HNRNPK

Gene Facts

• HGNC Symbol: HNRNPK (HGNC:5044)
• HGNC Name: heterogeneous nuclear ribonucleoprotein K
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: HNRPK
• Alias symbols: CSBP, TUNP
• %HI: 2.97
• pLI: 1
• LOEUF: 0.24
• Cytoband: 9q21.32
• Genomic Coordinates:

  GRCh37/hg19:	chr9:86582998-86595530
  GRCh38/hg38:	chr9:83968083-83980615

• MANE Select Transcript: NM_031263.4 ENST00000376263.8
• Function: One of the major pre-mRNA-binding proteins. Binds tenaciously to poly(C) sequences. Likely to play a role in the nuclear metabolism of hnRNAs, particularly for pre-mRNAs that contain cytidine-rich sequences. Can also bind poly(C) single-stranded DNA. Plays an important role in p53/TP53 response to DNA damage, acting at the level of both transcription activation and repression. When sumoylated, acts as a transcriptional coactivator of p53/TP53, playing a role in p21/CDKN1A and 14-3-3 sigma/SFN in... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-15819
• ClinGen Curation ID: CCID:007291
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 08/23/2023

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome

HI Evidence

• PUBMED: 26173930
  Au et al. (2015) describe two probands with de novo, loss-of-function variants identified through whole exome sequencing (NM_002140.3: c.953+1dup and NM_002140.3: c.257G>A). The probands have developmental delay, a "common facial phenotype, characterized by long palpebral fissures, ptosis, a broad prominent nasal bridge, hypoplastic alae nasi, an open downturned mouth with a cupid’s bow-shaped upper vermilion and full lower lip, ears with underdeveloped and thick helices, and a unique tongue with a prominent median crease." The authors also decribed the probands as having a "connective tissue and skeletal phenotype with features that partially overlap with TGFβ pathway-related disorders such as Loeys–Dietz or Shprintzen–Goldberg syndrome." Western blot studies of fibroblasts from Proband 2 (c.257G>A) demonstrated significantly decreased hnRNPK protein compared to controls (48.5%).
• PUBMED: 26954065
  Lange et al. (2016) describe an additional proband with features overlapping those described in Au et al. 2015, including "intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities." This individual was also found to have a de novo loss-of-function variant, c.931_932insTT, in HNRNPK by whole exome sequencing.
• PUBMED: 29904177
  Au et al. (2018) reported five additional subjects with de novo loss-of-function variants identified from whole exome sequencing (Patients 5-9), and reviewed the cases reported to date. Developmental delay/intellectual disability, distinctive facial features and skeletal findings were common to individuals with this disorder (see publication for additional phenotype). The authors noted the overlap of the disorder with Kabuki syndrome (KS), but stated that the distinct facial gestalt in individuals with HNRNPK variants allowed the disorder to be differentiated from KS.
• PUBMED: 36130591
  Choufani et al. (2022) developed a unique DNA methylation signature for Au-Kline syndrome caused by LoF HNRNPK variants, distinct from controls and Kabuki syndrome. They report seven new individuals with truncating variants in the HNRNPK gene (Table 1 - participants AKS12 and AKS13 with positive methylation signatures; and phenotype only cohort participants N2-N5, and N8). The authors propose additional diagnostic criteria for discriminating Au-Kline syndrome from Kabuki syndrome.

• HI Evidence Comments: Loss of function variants in HNRNPK gene are associated with Au-Kline syndrome (OMIM: 616580), and have been reported in numerous individuals to date (see above). Of note, at least two deletions have been reported in the literature that include this gene; descriptions of the probands overlap with descriptions of the probands with single nucleotide variants in HNRNPK. Pua et al. (2014) (24501764) describe a Mexican female patient with a 2.6 Mb de novo, interstitial deletion of 9q21.32q21.33, including HNRNPK and ~11 other genes. This child had similar dysmorphic features to those reported above, as well as cleft palate, atrial septal defect, hypotonia, congenital hip dysplasia, and other skeletal anomalies. She died at 14 months due to respiratory decompensation. Hancarova et al. (2015) (25348648) describe a 13 year old Czech female with a de novo 2Mb deletion involving 9q21.3 encompassing 7 genes, including HNRNPK. Her features included atrioventricular septal defect, congenital hip dysplasia, severe developmental delay, hypotonia, and dysmorphic features similar to those described above.

Triplosensitivity (TS) Score Details

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