Development of informant-report neurobehavioral survey scales for PTEN hamartoma tumor syndrome and related neurodevelopmental genetic syndromes

Thomas W Frazier; Robyn M Busch; Patricia Klaas; Katherine Lachlan; Shafali Jeste; Alexander Kolevzon; Eva Loth; Jacqueline Harris; Leslie Speer; Tom Pepper; Kristin Anthony; J Michael Graglia; Christal Delagrammatikas; Sandra Bedrosian-Sermone; Jenine Beekhuyzen; Constance Smith-Hicks; Mustafa Sahin; Charis Eng; Antonia Y Hardan; Mirko Uljarević

doi:10.1002/ajmg.a.63195

Development of informant-report neurobehavioral survey scales for PTEN hamartoma tumor syndrome and related neurodevelopmental genetic syndromes

Am J Med Genet A. 2023 Jul;191(7):1741-1757. doi: 10.1002/ajmg.a.63195. Epub 2023 Apr 12.

Authors

Thomas W Frazier^{1

2}, Robyn M Busch^{3

4}, Patricia Klaas³, Katherine Lachlan⁵, Shafali Jeste⁶, Alexander Kolevzon⁷, Eva Loth⁸, Jacqueline Harris⁹, Leslie Speer¹⁰, Tom Pepper¹¹, Kristin Anthony¹², J Michael Graglia¹³, Christal Delagrammatikas¹⁴, Sandra Bedrosian-Sermone¹⁵, Jenine Beekhuyzen¹⁶, Constance Smith-Hicks⁹, Mustafa Sahin¹⁷, Charis Eng⁴, Antonia Y Hardan¹⁸, Mirko Uljarević^{18

19}

Affiliations

¹ Department of Psychology, John Carroll University, University Heights, Ohio, USA.
² Departments of Pediatrics and Psychiatry, SUNY Upstate Medical University, Syracuse, New York, USA.
³ Department of Neurology, Neurological Institute, Clinic Cleveland, Cleveland, Ohio, USA.
⁴ Genomic Medicine Institute, Lerner Research Institute, Clinic Cleveland, Cleveland, Ohio, USA.
⁵ Human Genetics and Genomic Medicine, Faculty of Medicine, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
⁶ Division of Neurology, Children's Hospital of Los Angeles, Los Angeles, California, USA.
⁷ Departments of Psychiatry and Pediatrics, Seaver Autism Center for Research and Treatment Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁸ Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, Psychology and Neuroscience Kings College London, London, UK.
⁹ Krieger Institute and Johns Hopkins University School of Medicine, Department of Neurology Kennedy, Baltimore, Maryland, USA.
¹⁰ Department of Psychology, Frazier Behavioral Health, Cleveland, Ohio, USA.
¹¹ PTEN Research Foundation, Cheltenham, UK.
¹² PTEN Hamartoma Tumor Syndrome Foundation, Huntsville, Alabama, USA.
¹³ SYNGAP Research Fund, Palo Alto, California, USA.
¹⁴ Malan Syndrome Foundation, Old Bridge, New Jersey, USA.
¹⁵ ADNP Kids Foundation, Brush Prairie, Washington, USA.
¹⁶ Adroit Research, Brisbane, Queensland, Australia.
¹⁷ Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹⁸ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA.
¹⁹ Melbourne School of Psychological Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Victoria, Australia.

PMID: 37045800
DOI: 10.1002/ajmg.a.63195

Abstract

There are few well-validated measures that are appropriate for assessing the full range of neurobehavioral presentations in PTEN hamartoma tumor syndrome (PHTS) and other neurodevelopmental genetic syndromes (NDGS). As potential therapeutics are developed, having reliable, valid, free, and easily accessible measures to track a range of neurobehavioral domains will be crucial for future clinical trials. This study focused on the development and initial psychometric evaluation of a set of freely available informant-report survey scales for PHTS-the Neurobehavioral Evaluation Tool (NET). Concept elicitation, quantitative ratings, and cognitive interviewing processes were conducted with stakeholders and clinician-scientist experts, used to identify the most important neurobehavioral domains for this population, and to ensure items were appropriate for the full range of individuals with PHTS. Results of this process identified a PHTS neurobehavioral impact model with 11 domains. The final NET scales assessing these domains were administered to a sample of 384 participants (median completion time = 20.6 min), including 32 people with PHTS, 141 with other NDGS, 47 with idiopathic neurodevelopmental disorder (NDD), and 164 neurotypical controls. Initial psychometric results for the total scores of each scale indicated very good model (ω = 0.83-0.99) and internal consistency reliability (α = 0.82-0.98) as well as excellent test-retest reproducibility at 1-month follow-up (r = 0.78-0.98) and stability at 4-month follow-up (r = 0.76-0.96). Conditional reliability estimates indicated very strong measurement precision in key score ranges for assessing PHTS and other people with NDGS and/or idiopathic NDD. Comparisons across domains between PHTS and the other groups revealed specific patterns of symptoms and functioning, including lower levels of challenging behavior and more developed daily living and executive functioning skills relative to other NDGS. The NET appears to be a reliable and potentially useful tool for clinical characterization and monitoring of neurobehavioral symptoms in PHTS and may also have utility in the assessment of other NDGS and idiopathic NDD. Additional validation work, including convergent and discriminant validity analyses, are needed to replicate and extend these observations.

Keywords: ADNP; Measure; NFIX; Neurobehavioral; PTEN; SYNGAP1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Hamartoma Syndrome, Multiple* / diagnosis
Hamartoma Syndrome, Multiple* / genetics
Hamartoma Syndrome, Multiple* / pathology
Humans
PTEN Phosphohydrolase / genetics
Reproducibility of Results

Substances

PTEN Phosphohydrolase
PTEN protein, human