A Natural History Study of hnRNP-related Disorders

• ClinicalTrials.gov Identifier: NCT03492060
• Recruitment Status: Recruiting
• First Posted: April 10, 2018
• Last Update Posted: November 14, 2022
• Sponsor: Columbia University
• Collaborators: Simons Foundation; New York University; Hackensack Meridian Health; Universitätsklinikum Hamburg-Eppendorf
• Information provided by (Responsible Party): Jennifer Bain, Columbia University

Study Description

Brief Summary:

The purpose of this study is to analyze patterns in individuals with hnRNP (and other) genetic variants, including their neurological comorbidities, other medical problems and any treatment. The investigators will maintain an ongoing database of medical data that is otherwise being collected for routine medical care. The investigators will also collect data prospectively in the form of questionnaires, neuropsychological assessments, motor assessments, and electroencephalography to examine the landscape of deleterious variants in these genes.

Condition or disease
Neurodevelopmental Disorders; Intellectual Disability; Developmental Delay; Autism Spectrum Disorder; Seizures; Hypertonia, Muscle; Hypotonia

Detailed Description:

Neurodevelopmental disorders are a group of disorders in which the development of the central nervous system is disturbed. The genetic basis for many neurodevelopmental disorders has continued to expand and a recent gene called HNRNPH2 (Heterogeneous Nuclear Ribonucleoprotein H2, encoded by HNRNPH2) is one such gene that is associated with a common neurodevelopmental disorder characterized by developmental delay, intellectual disability, autism and autistic features, and tone abnormalities, among other multisystem problems.

The investigators will expand the genetic cohort to include any individual with a confirmed variant in any gene presenting with neurodevelopmental abnormalities. This is non-interventional study that examines both data previously used in clinical practice and prospective data collection in the form of questionnaires and assessments. The investigators will examine patterns of initial presentation, patterns in neurological evaluations; neurological testing including brain MRI and electroencephalography, and outcomes in individuals with genetic variants.

Genes of Focus:

hnRNPA1 hnRNPA2 hnRNPB1 hnRNPB2 hnRNPC2 hnRNPD hnRNPE1 hnRNPE2 hnRNPE3 hnRNPE4 hnRNPG hnRNPH1 hnRNP H2 hnRNPI hnRNPK hnRNPL hnRNPM hnRNPP hnRNPQ1 hnRNPQ2 hnRNPQ3 hnRNPR hnRNPU

Study Design

• Study Type: Observational [Patient Registry]
• Estimated Enrollment: 1000 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Target Follow-Up Duration: 5 Years
• Official Title: A Natural History Study of hnRNP and Other Gene-related Disorders
• Actual Study Start Date: June 13, 2018
• Estimated Primary Completion Date: April 2024
• Estimated Study Completion Date: April 2024

Groups and Cohorts

Group/Cohort
Variant in a hnRNP gene; Individuals with a variant in any hnRNP gene who present with neurodevelopmental abnormalities are eligible for the study.
Variant in other gene; Individuals with a confirmed variant in other genes who present with neurodevelopmental abnormalities are eligible for the study.

Outcome Measures

Primary Outcome Measures :

