 years of age showing dilatation of the lateral ventricles, perisylvian polymicrogyria (arrowheads), heterotopia (white arrows), radially‐oriented gyri (black arrows), and hypoplastic pyramidal tracts (asterisks). (b) Patient 6 brain MRI at 12 months of age, showing dilatation of the lateral ventricles, polymicrogyria (arrowheads) and high intensity signals in the deep white matter on T2WI