Mutations in HNRNPU and Childhood Neurocognitive Dysfunction: Whole Exome Sequencing Identifies Two Novel Disease-Associated Variants

Student Researcher:
Alexandra Roston

Supervisor / Principle Investigator:
Dr. Anna Lehman

Additional Authors:
Dr. William T. Gibson
Dr. Harinder K. Gill
Dr. Jill Mwenifumbo
Shelin Adam
Christele Du Souich
Alison Elliott
Clara van Karnebeek
Tanya Nelson
Jan Friedman
CAUSES Research Study

MD Class of 2019


Background: Recently, intellectual disability and/or childhood epileptic encephalopathy have been linked to mutations in HNRNPU, which encodes heterogenous nuclear ribonuclear protein U (hnRNP-U). There are occasional cardiac or renal anomalies. This emerging neurodevelopmental syndrome is not clinically diagnosable without comprehensive genomic testing to identify a mutation and rule out alternative or additional diagnoses. The data describing the spectrum of HNRNPU phenotypes and mutations remains limited to fewer than 30 individuals described thus far in the literature.

Objective: To augment data on phenotypes associated with rare HNRNPU variants.

Design/Method: Case series, ascertained through BC Children’s Hospital’s CAUSES research study. At the time of interim analysis, a cohort of ~200 children had been enrolled and underwent exome sequencing with an aim to identify a genetic diagnosis for a developmental disorder.

Results: Two children with de novo HNRNPU (NM_031844.2 (hg19)) mutations were identified. One child harboured a missense variant (p.His457Pro) and the other a frameshift variant (p.Pro200AlafsTer14). In both children, the phenotype was non-specific, and characterized primarily by developmental disability plus fever-triggered seizures in one, which is a recurrent HNRNPU phenotype. Both children had strabismus, and both had minor renal anomalies (nephrocalcinosis in one and unilateral hypoplasia in the other).

Conclusions: We report two additional individuals with a putative HNRNPU-related disorder. Epilepsy is a frequent but not constant feature of this disorder, being present in 93% of reported individuals. Mutation type (missense versus haploinsufficiency) does not yet appear to correlate with presence or absence of seizures.