KDM6B

Gene Facts

• HGNC Symbol: KDM6B (HGNC:29012)
• HGNC Name: lysine demethylase 6B
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: JMJD3
• Alias symbols: KIAA0346
• %HI: 40.32
• pLI: 1
• LOEUF: 0.21
• Cytoband: 17p13.1
• Genomic Coordinates:

  GRCh37/hg19:	chr17:7737535-7758114
  GRCh38/hg38:	chr17:7834217-7854796

• MANE Select Transcript: NM_001348716.2 ENST00000448097.7
• Function: Histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code (PubMed:17825402, PubMed:17851529, PubMed:17713478, PubMed:18003914). Demethylates trimethylated and dimethylated H3 'Lys-27' (PubMed:17825402, PubMed:17851529, PubMed:17713478, PubMed:18003914). Plays a central role in regulation of posterior development, by regulating HOX gene expression (PubMed:17851529). Involved in inflammatory response by participating in macrophage dif... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-16101
• ClinGen Curation ID: CCID:007362
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 11/28/2018

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• complex neurodevelopmental disorder

HI Evidence

• PUBMED: 25363768
  Iossifov et al. (2014) identified four unrelated males with autism spectrum disorder (ASD) who harbored de novo sequence variants in KDM6B. Whole exome sequencing identified a splice-site and frame-shift variant in two unrelated males with autism spectrum disorder. Sample ID: 11329 (Supplementary Table 2) harbored a spice-site variant (Chr17:7749188A>G, c.138-2A>G) while sample ID: 12683 (Supplementary Table 2) harbored a frame-shift variant (Chr17:7749921CG>C, c.575del). Neither of these variants were observed in gnomAD as of November 2018. Of note, sample ID: 12683 was reported previously in Iossifov et al. (2012; PMID: 22542183). Two additional de novo variants were observed in an additional two unrelated males with autism spectrum disorder. Sample ID: 13675 (Supplementary Table 2) harbored a 3 base pair synonymous deletion (17:7755287ACTT>A, c.4185_4187del) while sample ID: 13446 (Supplementary Table 2) harbored a single base pair intron substitution (17:7755659G>C, c.4468+5G>C). Neither of these variants were observed in gnomAD as of November 2018.

• HI Evidence Comments: 25363760: De Rubeis et al. (2015) identified a de novo missense variant in the KDM6B gene (Chr17:7755277G>A, c.4174G>A, E1392K) in an individual with autism spectrum disorder (ASD) through whole exome sequencing (Supplementary Table 3). Within this study cohort no other variants in KDM6B were observed in any of the other 3,870 autism cases or in any of the 9,937 ancestry-matched or parental controls. 27479843: Lelieveld et al. (2016) identified, through whole exome sequencing three unrelated individuals with intellectual disability (ID) who harbored de novo sequence variants in KDM6B. Patient 159 harbored a missense variant (NM_001080424.1:c.32G>A, p.R11H), patient 340 harbored a missense variant (NM_001080424.1:c.4696C>A, p.R1566S), and patient 507 harbored a synonymous variant (NM_001080424.1:c.3825C>A, p.T1275T) (Supplementary Table 3). None of these variants were observed in gnomAD as of November 2018. Of note, of the three de novo variants only one variant (patient 340) was confirmed by Sanger sequencing. 28263302: Yuen et al. (2017) identified an individual (sample AU4427301) with autism spectrum disorder (ASD) who harbored a nonsense variant in the KDM6B gene (NM_001080424:c.343C>T, p.Q115X; Supplementary Table 5). This variant was identified through whole exome sequencing. It's unclear if the variant was de novo or inherited. This variant was not observed in gnomAD as of November 2018. 28097321: Reuter et al. (2017) reported two male sibling probands from a consanguineous relationship that harbored a six base pair deletion in the KDM6B gene (NM_001080424.1:c.1668_1673del, p.Asn557_ Ser558del) (family MR208, Supplementary table 1). These individuals presented with severe intellectual disability, mental deterioration, seizures, sleep disturbances, aggressive behavior, abnormalities of the face, cerebral atrophy, and hypoplasia of the corpus callosum.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity