Clinical significance of copy number variants involving KANK1 in patients with neurodevelopmental disorders.

Copy number variants (CNV)s involving KANK1 are generally classified as variants of unknown significance. Several clinical case reports suggest that the loss of KANK1 on chromosome 9p24.3 has potential impact on neurodevelopment. These case studies are inconsistent in terms of patient phenotype and suspected pattern of inheritance. Further complexities arise because these published reports utilize a variety of genetic testing platforms with varying resolution of the 9p region; this ultimately causes uncertainty about the impacted genomic coordinates and gene transcripts. Beyond these case reports, large case-control studies and publicly available databases statistically cast doubt as to whether variants of KANK1 are clinically significant. However, these large data sources are neither easily extracted nor uniformly applied to clinical interpretation. In this report we provide an updated analysis of the data on this locus and its potential clinical relevance. This is based on a review of the literature as well as 28 patients who harbor a single copy number variant involving KANK1 with or without DOCK8 (27 of whom are not published previously) identified by our clinical laboratory using an ultra-high resolution chromosomal microarray analysis. We note that 13 of 16 patients have a documented diagnosis of autism spectrum disorder (ASD) while only two, with documented perinatal complications, have a documented diagnosis of cerebral palsy (CP). A careful review of the CNVs suggests a transcript-specific effect. After evaluation of our case series and reconsideration of the literature, we propose that KANK1 aberrations do not frequently cause CP but cannot exclude that they represent a risk factor for ASD, especially when the coding region of the shorter, alternate KANK1 transcript (termed "transcript 4" in the UCSC Genome Browser) is impacted.

Familial KANK1 deletion that does not follow expected imprinting pattern.

Deletion of the KANK1 gene (also called ANKRD15), located at chromosome position 9p24.3, has been associated with neurodevelopmental disease including congenital cerebral palsy, hypotonia, quadriplegia, and intellectual disability in a four-generation family. The inheritance pattern in this family was suggested to be maternal imprinting, as all affected individuals inherited the deletion from their fathers and monoallelic protein expression was observed. We present a family in which the proband's phenotype, including autism spectrum disorder, motor delay, and intellectual disability, is consistent with this previous report of KANK1 deletions. However, a paternally inherited deletion in the proband's unaffected sibling did not support maternal imprinting. This family raises consideration of further complexity of the KANK1 locus, including variable expressivity, incomplete penetrance, and the additive effects of additional genomic variants or the potential benign nature of inherited copy number variations (CNVs). However, when considered with the previous publication, our case also suggests that KANK1 may be subject to random monoallelic expression as a possible mode of inheritance. It is also important to consider that KANK1 has two alternately spliced transcripts, A and B. These have differential tissue expression and thus potentially differential clinical significance. Based upon cases in the literature, the present case, and information in the Database of Genomic Variants, it is possible that only aberrations of variant A contribute to neurodevelopmental disease. The familial deletion in this present case does not support maternal imprinting as an inheritance pattern. We suggest that other inheritance patterns and caveats should be considered when evaluating KANK1 deletions, which may become increasingly recognized through whole genome microarray testing, whole genome sequencing, and whole exome sequencing techniques.