Diagnostic Yield of Autism Spectrum Disorder Patients from Hong Kong Using Genome Sequencing with Extensive Comorbidity Characterizations
Laboratory Genetics and Genomics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
One out of 36 children is affected by autism spectrum disorder (ASD) according to recent CDC estimates. Fragile X repeat expansion, karyotyping, and chromosomal microarray analysis (CMA) testing are commonly used to diagnose the genetic etiology of ASD, with a combined diagnostic yield of about 10-15%. Since 2018, diagnostic genome sequencing (GS) has been available in Hong Kong’s private clinical setting. GS provides significantly higher diagnostic yield compared to conventional testing, especially in ASD patients with comorbidities such as language deficit, intellectual disabilities, or seizures.
In this study, GS testing was used for 106 pediatric patients of East Asian descent. Of these, 59 patients were affected by ASD with at least one comorbidity, 11 ASD patients were without comorbidity, and 36 patients were found to have abnormal behavior coupled with neurological signs. Here we report the mutational spectrum of pathogenic (P) and likely pathogenic (LP) variants, and variants of uncertain significance (VUS) with pathogenic evidence that are a priority for periodic review and reclassification. A significant number of these were LP variants, not previously reported in international databases such as ClinVar.
Methods:
106 affected children were tested with diagnostic GS. The ASD and comorbidity assessment was performed by developmental pediatricians, neurologists, or physicians specialized in pediatric genetics. GS at 40-80x sequencing depth was conducted at a U.S. CAP-accredited and CLIA-certified clinical laboratory. Copy number variants (CNVs) detected were confirmed with CMA testing, performed at the Victorian Clinical Genetics Services (A subsidiary of the Murdoch Children's Research Institute, Australia). Clinical interpretation was provided by Rainbow Genomics following current ACMG guidelines, and reports were issued by a board-certified medical director.
Results:
Copy number, mosaic and intronic variants in addition to single nucleotide variants were detected. The concordance of detected CNVs between GS and CMA testing was 100%.
The diagnostic yield of 106 ASD patients was 60% (P/LP variants). An additional 19% of the findings were potentially actionable VUS (approaching LP based on available evidence).
The diagnostic yield is 36% for ASD patients with no comorbidity, and 56% for those with at least one comorbidity.
For patients with abnormal behavior with neurodevelopmental disorder symptoms, including attention deficit hyperactivity disorders, the diagnostic yield was 75%. Most variant findings included autistic behavior as a part of the associated symptoms.
Genetic Counseling Implications: For affected families, their main motivations for testing were assisting clinical management (62%), understanding the prognosis (39%), and family planning or cascade screening (30%). The statistics provided insights for physicians and genetic counselors for their counseling.
Regular reviewing of VUS approaching LP classification: GS enables more reliable detection of variants not routinely obtained exome sequencing, resulting in significant improvement in detecting VUS with evidence of pathogenicity. This increases the need for regularly reviewing VUS for reclassification which may further increase GS diagnostic yield over time.
Conclusion:
In this retrospective review of Hong Kong ASD patients with diagnostic GS, significantly more patients were diagnosed with a genetic etiology across multiple symptom categories, compared to conventional testing approaches. We also found a significant difference in the diagnostic yields between ASD with and without comorbidities.
The findings can improve our genetic counseling services for children affected by ASD and neurodevelopmental disorders. The high diagnostic yield is equally significant for the families, especially since many of the parents hope to utilize GS results to guide the clinical management of their children and family planning.
One out of 36 children is affected by autism spectrum disorder (ASD) according to recent CDC estimates. Fragile X repeat expansion, karyotyping, and chromosomal microarray analysis (CMA) testing are commonly used to diagnose the genetic etiology of ASD, with a combined diagnostic yield of about 10-15%. Since 2018, diagnostic genome sequencing (GS) has been available in Hong Kong’s private clinical setting. GS provides significantly higher diagnostic yield compared to conventional testing, especially in ASD patients with comorbidities such as language deficit, intellectual disabilities, or seizures.
In this study, GS testing was used for 106 pediatric patients of East Asian descent. Of these, 59 patients were affected by ASD with at least one comorbidity, 11 ASD patients were without comorbidity, and 36 patients were found to have abnormal behavior coupled with neurological signs. Here we report the mutational spectrum of pathogenic (P) and likely pathogenic (LP) variants, and variants of uncertain significance (VUS) with pathogenic evidence that are a priority for periodic review and reclassification. A significant number of these were LP variants, not previously reported in international databases such as ClinVar.
Methods:
106 affected children were tested with diagnostic GS. The ASD and comorbidity assessment was performed by developmental pediatricians, neurologists, or physicians specialized in pediatric genetics. GS at 40-80x sequencing depth was conducted at a U.S. CAP-accredited and CLIA-certified clinical laboratory. Copy number variants (CNVs) detected were confirmed with CMA testing, performed at the Victorian Clinical Genetics Services (A subsidiary of the Murdoch Children's Research Institute, Australia). Clinical interpretation was provided by Rainbow Genomics following current ACMG guidelines, and reports were issued by a board-certified medical director.
Results:
Copy number, mosaic and intronic variants in addition to single nucleotide variants were detected. The concordance of detected CNVs between GS and CMA testing was 100%.
The diagnostic yield of 106 ASD patients was 60% (P/LP variants). An additional 19% of the findings were potentially actionable VUS (approaching LP based on available evidence).
The diagnostic yield is 36% for ASD patients with no comorbidity, and 56% for those with at least one comorbidity.
For patients with abnormal behavior with neurodevelopmental disorder symptoms, including attention deficit hyperactivity disorders, the diagnostic yield was 75%. Most variant findings included autistic behavior as a part of the associated symptoms.
Genetic Counseling Implications: For affected families, their main motivations for testing were assisting clinical management (62%), understanding the prognosis (39%), and family planning or cascade screening (30%). The statistics provided insights for physicians and genetic counselors for their counseling.
Regular reviewing of VUS approaching LP classification: GS enables more reliable detection of variants not routinely obtained exome sequencing, resulting in significant improvement in detecting VUS with evidence of pathogenicity. This increases the need for regularly reviewing VUS for reclassification which may further increase GS diagnostic yield over time.
Conclusion:
In this retrospective review of Hong Kong ASD patients with diagnostic GS, significantly more patients were diagnosed with a genetic etiology across multiple symptom categories, compared to conventional testing approaches. We also found a significant difference in the diagnostic yields between ASD with and without comorbidities.
The findings can improve our genetic counseling services for children affected by ASD and neurodevelopmental disorders. The high diagnostic yield is equally significant for the families, especially since many of the parents hope to utilize GS results to guide the clinical management of their children and family planning.