• Haploinsufficiency score: 3
• Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
• Haploinsufficiency Phenotype: KOOLEN-DE VRIES SYNDROME; KDVS

Evidence for haploinsufficiency phenotype

PubMed ID	Description
22544363	Koolen et al. (2012) identified one nonsense and one splice-site mutation in KANSL1 in two unrelated individuals with features of the 17q21.31 microdeletion syndrome. The splice-site mutation resulted in skipping of exon 6, causing a frameshift and premature termination of the KANSL1 mRNA. Both changes occurred de novo. Separately, the group performed whole-transcriptome (mRNA) sequencing on EBV transformed cell lines from 3 individuals with the classical 17q21.31 deletion and two of their unaffected parents: expression levels of KANSL1 were reduced by half in the individuals with the deletion.
22544367	Zollino et al. (2012) report two additional unrelated Italian individuals with features of the 17q21.31 microdeletion syndrome and heterozygous mutations in KANSL1: one nonsense mutation and one frameshift mutation that introduces a premature stop codon in exon 13. Both mutations were de novo; neither mutation was reported in the 1000 Genome Projects, in dbSNP, or amongst 400 control individuals of Italian origin.

Haploinsufficiency phenotype comments:

From OMIM: Koolen-De Vries syndrome (also known as 17q21.31 microdeletion syndrome) is characterized by moderate to severe intellectual disability, hypotonia, friendly demeanor, and highly distinctive facial features, including tall, broad forehead, long face, upslanting palpebral fissures, epicanthal folds, tubular nose with bulbous nasal tip, and large ears. More variable features include cardiac or genitourinary anomalies and seizures.

• Triplosensitivity score: 0
• Strength of Evidence (disclaimer): No evidence for dosage pathogenicity