The Fabry disease-causing mutation, GLA IVS4+919G>A, originated in Mainland China more than 800 years ago


The Fabry disease-causing mutation, the GLA IVS4+919G>A (designated GLA IVS4), is very prevalent in patients with hypertrophic cardiomyopathy in Taiwan. This X-linked mutation has also been found in patients in Kyushu, Japan and Southeast Asia. To investigate the age and the possible ancestral origin of this mutation, a total of 33 male patients with the GLA IVS4+919G>A mutation, born in Taiwan, Japan, Singapore, Malaysia, Vietnam, and the Fujian and Guangdong provinces of China, were studied. Peripheral bloods were collected, and the Ilumina Infinium CoreExome-24 microarray was used for dense genotyping. A mutation-carrying haplotype was discovered which was shared by all 33 patients. This haplotype does not exist in 15 healthy persons without the mutation. Rather, a wide diversity of haplotypes was found in the vicinity of the mutation site, supporting the existence of a single founder of the GLA IVS4 mutation. The age of the founder mutation was estimated by the lengths of the mutation-carrying haplotypes based on the linkage-disequilibrium decay theory. The first, second, and third quartile of the age estimates are 800.7, 922.6, and 1068.4 years, respectively. We concluded that the GLA IVS4+919G>A mutation originated from a single mutational event that occurred in a Chinese chromosome more than 800 years ago.

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The authors would like to thank Wen-Ya Ko for his professional advices in population genetics, as well as the journal reviewer #2 for the comprehensive guidance in the presentation of the manuscript.


This work was partly supported by the Ministry of Science and Technology, Taiwan (grant number 108-2321-B-075-003).

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Correspondence to Kimitoshi Nakamura or Dau-Ming Niu.

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Liang, K., Lu, Y., Niu, C. et al. The Fabry disease-causing mutation, GLA IVS4+919G>A, originated in Mainland China more than 800 years ago. J Hum Genet 65, 619–625 (2020).

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