"Building the Road to a Cure"

Published Studies and Papers

This ultra-rare disorder, caused by variations on the HNRNPH2 gene, was first identified by Drs. Jennifer Bain and Wendy Chung, who published the first paper on the disorder in the American Journal of Human Genetics in September 2016. Since then, there are several other publications found below.


Aug 2023

A Prospective, Longitudinal Study of Caregiver‑Reported Adaptive Skills and Function of Individuals with HNRNPH2‑related Neurodevelopmental Disorder

This study presents a cohort of individuals in a natural history study with de novo pathogenic missense variants in HNRNPH2 causative of HNRNPH2-related neurodevelopmental disorder (NDD) to describe individuals’ adaptive functional abilities.


May 2023

Rett-like Phenotypes in HNRNPH2-Related Neurodevelopmental Disorder


Rett Syndrome (RTT) is a neurodevelopmental disorder with a prevalence of 1:10,000 to 15,000 females worldwide. Classic Rett Syndrome presents in early childhood with a period of developmental regression, loss of purposeful hand skills along with hand stereotypies, gait abnormalities, and loss of acquired speech. Atypical RTT is diagnosed when a child shows some but not all the phenotypes of classic RTT, along with additional supporting criteria. Over 95% of classic RTT cases are attributed to pathogenic variants in Methyl-CpG Binding Protein 2 (MECP2), though additional genes have been implicated in other RTT cases, particularly those with the atypical RTT clinical picture. Other genetic etiologies have emerged with similar clinical characteristics to RTT Syndrome. Our team has characterized HNRNPH2-related neurodevelopmental disorder (HNRNPH2-RNDD) in 33 individuals associated with de novo pathogenic missense variants in the X-linked HNRNPH2 gene, characterized by developmental delay, intellectual disability, seizures, autistic-like features, and motor abnormalities. We sought to further characterize RTT clinical features in this group of individuals by using caregiver report. Twenty-six caregivers completed electronic surveys, with only 3 individuals having previously received an atypical RTT diagnosis, and no individuals with a typical RTT diagnosis. Caregivers reported a high number of behaviors and/or phenotypes consistent with RTT, including the major criteria of the syndrome, such as regression of developmental skills and abnormal gait. Based on the survey results, 12 individuals could meet the diagnostic clinical criteria for atypical RTT Syndrome. In summary, individuals with HNRNPH2-RNDD exhibit clinical characteristics that overlap with those of RTT, and therefore, HNRNPH2-RNDD, should be considered on the differential diagnosis list with this clinical picture.


Sept 2022

HNRNPH2-Related Neurodevelopmental Disorder

In September 2022, Dr Jennifer Bain and Dr Sehajvir Madhok published the first comprehensive gene review of HNRNPH2-Related Neurodevelopmental Disorder which summarizes the clinical characteristics, diagnosis and management of the condition.


March 2022

A murine model of hnRNPH2-related neurodevelopmental disorder recapitulates clinical features of human disease and reveals a mechanism for genetic compensation of HNRNPH2

In March 2022, the team at St Jude Children’s Research Hospital published the findings of their HNRNPH2 research on BioRx. The paper summarizes their work with mouse models of HNRNPH2-Related Disorder and a potential avenue for treatment.


Feb 2022

Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males


Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype-phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.


April 2021

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.


Feb 2021

Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder

Jennifer M. Bain, MD, PhD, Olivia Thornburg, BA, Cheryl Pan, Donnielle Rome-Martin, MS, OTR/L, ATR, Lia Boyle, BA, Xiao Fan, PhD, Orrin Devinsky, MD, Richard Frye, MD, PhD, Silke Hamp, MD, Cynthia G. Keator, MD, Nicole M. LaMarca, DNP, Alexis B.R. Maddocks, MD, Marcos Madruga-Garrido, MD, Karen Y. Niederhoffer, MD, Francesca Novara, PhD, Angela Peron, MD, Elizabeth Poole-Di Salvo, MD, MPH, Rachel Salazar, DPT, Steven A. Skinner, MD, Gabriela Soares, MD, Sylvie Goldman, PhD, and Wendy K. Chung, MD, PhD

To expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals.

Participants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures.

We expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2–38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition.

The spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.

Bain type of X-linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH2.  This study reports on two siblings, one male and one female, born to a consanguineous couple in India.


April 2019

HNRNPH2 Expanded Cohort

Find the full publication at the following link:




Sept 2016

Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females



Subsequent papers have been published as a result of evaluations conducted during the annual family meetings, as part of the critical Natural History Study.




HNRNPH2 Gait Analysis




HNRNPH2 Motor Function Analysis