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High prevalence of GAA c.[752C > T;761C > T] haplotype complicates high-risk screening for Pompe disease in the Chinese population
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DOI：10.1016/j.ymgme.2026.110187.png)
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Abstract
En 中文
Pseudodeficiency alleles pose a significant challenge to Pompe disease (PD) newborn and high-risk screening by causing false-positive enzyme reductions without clinical manifestations. The clinical significance of the GAA c.[752C > T;761C > T] haplotype, frequently identified in East Asian screening programs, remains uncertain. We conducted a retrospective review of the Chinese PD high-risk screening program, identifying 22 individuals from 11 independent families carrying this haplotype. PD phenotypes occurred exclusively when the haplotype was coupled with two pathogenic variants in trans (one in cis). Crucially, individuals homozygous for the haplotype or carrying it in trans with a single pathogenic variant remained asymptomatic, despite dried blood spot (DBS) GAA activity falling below the diagnostic threshold (34% of the lower normal limit). Computational structural modeling corroborated these clinical observations, revealing minimal conformational alterations that preserve the integrity of the catalytic site. Furthermore, the haplotype is markedly enriched in East Asian populations (allele frequencies: 0.259% for c.752C > T and 0.263% for c.761C > T) compared to other ethnic groups. Collectively, these clinical, structural, and population data support the classification of the GAA c.[752C > T;761C > T] haplotype as a pseudodeficiency allele. Genotyping to identify this haplotype is essential to prevent misdiagnosis and avoid unnecessary treatment in East Asian populations.
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