PSAP

Inheritance Pattern: AR

Disease ID:MONDO:0012720

Submitter: ClinGen

PSAP was first reported in relation to “Krabbe disease due to saposin A deficiency” (http://purl.obolibrary.org/obo/MONDO_0012720), an autosomal recessive lysosomal disease, in 2005 (Spiegel et al, PMID: 15773042). PSAP encodes prosaposin, a highly conserved glycoprotein which is a precursor for 4 cleavage products, the Sphingolipid Activator Proteins, or saposins A, B, C, and D. Saposins localize primarily to the lysosomes where they each have a different role the catabolism of glycosphingolipids (Meyer et al, 2014, PMID: 25130661). Because the location and type of different variants within PSAP determines which specific saposin is impacted, PSAP will be curated separately for four different conditions: Krabbe disease due to saposin A deficiency (this curation), metachromatic leukodystrophy due to saposin B deficiency, Gaucher disease due to saposin C deficiency, and combined PSAP deficiency. These “splits” in curations were made on the basis of the published disease assertions, molecular mechanism (impact of the variant on the different cleavage products of the prosapson protein), and phenotypic differences, based on the ClinGen Lumping and Splitting Guidelines. Specific to this gene-disease validity curation, Saposin A activates galactocerebrosidase (also known as galactosylceramide beta-galactosidase, galactosylceramidase) which is required for the degradation of galactosylceramide, galactosylsphingosine, and other galactolipids. Deficiency of galactocerebrosidase activity due to biallelic variants in the GALC gene causes Krabbe disease, a neurological condition with a range of age of onset and severity that is associated with rapid deterioration and death in childhood for individuals with the infantile onset form (Orsini et al, 2018, PMID: 20301416). This curation examines the evidence that variants in PSAP, which encodes Sapsoin A, an activator of galactocerebrosidase, can also cause Krabbe disease. Three published cases with biallelic variants in PSAP and clinical and biochemical features consistent with Krabbe disease were identified (Spiegel et al, 2005, PMID: 15773042; Kose et al, 2018, PMID: 29995202; Calderwood et al, 2020, PMID: 31439510). Each of these individuals was homozygous for either a missense or inframe deletion within the region of the PSAP gene that encodes Saposin A (amino acids 60-143) (Meyer et al, 2014, PMID: 25130661. Another case was mentioned in the text of an article, homozygous for a previously reported missense change, but no clinical details were available (Suzuki et al, 2016, PMID: 27638581). A total of 1.4 points was given for genetic evidence. This gene-disease relationship is also supported by experimental evidence including the biochemical functional of Saposin A, which is consistent with the biochemical and clinical findings in patients (Harzer et al, 1997, PMID: 9409731; Harzer et al, 2001, PMID: 11707278) and the clinical and biochemical features observed in a Saposin A-deficient knock-in mouse (Matsuda et al, 2001, PMID: 11371512). A total of 5 points was given for experimental evidence. In summary, there is moderate evidence to support the relationship between PSAP and the autosomal recessive lysosomal disease ““Krabbe disease due to saposin A deficiency”. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was first approved by the ClinGen Lysosomal Diseases GCEP on December 4, 2023 (SOP v10), and was re-evaluated, with no changes, on Sept 12, 2025 (SOP v11).

Inheritance Pattern: AR

Disease ID:MONDO:0012719

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0100517

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0012719

Submitter: ClinGen

PSAP was first reported in relation to combined PSAP deficiency (MONDO:0012719), an autosomal recessive lysosomal disease, by Schnabel et al in 1992 (PMID: 1371116). Combine PSAP deficiency is a fatal infantile storage disorder, resulting from abnormal accumulation of sphingolipids in body tissues, characterized by severe neurologic disease and hepatosplenomegaly. PSAP encodes prosaposin, a highly conserved glycoprotein which is a precursor for 4 cleavage products, the Sphingolipid Activator Proteins, or saposins A, B, C, and D. Saposins localize primarily to the lysosomes where they each have a different role the catabolism of glycosphingolipids (Meyer et al, 2014, PMID: 25130661). Because the location and type of different variants within PSAP determines which specific saposin is impacted, PSAP will be curated separately for four different conditions: combined PSAP deficiency (this curation), Krabbe disease due to saposin A deficiency, metachromatic leukodystrophy due to saposin B deficiency, and Gaucher disease due to saposin C deficiency. These “splits” in curations were made on the basis of the published disease assertions, molecular mechanism (impact of the variant on the protein), and phenotypic differences, based on the ClinGen Lumping and Splitting Guidelines. In this curation, data on 5 variants in PSAP (frameshift, nonsense, splice site, initiator codon) in 6 patients from 5 publications were collected (Schnabel et al, 1992, PMID: 1371116; Hulková et al, 2001, PMID: 11309366; Elleder et al, 2005, PMID: 15944902; Kuchar et al, 2009, PMID: 19267410; Motta et al, 2016, PMID: 26831127). More than the maximum twelve points were collected for genetic evidence. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence including the biochemical functional of prosaposin, which is consistent with the biochemical and clinical findings in patients (Henseler et al, 1996, PMID: 8626540; O’Brien et al, 1998; reviewed in Kishimoto et al, 1992, PMID: 1402395), the results of an experiment in which accumulation of ceramide in PSAP-deficient human fibroblast cells was rescued by culturing the cells in medium containing the precursor protein (Henseler et al, 1996, PMID: 8626540), and the clinical and biochemical features observed in a PSAP knock-out mouse (Fujita et al, 1996). Additional evidence is available in the literature, but the maximum points for genetic evidence (6 points) has been reached. In summary, PSAP is definitely associated with autosomal recessive “combined PSAP deficiency”. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases GCEP on July 20, 2023, SOP v9.

