HNRNPK

Inheritance Pattern: AD

Disease ID:MONDO:0014700

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014700

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0018681

Submitter: ClinGen

*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).

Inheritance Pattern: AD

Disease ID:MONDO:0014700

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014700

Submitter: Illumina

The HNRNPK gene is located on chromosome 9 at 9q21.32 and encodes the heterogeneous nuclear ribonucleoprotein K protein, which is one of the major pre-mRNA-binding proteins. HNRNPK was first reported in association with Au Kline syndrome in 2015 (26173930: Au et al. 2015). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least eight de novo heterozygous variants have been reported in the literature, including fives loss-of-function variants, two missense variants, and one intron variant predicted to result in an inframe insertion, in six publications (26173930: Au et al. 2015; 26954065: Lange et al. 2016; 28771707: Miyake et al. 2017; 28374925: Dentici et al. 2017; 29904177: Au et al. 2018; 32588992: Yamada et al. 2020). The mechanism for disease is loss-of-function. The hnRNP K protein was shown to be expressed in rat hippocampal neuron and colocalized with VGLUT1 (a presynaptic protein) and PSD-95 (a postsynaptic scaffolding protein), and in mouse leukemic monocyte macrophage RAW264.7 cells, a significant increase in GSK3β-hnRNPK interaction was observed (24990929: Folci et al. 2014; 26638989: Fan et al. 2015). In summary, there is strong evidence to support the relationship between HNRNPK and Au Kline syndrome (autosomal dominant).

Inheritance Pattern: AD

Disease ID:MONDO:0014700

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014700

Submitter: Orphanet