GLA missense and promoter variants co-segregating in a Chinese family with Fabry disease.

Background: Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder due to mutations in the GLA gene leading to deficiency of lysosomal alpha-galactosidase A (alpha-Gal A) and has a wide range of clinical presentations. Over 900 GLA gene mutations are currently known and of those most are thought not to be clinically significant, some with doubtful clinical significance, posing diagnostic and prognostic difficulties for the clinician. Methods: Whole-exome sequencing (WES) was performed to detect the mutation in family members with Fabry disease. The function of g.1170C>T mutation was confirmed by dual luciferase system. Results: A total of 1,375 variants were found in a Chinese family with FD. A missense variants c.1025C>T (p.Arg342Gln) which have been previously reported in association with FD and g.1170C>T singlenucleotide polymorphism (SNP) in the GLA gene were found in five patients. The g.1170C>T SNP affects transcription of GLA gene, presumably the transcription start site. Female patients only have hypohidrosis and neuropathic pain, while male patients have severe symptoms with simultaneous renal impairment. Conclusions: Two simultaneous variants in cis of the GLA gene, c. 1025C>T (p. Arg342Gln) and g.1170C>T, were verified in Chinese individuals, and the corresponding clinical symptoms were described. The disease severity in male patients is worse than in female patients. These results may be helpful for genetic counseling, diagnosis and prognosis of patients with FD.