GLA -- Fabry Disease (MIM 301500)
ClinGen: https://search.clinicalgenome.org/kb/genes/HGNC:4296
The relationship between GLA and Fabry disease, an X-linked lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of March 3rd, 2017. Deficiency of the gene product, alpha-galactosidase A, was first reported in males with Fabry disease in 1967 (Brady et al; PMID 6023233), and variants in GLA were first associated with this disease in 1989 (Bernstein et al, PMID 2539398). Over 400 unique variants, including missense, nonsense, splice site, frameshift, in-frame deletions, and complex rearrangements, have been reported in humans (reviewed in Gal et al, 2006, PMID 21290673; Mehta, 2017, PMID 20301469). Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Twenty-five variants were curated in 25 probands from 3 publications (Bernstein et al, 1989, PMID 2539398; Topaloglu et al, 1989, PMID 10666480; Shimotori et al, 2008, PMID 18205205). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is loss of function. This gene-disease association is supported by the function of the gene product (Brady et al, 1967, PMID 6020428) animal models and rescue (Oshima et al, 1997, PMID 9122231; Taguchi et al, 2013, PMID 24094090), and studies of the clinical impact of enzyme replacement therapy in humans (Beck et al, 2015, PMID 26937390). In summary, GLA is definitively associated with Fabry disease. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. [CLINGEN GENE VALIDITY CURATION]
Literature review:
Sequence analysis of GLA followed by MLPA
Targeted analysis p.Ala143Pro in individuals from Nova Scotia (incidence 1:15,000).
Targeted analysis IVS4+919G>A in individuals of Chinese ancestry with atypical presentation [Liu et al].
More than 800 GLA pathogenic variants have been identified, and most are family specific, occurring only in single pedigrees. Affected males with frameshift and nonsense variants typically present with classic Fabry disease; males with missense pathogenic variants can present with either classic or atypical phenotypes [Pan et al 2016].
GLA pathogenic variants that result in residual α-gal A activity of about 20% have been identified in individuals with atypical variants of Fabry disease. The clinical manifestations of atypical cases are not specific to Fabry disease (e.g., stroke, cardiomyopathy); therefore, the pathogenicity of some variants is unclear [Lukas et al 2016]. A number of variants including p.Ile91Thr, p.Arg112His, p.Phe113Leu, p.Asn215Ser, p.Met296Ile, p.Arg301Gln, and p.Gly328Arg are recurrent and associated with late-onset cardiac disease [Patel et al 2015]. Most individuals with the IVS4+919G>A pathogenic variant were not diagnosed until newborn screening identified this variant in their grandsons [Liu et al 2015].
The pathogenicity of some GLA variants is disputed. The p.Arg118Cys variant has been recurrently described in large Fabry disease screening studies of high-risk individuals; however, this variant does not always segregate with Fabry disease in a Mendelian fashion, and could be a modulator of cerebrovascular disease risk [Ferreira et al 2015]. The p.Ala143Thr variant has been associated with renal failure, stroke, and left ventricular hypertrophy which could potentially be the result of selection bias, as most individuals were detected in screening studies [Terryn et al 2013].*
Abnormal gene product. GLA pathogenic variants result in mRNA instability and/or severely truncated α-Gal A or an enzyme with markedly decreased activity.
Plasma globotriaosylsphingosine (lyso-Gb3) (the lyso derivative of the accumulated substrate) levels appear to correlate with disease severity and to decline with enzyme replacement therapy [Aerts et al 2008]. Urinary levels of lyso-Gb3 derivatives also correlate with disease severity [Auray-Blais et al 2015]. Plasma lyso-Gb3 levels are higher in affected males than females.
Identification of elevated plasma and urinary lyso-Gb3 can confirm the diagnosis in an individual with a GLA variant of uncertain significance identified by molecular genetic testing or late-onset disease manifestations. Niemann et al [2014] reported that individuals with a novel variant and organ involvement consistent with Fabry disease had lyso-Gb3 levels ≥2.7ng/mL; Individuals with a novel GLA variant and no organ involvement had lyso-Gb3 levels <2.7 ng/mL.
GENEREVIEWS: https://www.ncbi.nlm.nih.gov/books/NBK1292/pdf/Bookshelf_NBK1292.pdf
OMIM: https://www.omim.org/entry/301500
"The genetic cause of Fabry's disease is well known. The GLA gene has been sequenced and hundreds of mutations identified. Point mutations (mis-sense or 20 non-sense mutations) are the most frequent, but small and large deletions or insertions are also seen.
