Application of whole genome sequencing for carrier and diagnostic assessment of spinal muscular atrophy in Taiwan

Q: What is the clinical evidence from this study?

Study design: Cross-Sectional. Population: Spinal muscular atrophy (SMA) (n=1494). Intervention: Whole-genome sequencing (WGS) vs. Multiplex ligation-dependent probe amplification (MLPA). Primary outcome: SMA carrier frequency.

Li‐Ling Lin; Tzu‐Hung Hsiao; Han-Yu Ye; S.-S. Liu; Tsang‐Ming Ko; Chien‐Hao Huang; Pei‐Lung Chen; Yuh-Tsyr Chou; Chao-Szu Wu; Hung‐Hsin Chen; Yin‐Hsiu Chien; Jacob Shujui Hsu

doi:10.1038/s41525-025-00524-1

October 29, 2025npj Genomic MedicineOpen Access

Application of whole genome sequencing for carrier and diagnostic assessment of spinal muscular atrophy in Taiwan

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Key result

Whole-genome sequencing identified an SMA carrier frequency of 1.55% in the Taiwanese population and successfully detected compound heterozygous variants in clinical patients.

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Why the study?

Does whole-genome sequencing combined with computational tools accurately determine SMN1 and SMN2 copy numbers for SMA carrier screening and diagnosis compared to MLPA?

Key Points

Evaluate the clinical feasibility of whole-genome sequencing combined with computational variant callers for spinal muscular atrophy carrier screening and diagnosis.
Analyzed whole-genome sequencing data from 1,492 Taiwan Biobank participants and two patients with spinal muscular atrophy using the Illumina DRAGEN SMN Caller.
Validated SMN1 and SMN2 copy number variations and specific nucleotide variants using multiplex ligation-dependent probe amplification (MLPA).
Identified 23 spinal muscular atrophy carriers among 1,480 analyzed biobank samples, establishing a population carrier frequency of 1.55%.
Confirmed SMN1 and SMN2 copy number determinations with 100% concordance between whole-genome sequencing and MLPA validation.
Identified compound heterozygous genotypes in both spinal muscular atrophy patients, each carrying one SMN1 copy deletion paired with a specific point mutation (c.815A>G or c.81+2_81+3delTG).

Study Design

Type

Cross-Sectional (n=1,494)

Structured PICO

Does whole-genome sequencing combined with computational tools accurately determine SMN1 and SMN2 copy numbers for SMA carrier screening and diagnosis compared to MLPA?

P

Population

1,492 adults aged 20 to 70 years from the Taiwan Biobank and 2 clinical patients with SMA, evaluated for SMA carrier status and diagnosis using whole-genome sequencing.

E

Exposure

Whole-genome sequencing (WGS) combined with computational tools (Illumina DRAGEN SMN Caller)

C

Comparator

Multiplex ligation-dependent probe amplification (MLPA)

O

Outcome

Accuracy of determining SMN1 and SMN2 copy numbers for SMA carrier screening and disease diagnosissurrogate

Combining whole-genome sequencing with advanced bioinformatics tools is a feasible and accurate approach for spinal muscular atrophy carrier screening and disease diagnosis.

Limitations

Only 10 non-carrier samples underwent MLPA confirmation, leaving most of the cohort unvalidated.
The cohort lacked cases with homozygous SMN1 deletions, limiting diagnostic generalisability.
High sequence similarity between paralogous regions continues to complicate variant calling.
MLPA detected two gene conversion events involving SMN2 exon 8 that were missed by WGS.
Reliance on copy number for carrier classification cannot detect '2+0' silent carriers.
Pathogenic SNVs and structural variants beyond SMN1 copy loss were not systematically screened.
The Taiwan Biobank is not specifically designed to collect couple-based cohorts.

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Implication

Supports WGS for SMA carrier screening in Taiwan; leaves open prospective validation versus MLPA before wider adoption.

Abstract

This study aimed to evaluate the feasibility of whole-genome sequencing (WGS) combined with computational tools for spinal muscular atrophy (SMA) carrier screening and disease diagnosis in Taiwan. WGS data from 1492 Taiwan Biobank participants and two patients with SMA were analysed to determine the SMN1 and SMN2 copy numbers using Illumina DRAGEN SMN Caller and validated by multiplex ligation-dependent probe amplification (MLPA). Among 1480 samples analysed, 23 SMA carriers were identified, yielding a carrier frequency of 1.55%. MLPA confirmed the accuracy of SMN1 and SMN2 copy number results detected using WGS. Both patients with SMA presented compound heterozygous variants with one SMN1 copy loss and the other SMN1 variant, specifically SMN1,c.815A>G, and SMN1,c.81+2_81+3delTG, respectively. Taken together, combining WGS with advanced bioinformatics tools is a feasible and promising approach for SMA carrier screening and disease diagnosis.

Discussion

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Cite This Study

Lin et al. (2025) conducted a cross-sectional in Spinal muscular atrophy (SMA) (n=1,494). Whole-genome sequencing (WGS) vs. Multiplex ligation-dependent probe amplification (MLPA) was evaluated on SMA carrier frequency. Whole-genome sequencing identified an SMA carrier frequency of 1.55% in the Taiwanese population and successfully detected compound heterozygous variants in clinical patients.

synapsesocial.com/papers/6ab2420b0240a86829786295 https://doi.org/10.1038/s41525-025-00524-1

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Application of whole genome sequencing for carrier and diagnostic assessment of spinal muscular atrophy in Taiwan

Figures

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Application of whole genome sequencing for carrier and diagnostic assessment of spinal muscular atrophy in Taiwan

Figures

Key Points

Study Design

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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