HNRNPK was first reported in relation to autosomal dominant neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome (Au-Kline syndrome) in 2015 (Au et al., PMID: 26173930). Au-Kline syndrome (AKS) is caused by de novo variants in HNRNPK, leading to variable dysmorphic features, cardiac malformations, developmental delay, and intellectual disability. Multiple patients diagnosed with AKS were initially diagnosed with Kabuki syndrome.
Ten variants (all de novo loss of function caused by missense, nonsense, frameshift, and splice variants) that have been reported in 10 probands in 5 publications (PMIDs: 26173930, 26954065, 28374925, 28771707, 29904177) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss of function.
This gene-disease relationship is also supported by the biochemical function of HNRNPK in osteoclast differentiation as the phenotype involves skeletal abnormalities, including craniosynostosis (PMID: 26638989).
In summary, there is definitive evidence to support the relationship between HNRNPK and autosomal dominant Au-Kline syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the General Gene Curation Expert Panel in 2016. It was reevaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 21, 2021. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of new literature (SOP Version 8).
HNRNPK was first reported in relation to autosomal dominant neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome (Au-Kline syndrome) in 2015 (Au et al., PMID: 26173930). Au-Kline syndrome (AKS) is caused by de novo variants in HNRNPK, leading to variable dysmorphic features, cardiac malformations, developmental delay, and intellectual disability. Multiple patients diagnosed with AKS were initially diagnosed with Kabuki syndrome. Ten variants (all de novo loss of function caused by missense, nonsense, frameshift, and splice variants) that have been reported in 10 probands in 5 publications (PMIDs: 26173930, 26954065, 28374925, 28771707, 29904177) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss of function.
This gene-disease relationship is also supported by the biochemical function of HNRNPK in osteoclast differentiation as the phenotype involves skeletal abnormalities, including craniosynostosis (PMID: 26638989).
In summary, there is definitive evidence to support the relationship between HNRNPK and autosomal dominant Au-Kline syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the General Gene Curation Expert Panel GCEP in 2016. It was reevaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 20, 2021. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of new literature (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.