The HNRNP gene family encodes for over 30 distinct heterogeneous nuclear ribonucleoproteins [1]. These RNA-binding proteins perform many functions related to RNA processing, including regulation of alternative splicing (AS), mRNA transport, and mRNA degradation. Many hnRNPs have been shown to be critical for and highly expressed during development [2]. Beyond development, hnRNPs play a role in synaptic plasticity, as neurons are postmitotic cells and are dependent on spatiotemporal changes in RNA expression for growth and function. The hnRNPs work independently, cooperatively, and compensatorily [3].

The hnRNPs have long been a focus for research in neurodegenerative disorders, particularly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, as well as myopathies and cancer 1, 4. Within the last decade, neurodevelopmental disorders (NDDs) have been associated with HNRNP genes 2••, 5•, 6•, 7•, 8•, 9•, 10•, 11•, 12•, 13•, 14•. To date, HNRNPC, RBMX (also referred to as HNRNPG), HNRNPH1, HNRNPH2, HNRNPK SYNCRIP (also referred to as HNRNPQ), HNRNPR, and HNRNPU have been independently associated with NDDs by multiple groups; thus, we categorize them as ‘established HNRNP-related neurodevelopmental disorders’ (RNDDs) 2••, 5•, 10•, 14•, 15•, 16•. Of these, HNRNPC-RNDD and Gustavson syndrome (an RBMX-RNDD) were the most recently published 5•, 14•. HNRNPD, HNRNPUL1, and HNRNPUL2 are strong candidate NDD genes that have sufficient evidence to be considered HNRNP-RNDDs and have ongoing characterization (personal communication), so they are considered ‘strong candidate HNRNP-RNDDs’ [2]. HNRNP-RNDDs throughout this review will refer to all 11 established and strong candidate HNRNP-RNDDs. Other HNRNP genes are emerging candidates for NDDs under investigation [2]. Here, we aim to review the clinical features of affected individuals and molecular mechanisms of the HNRNP-RNDDs.