GENETIC INHERITANCE OF FABRY DISEASE

What GLA variants are associated with Fabry disease?
Fabry disease is caused by variants in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A (α-Gal A).¹ To date, more than 1000 variants in the GLA gene leading to a deficiency of α-Gal A activity have been identified.^7-10 There are some key GLA variants associated with classical and late-onset Fabry disease (Table 1). Generally, nonsense,* consensus splice-site^† and frameshift^‡ variants result in no or little α-Gal A enzyme activity. These GLA variants are typically associated with classical Fabry disease.¹¹ Conversely, some of the missense^§ variants and rare cryptic splicing,^¶ such as IVS4+919G>A (c.936+919G>A), GLA variants can lead to residual α-Gal A activity.^11,12 These variants may underlie late-onset Fabry disease, although some missense variants have also been associated with classical Fabry disease.^11,13

Table 1.
Examples of pathogenic GLA variants associated with Fabry disease, as characterised in fabry-database.org.¹⁴

Initiated in 2001, the Fabry Registry (sponsored by Sanofi Genzyme) is an ongoing, international, multicentre, observational programme for patients with Fabry disease.¹⁵ Data published in 2016 from 1044 adult patients (males, n=641; females, n=403) enrolled in the Fabry Registry indicated that missense (42%), nonsense (14%) and frameshift (10%) variants of GLA were the most commonly reported.¹⁶ In this study, genotype data were not available for 27% of enrolled patients; however, according to GLA variants categorised in fabry-database.org,¹⁴ 400 patients had variants associated with classical Fabry disease, and 365 patients had variants not entered or classified in this database.¹⁶ In a separate study of 2236 patients (males, n=1159; females, n=1077) enrolled in the Fabry Registry, published in 2008, variants in the GLA gene were reported for 69.6% of male patients (n=788) and 76.4% of female patients (n=806). No significant differences in the frequency of specific GLA variants between male and female patients were reported; however, the R227X (c.679C>T) GLA variant was most commonly reported and was present in 2.3% of patients (n=50).⁶

The majority of GLA variants are private, occurring in single or a few families. Studying genotype–phenotype correlations can be complicated by intrafamilial phenotypic variability.^11,17 Nevertheless, some correlations between genotype and Fabry disease phenotype have been observed. For example, the missense mutation N215S (c.644A>G) is consistently observed in patients with predominantly cardiac disease manifestations.^18,19 Conversely, renal and cerebrovascular involvement appears to be rare in patients with this GLA variant.¹⁸ Moreover, even in families with the same gene variants, disease manifestations may vary between patients with Fabry disease. Numerous factors may alter the impact of gene variants, including the presence of additional deleterious GLA variants or variants of unknown significance, the genetic background of a patient, concomitant diseases or environmental modifiers.¹⁶

In females with X-linked disorders such as Fabry disease, the severity of disease manifestations is considered dependent on the level of X-chromosome inactivation.²⁰ This phenomenon is the normal failure of expression of one of the X chromosomes in females, whereby the genes on one of the chromosomes are inactivated, apparently at random, and have no phenotypic expression.²¹ Variation in the normal expression of enzyme levels by 25‒75% may be due to random skewing of X-chromosome inactivation, whereas non-random skewing may be associated with more severe disease phenotypes where enzymatic activity may be <25%.²⁰ In a study of 56 females with Fabry disease, 16 patients (29%) exhibited skewed X-chromosome inactivation of the GLA gene. Six of these patients predominantly expressed the wild-type GLA allele and 10 had variants in the GLA allele. Female patients with skewed X-chromosome inactivation profiles exhibited a different disease course, which was dependent on the predominantly expressed allele. The mild phenotype of Fabry disease was associated with the wild-type GLA allele and minimal disease progression, whereas females with predominant expression of variants in the GLA allele exhibited early-onset disease, rapid progression with advancing age and poorer prognosis. Consequently, X-chromosome inactivation can impact the phenotype and disease course in female patients with Fabry disease.³

^*Nonsense variant: a change in one DNA base pair. The altered DNA sequence prematurely signals the cell to stop building a protein. This variant culminates in a shortened protein that may function improperly or not at all.²²

^†Consensus splice-site variant: a splicing variant at the consensus sequence of a gene results in improper exon and intron recognition in messenger RNA causing aberrant transcription of the variant gene, which affects protein synthesis.²³ Splicing is the process in which introns (non-coding regions) in an RNA transcript are removed and exons (coding regions for protein synthesis) are joined to form a functional messenger RNA.^24-26

^‡Frameshift variant: the addition or loss of DNA bases changes the reading frame of a gene. A reading frame consists of groups of three bases that each encode one amino acid. A frameshift variant alters the grouping of these bases and changes the amino acid code. The protein is then non-functional. Insertion, deletion or duplication of a piece of DNA can cause frameshift variants.²²

^§Missense variant: a change in one DNA base pair that causes the substitution of one amino acid for another in a protein.²²

^¶Rare cryptic splicing: a splicing variant at the consensus sequence of a gene results in improper exon and intron recognition in messenger RNA, causing aberrant transcription of the variant gene, which affects protein synthesis.²³ Splicing is the process in which introns (non-coding regions) in an RNA transcript are removed and exons (coding regions for protein synthesis) are joined to form a functional messenger RNA.^24-26 The splicing variant may occur in both introns and exons, and may interfere with the existing splice sites, create new splice sites or activate cryptic splice sites.²³ Cryptic splice sites are typically silenced due to a single nucleotide substitution, and are present at a high frequency in a population; however, a single variant can reactivate this cryptic splice site, leading to aberrant protein synthesis.²⁷

C-ANPROM/INT/FAB/0015; Date of preparation: March 2021