1. Medical abnormalities associated with genetic variants [ Time Frame: 5 years ]
   Gene variants are known to result in a variety of clinical phenotypes. The study is intended to accrue data from medical records that document the range of neurological phenotypes and explore their incidence and frequency across genetic cohorts.
2. Education-based impairments associated with genetic variants [ Time Frame: 5 years ]
   The study seeks to collect records from the schools attended by participants; including: Individualized Education Programs (IEPs) and school records. We intend to use these records, in tandem with medical records, to explore meaningful statistical and clinical relationships in the phenotypes expressed by the population of the study.
3. Repetitive Behavior [ Time Frame: 5 years ]
   Correlations (r) between mutant allele (obtained from retrospective data) and repetitive behavior (measured by the Repetitive Behavior Scale - Revised; RBS-R)
4. Sleep Habits [ Time Frame: 5 years ]
   Correlations (r) between mutant allele (obtained from retrospective data) and sleep habits (measured by The Children's Sleep Habits Questionnaire; CSHQ)
5. Sensory Issues [ Time Frame: 5 years ]
   Correlations (r) between mutant allele (obtained from retrospective data) and sensory issues (measured by The Short Sensory Profile; SSP)
6. Social Interaction and Communication SRS-II Score [ Time Frame: 5 years ]
   Correlations (r) between mutant allele (obtained from retrospective data) and social interaction and communication issues (measured by The Social Responsiveness Scale - Second Edition; SRS-II)
7. Anxiety [ Time Frame: 5 years ]
   Correlations (r) between mutant allele (obtained from retrospective data) and anxiety (measured by The Spence Children's Anxiety Scale - Preschool and Parent Reports; SCAS - Preschool and SCAS - P)
8. Receptive Language Skills [ Time Frame: 5 years ]
   Correlations (r) between mutant allele (obtained from retrospective data) and receptive language skills (measured by a 20-item music exposure questionnaire evaluating exposure on a 3-point scale: rarely, sometimes, often; and an EEG with music paradigm)
9. Executive Functioning [ Time Frame: 5 years ]
   Correlations (r) between mutant allele (obtained from retrospective data) and executive functioning (measured by The Behavior Rating Inventory of Executive Function - Parent Report; BRIEF-P)
10. Autism [ Time Frame: 5 years ]
    Correlations (r) between mutant allele (obtained from retrospective data) and autism (measured by The Childhood Autism Rating Scale; CARS)
11. Adaptive Behavior [ Time Frame: 5 years ]
    Correlations (r) between mutant allele (obtained from retrospective data) and adaptive behavior (measured by The Vineland Adaptive Behavior Scales, Third Edition; Vineland - 3)
12. Social Interaction and Communication SCQ Score [ Time Frame: 5 years ]
    Correlations (r) between mutant allele (obtained from retrospective data) and social interaction and communication issues (measured by The Social Communication Questionnaire; SCQ)
13. Emotional Regulation [ Time Frame: 5 years ]
    Correlations (r) between mutant allele (obtained from retrospective data) and emotional regulation (measured by The Behavioral Assessment System for Children - Third Edition; BASC - 3)
14. Motor Performance [ Time Frame: 5 years ]
    Correlations (r) between mutant allele (obtained from retrospective data) and motor performance (measured by The Movement Assessment Battery for Children - Second Edition; MASC-II)
15. Function in Daily Activities, Mobility, Social and Cognitive, and Responsibility [ Time Frame: 5 years ]
    Correlations (r) between mutant allele (obtained from retrospective data) and functional capability in daily activities and mobility (measured by The Pediatric Evaluation of Disability Inventory Computer Adaptive Test; PEDI-CAT)
16. Functional Balance [ Time Frame: 5 years ]
    Correlations (r) between mutant allele (obtained from retrospective data) and functional balance and gross motor function (measured by a 14-item Pediatric Balance Scale)
17. Functional Capability and Mobility [ Time Frame: 5 years ]
    Correlations (r) between mutant allele (obtained from retrospective data) and functional mobility (measured by an 11-point Movement Questionnaire)
18. Coordination and Gait [ Time Frame: 5 years ]
    Correlations (r) between mutant allele (obtained from retrospective data) and gait (measured by a Kinematic Evaluation utilizing Solesound Pedishoe Sandals and GaitRite Walkway)

Biospecimen Retention:   Samples With DNA

Blood and tissue samples will be obtained through one of three ways:

1. The sample can be taken as part of routine clinical care; for example, by a referring physician, and sent to our site for storage.
2. An existing sample you may have provided for research in another study can be transferred to our site for storage.
3. The sample can be taken by the Principal Investigator of this study for research and will be stored at our site.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Individuals who have already undergone genetic testing and carry a variant in any gene. Individuals will often present with neurological abnormalities, although the absence of symptoms is not exclusion criterion for the study. International subjects are welcome to enroll if eligibility criteria is met.

