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Clinical Genome Sequencing in the Neurodevelopmental Clinic: A Single Center Experience

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
A growing number of genes are associated with neurodevelopmental disorders and highlight the overlapping genetic architecture of autism spectrum disorder (ASD) and intellectual disability (ID). Children with ASD are often identified first by psychologists or neurologists and the extent of genetic testing or genetics referral is variable. Applying clinical whole genome sequencing (cWGS) has the potential to circumvent the diagnostic odyssey through timely molecular diagnosis. Here we report the findings of a prospective study of the diagnostic efficacy and utility of cWGS in a clinical ASD cohort.

Methods:
Children with ASD and moderate cognitive delays or ID were referred by neurologists or psychologists at a regional healthcare organization. 15 children had prior non-diagnostic genetic testing (e.g. chromosomal microarray, FMR1 testing, or targeted panel) but none had prior whole exome sequencing.  Probands were classified as 1) essential ASD/ID or 2) complex ASD (defined as 1 or more major malformations, abnormal head circumference, or dysmorphic features). cWGS was performed at Rady Children's Institute for Genomic Medicine using previously described methods. cWGS was analyzed as either parent-child trio (simplex families; n= 27) or parent-child-affected sibling (multiplex families; n=3). Variants were classified according to ACMG guidelines. Pathogenic and/or likely pathogenic variants associated with ASD/ID were considered definitive molecular diagnoses and the diagnostic rate was calculated. Changes in management informed by cWGS results were assessed by structured clinician survey.   

Results:
33 children (9 females) received cWGS at a median age of 4 yrs (range 2-7 yrs). 11 children (33%) were classified as complex ASD. The overall diagnostic rate was 30% (n=10). Higher diagnostic rates were observed in complex ASD (63%, n=7) and in females (67%,n=6), Fisher’s exact test two-tailed p=0.0059 and p=0.01 respectively. Molecular diagnoses included de novo coding single nucleotide variants (SNV, n=7) in frequently associated ASD/ID genes (PTEN, MECP2, DDX3X) and more rare ASD/ID genes (MED12, PUM1, FBXW7), de novo copy number variants (CNV, n=1, proximal 16p11.2 duplication), rare inherited SNV (n=1, HIVEP2) and rare inherited CNV (n=1, maternal 15q duplication, interstitial).  Two unrelated multiplex families had children with ASD with discordant cognitive impairment.  De novo variants were identified in the proband with cognitive impairment (DDX3X, n=1; FBXW7, n=1). Sanger sequencing confirmed these variants were absent in the comparator sibling with ASD without cognitive impairment. Definitive diagnoses resulted in one or more changes in management in 50% (5/10) including eligibility for targeted therapy (n=1), tumor surveillance (n=1), specialist referral (n=3). Four children (12%) had additional clinically significant findings unrelated to ASD.

Conclusion:
Genome sequencing is effective to identify both common and more rare genomic disorders in young children with ASD and cognitive delays. cWGS could be considered as a first-line genetic testing, particularly in children with complex phenotypes.  This study adds to the growing literature supporting genome-wide sequencing in children with neurodevelopmental disorders.

 

 

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