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

Abstract

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.

Genome-Wide Association Study (GWAS) on Bilirubin Concentrations in Subjects with Metabolic Syndrome: Sex-Specific GWAS Analysis and Gene-Diet Interactions in a Mediterranean Population

“…The possible link between this disease and bilirubin concentrations is unknown. However, for the other gene, KANK1, there may be a stronger relationship, given that deletions in this gene have been associated with cerebral palsy and alterations in neurodevelopment [74] and it is known that, in the case of extreme hyperbilirubinemia in the newborn neurological sequelae can occur, including the Kernicterus Spectrum Disorders [30,75]. However, our data on this level of statistical significance only provide suggestive results for later replication.…”

Unbalanced segregation of a paternal t(9;11)(p24.3;p15.4) translocation causing familial Beckwith-Wiedemann syndrome: a case report

“…Since the DMRT genes in cis are deleted in our patients, they do not present with CPSQ2. Both gains and losses of KANK1 have been associated with childhood seizures and developmental delay [26] which are seen in our two patients but are not typical for BWS. Haploinsufficiency of doublesex- and mab3-related transcription factors ( DMRT ) in 9p24.3 has been associated with failure of testicular development and XY sex reversal [27, 28].…”

Impact of extracellular matrix stiffness on genomic heterogeneity in MYCN-amplified neuroblastoma cell line

“…Interestingly, some genes of the new SCAs undergoing positive selection in VN-KO tumors and stiff and/or long-cultured hydrogels are involved in ECM composition and architecture, mechanotransduction and cell migration. In chromosome 1 there is special focus on the collagen gene COL11A1 (in the nearer centrometic fragment of 1p-), the genes related to actin ARPC5 and ACTN2 , some laminins and the integrin α10 (in +1q), while the deleted FSCA of chromosome 9p contains the genes KANK1 and DOCK8, both involved in actin polymerization [ 58 – 60 ]. In our customized NB-mechanopanel, COL11A1 and DOCK8 genes specifically showed certain gene variants that had disappeared in the tumors from VN-KO mice with the mentioned heterozygous deletions.…”