Criteria

Inclusion Criteria:

• Individuals must have had whole genome/exome sequencing and have a confirmed variant in any gene.

Exclusion Criteria:

• Subjects who cannot provide genetic confirmation of a predicted deleterious variant in any gene.

Contacts and Locations

Contacts

Contact: Jennifer M. Bain, MD, PhD; 646-426-3876; jb3634@cumc.columbia.edu

Contact: Joanna Feng; jlf2218@cumc.columbia.edu

Locations

United States, New York

Columbia University Irving Medical Center; Recruiting

New York, New York, United States, 10032

Contact: Study Team hnrnp@columbia.edu

Contact: Joanna Feng jlf2218@cumc.columbia.edu

Sub-Investigator: Wendy K. Chung, MD, PhD

Sponsors and Collaborators

Columbia University

Simons Foundation

New York University

Hackensack Meridian Health

Universitätsklinikum Hamburg-Eppendorf

Investigators

• Principal Investigator: Jennifer M. Bain, MD, PhD; Columbia University

More Information

Additional Information:

Original HNRNPH2 genetic cohort website 

Publications of Results:

Bain JM, Thornburg O, Pan C, Rome-Martin D, Boyle L, Fan X, Devinsky O, Frye R, Hamp S, Keator CG, LaMarca NM, Maddocks ABR, Madruga-Garrido M, Niederhoffer KY, Novara F, Peron A, Poole-Di Salvo E, Salazar R, Skinner SA, Soares G, Goldman S, Chung WK. Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder. Neurol Genet. 2021 Jan 29;7(1):e551. doi: 10.1212/NXG.0000000000000551. eCollection 2021 Feb.

Other Publications:

Bain JM, Cho MT, Telegrafi A, Wilson A, Brooks S, Botti C, Gowans G, Autullo LA, Krishnamurthy V, Willing MC, Toler TL, Ben-Zev B, Elpeleg O, Shen Y, Retterer K, Monaghan KG, Chung WK. Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females. Am J Hum Genet. 2016 Sep 1;99(3):728-734. doi: 10.1016/j.ajhg.2016.06.028. Epub 2016 Aug 18.

• Responsible Party: Jennifer Bain, Assistant Professor of Neurology, Columbia University
• ClinicalTrials.gov Identifier: NCT03492060
• Other Study ID Numbers: AAAR7203
• First Posted: April 10, 2018
• Last Update Posted: November 14, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data will be shared with the Simons Foundation. This is applicable only to participants dually enrolled in both studies (as stipulated in the consent process). Individual data for all primary and secondary outcome measures will be made available. Subject data will also be shared with affiliated institutions for relevant genotypes, as outlined in the consent process.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Data will be available per request as it is accrued throughout the course of the study.
• Access Criteria: Data access requests will be reviewed by the PI and study team. Requestors will be required to sign a data access agreement.
• URL: https://simonsfoundation.org

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jennifer Bain, Columbia University:

Gene Variant; HNRNPA1; HNRNPA2; HNRNPB1; HNRNPC1; HNRNPC2; HNRNPD; HNRNPE1; HNRNPE2; HNRNPE3; HNRNPE4; HNRNPG; HNRNPH1; HNRNPH2; HNRNPI; HNRNPK; HNRNPL; HNRNPM; HNRNPP; HNRNPQ1; HNRNPQ2; HNRNPQ3; HNRNPR; HNRNPU

Additional relevant MeSH terms:

Seizures; Intellectual Disability; Muscle Hypertonia; Muscle Hypotonia; Disease; Autism Spectrum Disorder; Neurodevelopmental Disorders; Pathologic Processes; Neurologic Manifestations; Nervous System Diseases; Child Development Disorders, Pervasive; Mental Disorders; Neurobehavioral Manifestations; Neuromuscular Manifestations