How is Fabry disease inherited?
Fabry disease is an X-linked lysosomal storage disorder.1 Diseases with an X-linked recessive pattern of inheritance generally manifest in males. Males with an affected allele on the X chromosome are hemizygous for the disease and cannot transmit the disorder to their male offspring; however, all female offspring will be obligate heterozygotes of the disease. There is a 50% chance that an unaffected heterozygous female of the disease can pass the disease to male offspring, and their female offspring have a 50% chance of being an obligate heterozygote of the disease (Figure 1).2 Due to the X-linked inheritance of Fabry disease, females were historically recognised as ‘asymptomatic heterozygotes’. It is now recognised that females with Fabry disease may present with a variable spectrum of disease manifestations which may be equally as severe as for male patients.3-6
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
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
- Vardarli I, Rischpler C, Herrmann K, et al. Diagnosis and screening of patients with Fabry disease. Ther Clin Risk Manag 2020; 16: 551-558.
- Basta M, Pandya AM. Genetics, X-Linked Inheritance. In: Abai B, Abu-Ghosh A, Acharya AB, et al., eds. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing, 2020.
- Echevarria L, Benistan K, Toussaint A, et al. X-chromosome inactivation in female patients with Fabry disease. Clin Genet 2016; 89: 44-54.
- Whybra C, Kampmann C, Willers I, et al. Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis 2001; 24: 715-724.
- MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 2001; 38: 769-775.
- Wilcox WR, Oliveira JP, Hopkin RJ, et al. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab 2008; 93: 112-128.
- McCafferty EH, Scott LJ. Migalastat: a review in Fabry disease. Drugs 2019; 79: 543-554.
- Tuttolomondo A, Simonetta I, Duro G, et al. Inter-familial and intra-familial phenotypic variability in three Sicilian families with Anderson-Fabry disease. Oncotarget 2017; 8: 61415-61424.
- Schiffmann R, Hughes DA, Linthorst GE, et al. Screening, diagnosis, and management of patients with Fabry disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 2017; 91: 284-293.
- Felis A, Whitlow M, Kraus A, et al. Current and investigational therapeutics for Fabry disease. Kidney Int Rep 2019; 5: 407-413.
- Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab 2018; 123: 416-427.
- Hwu W-L, Chien Y-H, Lee N-C, et al. Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A). Hum Mutat 2009; 30: 1397-1405.
- Germain DP, Oliveira JP, Bichet DG, et al. Use of a rare disease registry for establishing phenotypic classification of previously unassigned GLA variants: a consensus classification system by a multispecialty Fabry disease genotype-phenotype workgroup. J Med Genet 2020; 57: 542-551.
- Fabry disease mutation database. Available at: http://fabry-database.org/mutants/. Accessed November 2020.
- ClinicalTrials.gov. Fabry Disease Registry & Pregnancy Sub-registry. Available at: https://clinicaltrials.gov/ct2/show/NCT00196742. Accessed November 2020.
- Ortiz A, Abiose A, Bichet DG, et al. Time to treatment benefit for adult patients with Fabry disease receiving agalsidase b: data from the Fabry Registry. J Med Genet 2016; 53: 495-502.
- Wanner C, Oliveira JP, Ortiz A, et al. Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry. Clin J Am Soc Nephrol 2010; 5: 2220-2228.
- Germain DP, Brand E, Burlina A, et al. Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: a multicenter Fabry Registry study. Mol Genet Genomic Med 2018; 6: 492-503.
- Patel V, O'Mahony C, Hughes D, et al. Clinical and genetic predictors of major cardiac events in patients with Anderson-Fabry disease. Heart 2015; 101: 961-966.
- Deegan PB, Bähner F, Barba M, et al. Fabry disease in females: clinical characteristics and effects of enzyme replacement therapy. In: Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, UK: Oxford PharmaGenesis, 2006.
- The Free Dictionary. X chromosome inactivation. Available at: https://medical-dictionary.thefreedictionary.com/X+chromosome+inactivation. Accessed November 2020.
- Genetics Home Reference. What kinds of gene mutations are possible? Available at: https://ghr.nlm.nih.gov/primer/mutationsanddisorders/possiblemutations. Accessed November 2020.
- Abramowicz A, Gos M. Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet 2018; 59: 253-268.
- Merriam-Webster. Splicing. Available at: https://www.merriam-webster.com/medical/splicing. Accessed November 2020.
- Merriam-Webster. Intron. Available at: https://www.merriam-webster.com/dictionary/intron. Accessed November 2020.
- Merriam-Webster. Exon. Available at: https://www.merriam-webster.com/dictionary/exon. Accessed November 2020.
- Oxford Reference. Cryptic gene. Available at: https://www.oxfordreference.com/search?q=cryptic+gene&searchBtn=Search&isQuickSearch=true. Accessed November 2020.