2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Clinical genome sequencing and targeted mouse modeling in nonverbal or minimally verbal individuals with autism spectrum disorders and neurodevelopmental delays

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Researchers conducted clinical genome sequencing on a cohort of nonverbal or minimally verbal individuals with autism spectrum disorders (ASDs) or neurodevelopmental delays (NDDs). The study aimed to identify the underlying genetic causes in these individuals who often face challenges accessing genetic testing due to insurance denials. The results of the sequencing were returned to the families, and certain variants of uncertain significance (VUSs) were selected for targeted mouse modeling to determine their pathogenicity and facilitate the development of future therapeutic options. <br /><br />The cohort consisted of 85 individuals, ranging in age from 2 to 34 years old, with a majority being Hispanic or White Caucasian. Among them, a definitive pathogenic variant was identified in 22 individuals. Mouse models were developed for five of these variants. One significant finding was the identification of DPH5 as a novel NDD gene. Additionally, two individuals with ASD were found to have pathogenic variants in the WDR45 gene, which causes a disorder characterized by brain iron accumulation. The researchers are using a targeted knock-in mouse model of WDR45 to test potential therapeutic options. <br /><br />The study also highlighted several other genetic variants associated with various neurodevelopmental disorders, including Allan-Herndon-Dudley Syndrome and KBG syndrome. The researchers utilized a rapid mouse modeling approach to compare the phenotypes of variant mouse models with control mice. Various behavioral, physiological, metabolic, sensory, and morphological abnormalities were assessed. <br /><br />Overall, clinical genome sequencing proved useful in identifying the genetic etiology of individuals with NDDs, who often undergo lengthy diagnostic journeys. This approach enables more precise healthcare and prognosis assessment, as well as genetic counseling. It also provides opportunities for targeted therapeutics and participation in clinical trials. While many individuals had variants of unknown significance, targeted rapid mouse modeling holds promise for discovering new genes and developing potential treatments. The study was supported by grants from the Children's Miracle Network and the MIND Institute Intellectual and Developmental Disabilities Research Center Pilot.

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Presenting Author - Suma P. Shankar, MD,PhD; Co-Author - Kristin Grimsrud, DVM, PhD; Co-Author - Prabhu Shankar, MD, MS; Co-Author - Van Ma, MD; Co-Author - Ellen Osborne, BS; Co-Author - Leigh Ann Higa, Phd, MS; Co-Author - Ishaan Iyer, BS; Co-Author - Kent Lloyd, DVM, PhD; Co-Author - Katherine Rauen, MD, PhD;

Meta Tag

Cognitive Disorders

Genetic Testing

Genome sequencing

Genotype-Phenotype Correlations

Identification of Disease Genes

Co-Author Kristin Grimsrud, DVM, PhD

Co-Author Prabhu Shankar, MD, MS

Co-Author Van Ma, MD

Co-Author Ellen Osborne, BS

Co-Author Leigh Ann Higa, Phd, MS

Co-Author Ishaan Iyer, BS

Co-Author Kent Lloyd, DVM, PhD

Co-Author Katherine Rauen, MD, PhD

Presenting Author Suma P. Shankar, MD,PhD

Keywords

clinical genome sequencing

nonverbal individuals

autism spectrum disorders

genetic causes

variants of uncertain significance

targeted mouse modeling

DPH5

WDR45 gene

neurodevelopmental disorders

rapid mouse modeling