Genomics for KIDS in ASEAN: Improving access to genomic testing through regional collaborations in Southeast Asia
Laboratory Genetics and Genomics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Application of clinical whole exome sequencing (WES) is especially transformative for paediatric rare diseases, however, equitable access is a key barrier especially in under-privileged communities. The Genomics for KIDS in ASEAN project aims to establish a clinical workflow for providing clinical WES to 510 under-resourced families in Southeast Asia and to build a knowledgebase in collaboration with regional experts to better serve the specific needs of Southeast Asian families.
Methods:
We developed an International Organization for Standardization (ISO)-accredited clinical workflow for germline WES with our regional partners using Twist Exome 2.0 panel on Illumina short-read sequencing platform with in-house developed framework for clinical bioinformatics. Variants were interpreted according to ACMG and ClinGen guidelines.
Results:
To date, we have 112 participating Southeast Asian families across 12 ethnicities from 3 study sites in Singapore, Malaysia and the Philippines. All but 1 are proband-parent trio analyses; 65% (n=73) involved a proband with neurodevelopmental disorder with/without congenital abnormalities, 17% (n=19) with multiple congenital anomalies, 7% (n=8) with developmental/intellectual disability and 11% (n=12) reported isolated congenital anomalies. Probands ranged from age 7 days to 42 years, with median age 2 years, all of whom reported phenotypes before adulthood. Reportable findings were detected in 75/112 (67%) probands, of whom 67 carried at least a pathogenic/likely pathogenic variant (PV) and 8 carried variants of uncertain significance (VUS) in genes relevant to their clinical presentation. Diagnostic yield was highest in probands manifesting neurodevelopmental disorder with/without congenital abnormalities (75%, 55/73), whereas only 25% (2/8) of probands with developmental/intellectual disability had a reportable finding. Among 67 probands with PVs detected, 10 (15%) harboured large copy-number variants and 1 with multi-exon intragenic deletion. Of the remaining 56 probands, 4 were detected with multiple PVs and the rest harboured small nucleotide variants associated with autosomal dominant (n=40), recessive (n=8) and X-linked (n=4) conditions. Collectively, 80 PVs were reported, with the majority being missense variants (41%, n=33) and protein-truncating variants (35%, n=28). Two probands had PVs in genes affecting cellular pathways which are targetable by FDA-approved drugs.
Conclusion:
Our study provided clinical WES test to 112 under-resourced families with paediatric rare disease in Southeast Asia and demonstrated a diagnostic yield of 67%, with the highest rate among those presenting neurodevelopmental phenotypes with/without congenital anomalies. Our genotype-first approach to variant analysis also revealed approximately 4% of paediatric rare disease cases may harbour multiple PVs associated with multiple conditions and demonstrated the opportunities for immediate therapeutic intervention following a molecular diagnosis through clinical WES. Finally, our study demonstrated that regional collaborations can positively impact families with rare disease, especially those with limited access to genomic testing in underserved communities.
Application of clinical whole exome sequencing (WES) is especially transformative for paediatric rare diseases, however, equitable access is a key barrier especially in under-privileged communities. The Genomics for KIDS in ASEAN project aims to establish a clinical workflow for providing clinical WES to 510 under-resourced families in Southeast Asia and to build a knowledgebase in collaboration with regional experts to better serve the specific needs of Southeast Asian families.
Methods:
We developed an International Organization for Standardization (ISO)-accredited clinical workflow for germline WES with our regional partners using Twist Exome 2.0 panel on Illumina short-read sequencing platform with in-house developed framework for clinical bioinformatics. Variants were interpreted according to ACMG and ClinGen guidelines.
Results:
To date, we have 112 participating Southeast Asian families across 12 ethnicities from 3 study sites in Singapore, Malaysia and the Philippines. All but 1 are proband-parent trio analyses; 65% (n=73) involved a proband with neurodevelopmental disorder with/without congenital abnormalities, 17% (n=19) with multiple congenital anomalies, 7% (n=8) with developmental/intellectual disability and 11% (n=12) reported isolated congenital anomalies. Probands ranged from age 7 days to 42 years, with median age 2 years, all of whom reported phenotypes before adulthood. Reportable findings were detected in 75/112 (67%) probands, of whom 67 carried at least a pathogenic/likely pathogenic variant (PV) and 8 carried variants of uncertain significance (VUS) in genes relevant to their clinical presentation. Diagnostic yield was highest in probands manifesting neurodevelopmental disorder with/without congenital abnormalities (75%, 55/73), whereas only 25% (2/8) of probands with developmental/intellectual disability had a reportable finding. Among 67 probands with PVs detected, 10 (15%) harboured large copy-number variants and 1 with multi-exon intragenic deletion. Of the remaining 56 probands, 4 were detected with multiple PVs and the rest harboured small nucleotide variants associated with autosomal dominant (n=40), recessive (n=8) and X-linked (n=4) conditions. Collectively, 80 PVs were reported, with the majority being missense variants (41%, n=33) and protein-truncating variants (35%, n=28). Two probands had PVs in genes affecting cellular pathways which are targetable by FDA-approved drugs.
Conclusion:
Our study provided clinical WES test to 112 under-resourced families with paediatric rare disease in Southeast Asia and demonstrated a diagnostic yield of 67%, with the highest rate among those presenting neurodevelopmental phenotypes with/without congenital anomalies. Our genotype-first approach to variant analysis also revealed approximately 4% of paediatric rare disease cases may harbour multiple PVs associated with multiple conditions and demonstrated the opportunities for immediate therapeutic intervention following a molecular diagnosis through clinical WES. Finally, our study demonstrated that regional collaborations can positively impact families with rare disease, especially those with limited access to genomic testing in underserved communities.