GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK

Abstract

We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual disability, a shared unique craniofacial phenotype, and connective tissue and skeletal abnormalities. The identification of this syndrome was made possible by a new online tool, GeneMatcher, which facilitates connections between clinicians and researchers based on shared interest in candidate genes. This report demonstrates that new Web-based approaches can be effective in helping investigators solve exome sequencing projects, and also highlights the newer paradigm of "reverse phenotyping," where characterization of syndromic features follows the identification of genetic variants.

Keywords: GeneMatcher; HNRNPK; WES; matchmaker exchange; reverse phenotyping.

Figure 1. Clinical features of probands with HNRNPK loss of function variants

Proband 1 (A-G) and Proband 2 (H-K). A) Proband 1 at 13 years. B) Hands of proband 1, with fifth finger clinodactyly, prominent joints and shorter distal phalanges. C) High palate and bifid uvula in proband 1. D) T2 coronal MRI of proband 1 at age 12, demonstrating multiple vertebral segmentation defects and thoracolumbar scoliosis. H) Proband 2 at 11 years. E and I) Bifid tongues with prominent midline groove in proband 2 (I), and prominent midline groove of tongue in proband 1 (E). F and G) Proband 1 at ages 14 months and 8 years. J and K) Proband 2 at 1 year and 8 years. L) Individual described by Hancarova et al. (2015) at age 6 years. M) Representative western blot demonstrating reduced hn RNPK protein expression in proband 2 fibroblasts (P2) versus control fibroblasts (C1-3). N) Comparison of mean hn RNPK protein expression levels determined from 3 independent western blots, p = 0.008426. Republished with permission.