See Table A. Genes and Databases for chromosome locus and protein.

See Molecular Genetics for information on variants detected in this gene.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including KANSL1) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 17q21.31 region. CMA designs in current clinical use target the 17q21.31 region.

Many affected individuals are identified by a genome-wide CMA screen for deletions/duplications that includes probe coverage of KANSL1. It is too early to ascertain the frequency of the 17q21.31 deletion that contains KANSL1 and a KANSL1 pathogenic sequence variant. Given the fact that the chromosome locus involved is flanked by segmental duplications, predisposing the locus to undergo deletion, it is likely that the recurrent 17q21.31 deletion that includes KANSL1 occurs more frequently than intragenic pathogenic KANSL1 sequence variants [Koolen et al 2006, Koolen et al 2012b, Zollino et al 2012, Zollino et al 2015, Koolen et al 2016].

To date, testing in all unaffected parents from whom the deleted chromosome 17 originated has shown a 900-kb inversion involving chromosome 17q21.31. The frequency of this inversion (also referred to as the H2 lineage) in these parents is significantly greater than the ~20% frequency of the inversion found in the European population as a whole [Stefansson et al 2005] (p<10^-5, Pearson's chi-square test) [Koolen et al 2008]. Testing for the inversion is not routinely indicated (see Molecular Genetics).

Koolen et al [2006], Sharp et al [2006], Shaw-Smith et al [2006]. CMA testing is appropriate to define breakpoints of large deletions; however, intragenic deletions in KANSL1 may not be detected by this method. Note: To date, all KANSL1 intragenic deletions reported have been identified through CMA analysis.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Koolen et al [2012b], Zollino et al [2012], Zollino et al [2015], Koolen et al [2016]

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. KANSL1 gene-targeted deletion/duplication analysis could be considered if CMA and sequence analysis are not diagnostic, as smaller, atypical deletions encompassing part of KANSL1 have been reported [Cooper et al 2011, Dubourg et al 2011, Kitsiou-Tzeli et al 2012, Koolen et al 2012b].

Moreno-Igoa et al [2015]