Mutations leading to complete loss of function of the gene product are associated with classic forms of the disease, whereas mutations resulting in amino acid substitutions might occasionally be associated with a mild phenotype and late variants. Attempts to correlate genotype with clinical presentation have been largely unsuccessful.
For women, X inactivation probably has a role, but that it alone explains all the clinical variability is unlikely. Symptomatic heterozygous women with Fabry's disease have skewed X inactivation in some cases, but not consistently"
Zarate YA and Hopkin RJ, 2008 PMID: 18940466
This study -paediatric group consisted of 15 male hemizygotes and 17 female heterozygotes with different types of mutations: 20 had missense mutations, 5 had nonsense (stop) mutations, 4 had splice-site defects, and 3 had frameshift mutations (1 deletion, 2 duplications). The adult group consisted of 36 male hemizygotes, 42 were female heterozygotes with also different types of mutations: 64 had missense mutations and 13 had nonsense mutations, 1 had a frameshift mutation, and no splice-site defects mutation were observed.
The GLA gene is approximately 12 kb and comprised of seven exons (varying in size from 92 to 291 base pairs) each carrying a wide variety of molecular lesions [11]. The processed message is 1.45 kb long and encodes a 50-kDa precursor polypeptide of 429 amino acids [3]. Exon 1 contains the entire 5′ untranslated region, the sequence encoding the signal peptide, and the first 33 residues of the mature enzyme subunit [12]. Point mutations in the α-Gal protein may be sufficient to produce either a classic or severe Fabry phenotype, where no α-galactosidase activity is detectable, or a milder phenotype showing residual enzyme activity [13]. Different substitutions of the same codon may result in markedly different disease phenotypes [14], [15], [16], [17], [18], [19], [20]. Mutant alleles involving nonsense codons or frameshifts, causing premature termination of transcription, are usually associated with classic Fabry disease. The relationship between the genotype and phenotype in Fabry disease has been studied [8], [21]. Branton et al. [21] studied categories of missense mutations and found that patients with conservative single amino acid change have a significantly delayed onset of chronic insufficiency compared to those with non-conservative single amino acid change.
Auray Blaise et al. 2008. PMID: 18023222
Pilot application of harmonised terms:
Inheritance:
X-linked - Primarily recessive (with milder female expression)
Allelic requirement:
Monoallelic_X_hem
Disease associated variant consequences:
Dose change -decreased gene product level
Dose change - absent gene product
Altered gene product structure
Narrative summary of molecular mechanisms:
Mechanism is loss of function of GLA due to reduction/absence of gene product or altered gene product structure. Variant classes include missense, nonsense, splice site, frameshift, in-frame deletions, and complex rearrangements. A recurrent intronic variant (c.640-801G>A) is recognised as pathogenic and leads to aberrant mRNA splicing. GLA pathogenic variants result in mRNA instability and/or severely truncated α-Gal A or an enzyme with markedly decreased activity. Many variants are unique however there are recognised recurrent variants also.
Mutations leading to complete loss of function of the gene product are usually associated with classic forms of the disease, whereas mutations resulting in amino acid substitutions and residual enzyme activity can present atypically with either symptoms not specific to Fabry's (e.g. cardiomyopathy) or a milder phenotype and later onset. Attempts to correlate genotype with clinical presentation have been largely unsuccessful.
Fabry disease is inherited in an X linked manner. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, they may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype.
Identification of elevated plasma and urinary lyso-Gb3 can confirm the diagnosis in an individual with a GLA variant of uncertain significance identified by molecular genetic testing or late-onset disease manifestations.
List variant classes in this gene proven to cause this disease:
Missense
Frameshift variant
Frameshift variant predicted to undergo NMD
Inframe deletions
Inframe insertion
Stop gain
Stop gained predicted to undergo NMD
Spice acceptor variant
Splice donor variant
Splice acceptor variant predicted to undergo NMD
Splice donor variant predicted to undergo NMD
Intronic (?IVS4+919G>A aka c.640-801G>A) (Cryptic splice site)
Structural variants
List other variant classes predicted to lead to the same functional consequence
Splice acceptor variant predicted to escape NMD
Splice donor variant predicted to escape NMD
Frameshift variant predicted to escape NMD
start_lost
stop_gained predicted to escape NMD
stop_lost
gain of upstream Start [uORF]
gain of upstream Start [oORF]
Stop lost [oORF]
Frameshift [oORF]