Abstract Details

Title A Expanded Cohort Study of the X-linked HNRNPH2-related Neurodevelopmental Disorder

Topic Child Neurology and Developmental Neurology

Presentation(s) P1 - Poster Session 1 (5:30 PM-6:30 PM)

Poster/Presentation
Number 7-039

Objective To expand the neurobehavioral phenotype in individuals with a pathogenic variant in the X-linked hnRNPH2 gene.

Background X linked genes are a frequent cause of neurodevelopmental disorders. One X linked gene, HNRNPH2, encodes the hnRNPH2 protein, a member of the heterogeneous ribonucleoprotein family and was associated in 6 unrelated females to developmental delay, intellectual disability, autism, hypotonia, and seizures.

Design/Methods Our expanded cohort includes twenty-five females and three males with de novo predicted pathogenic variants. There are nine missense mutations in HNRNPH2 identified via whole genome/whole exome sequencing. Medical history was provided by the primary caregiver, medical records, and genetic reports and parent-reported questionnaires were completed, submitted online, and combined in a REDCap database. The testing battery included the Vineland Adaptive Behavior Scale, Behavioral Assessment for Children, Social Responsiveness Scale-II, Social Communication Questionnaire, Repetitive Behavior Scale, Spence Children's Anxiety Scale and Short Sensory Profile.

Results Nine distinct variants were identified a single recurrent missense variant (p. R206W; N=19) accounting for the majority of mutations with other mutations largely located in the same protein domain (p.Y210C (N=2), p. R206Q (N=1); p. P209L (N=1), p.R206G (N=1), p. R212T (N=1), and p. D340V (N=1)). Participants ranged from ages 3 to 37 years and were reported to have global developmental delays, dysmorphic features and other neurologic abnormalities, including unsteady gait and mixed tone. Seizures were less often diagnosed than initially reported. A neurobehavioral battery demonstrated social communication difficulties, restricted and repetitive behaviors, anxiety, and sensory processing issues in nearly all individuals, regardless of genotype.

Conclusions

hnRNPH2 is associated with a common neurodevelopmental disorder. Here we present an expanded cohort, including the description of 3 boys. hnRNPH2 is an important single gene disorder to study neurodevelopment. It is important to defined the natural history of this X-linked neurodevelopmental disorder for earlier diagnosis and future therapeutic interventions.

Authors/Disclosures
Jennifer Bain, MD, PhD (Columbia Doctors) PRESENTER	Dr. Bain has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint Consulting. Dr. Bain has received personal compensation in the range of $0-$499 for serving as a Consultant for M3 Consulting. Dr. Bain has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Legal Company . Dr. Bain has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Grin Therapeutics. The institution of Dr. Bain has received research support from Yellow Brick Road Project.
Olivia Thornburg	Olivia Thornburg has nothing to disclose.
Rachel Salazar, PT (Columbia University)	No disclosure on file
Nicole LaMarca	Ms. LaMarca has received personal compensation for serving as an employee of Novartis Gene Therapies.
Wendy Chung, MD, PhD (Boston Children's Hospital)	Wendy Chung, MD, PhD has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Prime Medicine. The institution of Wendy Chung, MD, PhD has received research support from GeneDx. The institution of Wendy Chung, MD, PhD has received research support from Illumina.

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