ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.