KANSL1 was first reported in relation to autosomal dominant Koolen-de Vries syndrome (KdVS) in 2012 (Kooken et al. and Zollino et al., PMIDs: 22544363, 22544367). Prior to its association with KdVS, KANSL1 was known to be one of the protein-coding genes deleted in patients with 17q21.31 deletion syndrome (PMIDs: 16906163, 16906164). KdVS is caused by pathogenic sequence variants in KANSL1 or by 17q21.31 microdeletions encompassing KANSL1 (PMIDs: 22544363, 22544367). KdVS is characterized by intellectual disability and/or developmental delay, hypotonia, speech and language delay, dysmorphic features, and behavioral disorders including autism and attention deficit hyperactivity disorder (PMIDs: 22544363, 22544367, 26306646). Truncating variants, including nonsense, frameshift, and splice site variants, have been identified in over 20 individuals with KdVS reported in 6 publications (PMIDs: 22544363, 22544367, 26306646, 30293248, 33361104, 33393407). The disease mechanism is haploinsufficiency. This gene-disease relationship is also supported by experimental evidence, including non-human model organisms, and functional in vitro studies (PMID: 28704368).
In summary, KANSL1 is definitively associated with Koolen-de Vries syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 18, 2022 (SOP Version 8).
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