ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000018.9) (NC_000018.10)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
22495311 Neale et al (2012) completed exome sequencing of 175 autism trios and identified de novo variants. One candidate gene identified was KATNAL2. They evaluated strong candidates further using exome sequencing on 935 cases and 870 controls, and at KATNAL2, three additional loss-of-function mutations were observed in cases with none in controls. However, using data from more than 5,000 individuals in the NHLBI Exome Variant Server ( as additional controls, three loss-of-function mutations were seen in KATNAL2. Nonetheless, the authors suggest that results from de novo events and a large parallel case?control study provide strong evidence in favour of KATNAL2 as genuine autism risk factor, acknowledging that additional variants may be required to express the phenotype.
22495309 O'Roak et al (2012) completed exome sequencing Simons Simplex Collection trios (189 new trios and 20 that were previously reported). Additionally, they also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. They detected one de novo splice mutation in KATNAL2 in this cohort.
28191889 Stessman et al (2017) sequenced 208 candidate genes from >11,730 cases from the Autism Genetic Resource Exchange (AGRE) and >2,867 controls. They identified a de novo loss-of-function variant and a likely damaging de novo missense variant in KATNAL2.

Haploinsufficiency phenotype comments:

Neurodevelopmental delay, including autism spectrum disorder, schizophrenia Two groups (Sanders et al (2012) and O`Roak et al (2012)) performed whole exome sequencing of Simons Simplex Collection (SSC) cases of well-phenotyped individuals with autism spectrum disorder. From a total of 414 non-overlapping probands, two de novo potentially-disruptive splice-site variants were detected at KATNAL2. These results were replicated in additional analyses of the SSC cohort (Iossifov et al ,2015, PMID: 25363768). Additional, de novo potentially-disruptive variants have been detected to be enriched in cases by Stessman et al (2017) and Neale et al (2012) in independent cohorts, though Neale et al also detected three loss-of-function mutations at KATNAL2 from more than 5,000 control individuals in the NHLBI Exome Variant Server ( Yuen et al (2015) completed whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD. They identified one maternally-inherited, nonsense mutation in KATNAL2 that was present in one of two siblings with ASD (PMID:25621899). Likely disruptive variants in KATNAL2 appear to be associated with risk for autism spectrum disorder, however variable penetrance/expressivity may occur as evidenced by the presence of loss-of-function variants in controls and unaffected/sub-clinically affected relatives.

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