ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
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 TGF? 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%).
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.

Haploinsufficiency phenotype comments:

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