A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia

Abstract

Kabuki syndrome is a heterogeneous condition characterized by distinctive facial features, intellectual disability, growth retardation, skeletal abnormalities and a range of organ malformations. Although at least two major causative genes have been identified, these do not explain all cases. Here we describe a patient with a complex Kabuki-like syndrome that included nodular heterotopia, in whom testing for several single-gene disorders had proved negative. Exome sequencing uncovered a de novo c.931_932insTT variant in HNRNPK (heterogeneous nuclear ribonucleoprotein K). Although this variant was identified in March 2012, its clinical relevance could only be confirmed following the August 2015 publication of two cases with HNRNPK mutations and an overlapping phenotype that included intellectual disability, distinctive facial dysmorphism and skeletal/connective tissue abnormalities. Whilst we had attempted (unsuccessfully) to identify additional cases through existing collaborators, the two published cases were 'matched' using GeneMatcher, a web-based tool for connecting researchers and clinicians working on identical genes. Our report therefore exemplifies the importance of such online tools in clinical genetics research and the benefits of periodically reviewing cases with variants of unproven significance. Our study also suggests that loss of function variants in HNRNPK should be considered as a molecular basis for patients with Kabuki-like syndrome.

Keywords: HNRNPK; Kabuki; exome; heterotopia.

Figure 1

(a, b) Proband at ages 7 months and 8 years, respectively. Note the prominent metopic ridge, turricephaly, sparseness of lateral eyebrows with medial flare, long palpebral fissures, eversion of lower eyelids, low‐set prominent ears. (c) Thick, wrinkled skin on the neck posteriorly. (d, e) Deep plantar and palmar creases with fetal finger pads. (f) Coronal MRI image from inversion recovery volume sequence demonstrating two grey matter rounded nodules (blue arrows) adjacent to the borders of the lateral ventricles, in keeping with periventricular heterotopia. Written consent from the family to publish these images was obtained.

Figure 2

(a) Gene structure with position of variants in relation to known functional domains. (b) Sanger sequencing electropherogram showing validation results for the c.931_932insTT variant alongside the predicted effect at the amino‐acid level. Sequencing was also performed in the non‐coding direction (data not shown).

Figure 3

Timeline of significant events leading to the mutation being reported back to the family.