Inheritance Pattern: AR

Disease ID:MONDO:0012517

Submitter: ClinGen

The relationship between the PSAP gene and atypical Gaucher disease due to saposin C deficiency (GDSAPC), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 6, 2022. PSAP encodes prosaposin (pSap), a precursor protein that is cleaved in the endosome to form saposins A-D, which are small glycoproteins involved in sphingolipid degradation via activating lysosomal hydrolases; saposin C activates glucocerebrosidase for the hydrolysis of glucosylceramide in lysosomes (as reviewed in PMID: 22652185). Among patients with GDSAPC, deficiency of saposin C results in impaired glucocerebrosidase activation, causing lysosomal accumulation of glucocerebroside (PMID: 20484222), which leads in the characteristic clinical manifestations of Gaucher’s disease which include hepatosplenomegaly, thrombocytopenia, bone lesions, anemia, and in some cases, neurologic anomalies (as reviewed in PMID: 15464415) The disease mechanism of GDSAPC is loss of function. GDSAPC was first reported by Christomanou et al. in 1986 (PMID: 3024666) and the first report of biallelic variants in PSAP among GDSAPC cases was by Diaz-Font in 2005 (PMID: 15856305). Both case-level (genetic) and experimental evidence support the relationship between PSAP and GDSAPC. Reported causal variants include missense, nonsense, deletions, and splice-altering variants (PMID: 20484222, PMID: 15856305, PMID: 2060627, PMID: 17919309, PMID: 28457694, PMID: 35316504, PMID: 31061751, PMID: 35456468). In total, thirteen variants from nine probands in eight publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between PSAP and GDSAPC includes: the biochemical function of the gene product (prosaposin) being consistent with the clinical and biochemical findings identified individuals with GDSAPC (PMID: 20484222, PMID: 22652185, PMID: 15464415); the biochemical and clinical features of PSAP knockout mice (PMID: 20015957); and partial rescue of central nervous system glucocerebrosidase accumulation and neurologic impairment via insertion of saposin C cDNA into PSAP knockout mice (PMID: 12208132). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, PSAP is definitively associated with GDSAPC. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. Classification aproved by the Clingen Lysosomal Diseases Gene Curation Expert Panel on October 6, 2022 (SOP v9).

Inheritance Pattern: AR

Disease ID:MONDO:0012720

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: Unknown

Disease ID:MONDO:0859183

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009590

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012517

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012517

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0012719

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012719

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012517

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012720

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009590

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0859183

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009590

Submitter: ClinGen

PSAP was first reported in relation to “metachromatic leukodystrophy due to saposin B deficiency” (MONDO:0009590), an autosomal recessive lysosomal disease, in 1990 (Rafi et al, PMID: 2302219; Kretz et al, PMID: 2320574). PSAP encodes prosaposin, a highly conserved glycoprotein which is a precursor for 4 cleavage products, the Sphingolipid Activator Proteins, or saposins A, B, C, and D. Saposins localize primarily to the lysosomes where they each have a different role the catabolism of glycosphingolipids (Meyer et al, 2014, PMID: 25130661). Because the location and type of different variants within PSAP determines which specific saposin is impacted, PSAP will be curated separately for four different conditions: Krabbe disease due to saposin A deficiency, metachromatic leukodystrophy due to saposin B deficiency (this curation), Gaucher disease due to saposin C deficiency, and combined PSAP deficiency. These “splits” in curations were made on the basis of the published disease assertions, molecular mechanism (impact of the variant on the protein), and phenotypic differences, based on the ClinGen Lumping and Splitting Guidelines. Specific to this gene-disease validity curation, Saposin B activates the hydrolysis of cerebroside sulfate (sulfatide) by arylsulphatase A (ARSA). Both the deficiency of ARSA activity, caused by biallelic pathogenic variants within the ARSA gene, and the deficiency of saposin B, caused by variants in PSAP, can result in metachromatic leukodystrophy (MLD), with ARSA being the more common cause (Cessani et al, 2015, PMID: 26462614). In individuals with this condition, sulfatides accumulate resulting in progressive demyelination and dysfunction of the central and peripheral nervous systems. Symptoms include progressive motor and cognitive decline, ataxia, seizures, spasticity, and vision and hearing loss. In this curation, data on 11 variants in PSAP (missense, splice site, initiator codon) in 9 patients from 9 publications were collected (Rafi et al, 1990, PMID: 2302219; Kretz et al, 1990, PMID: 2320574; Holtschmidt et al, 1991, PMID: 2019586; Henseler et al, 1996, PMID: 8554069; Wrobe et al, 2000, PMID: 10682309; Deconinck et al, 2008, PMID: 17616409; Kuchar et al, 2009, PMID: 19267410; Siri et al, 2014, PMID: 24478108; Kolnikova et al, 2019, PMID: 31319425; Madaan et al, 2019, PMID: 31319425). The most commonly observed variants are c.645C>A (p.Asn215Lys) and c.722G>C (p.Cys241Ser). Additional evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence including the biochemical functional of Saposin B, which is consistent with the biochemical and clinical findings in patients (Gieselmann and von Figura, 1990, PMID: 1977956), the results of an experiment in which breakdown of sulfatide in Saposin B-deficient cells was rescued by the addition of Saposin B (Wrobe et al, 2000, PMID: 10682309), and the clinical and biochemical features observed in a Saposin B-deficient knock-in mouse (Sun et al, 2008; PMID: 18480170). In summary, PSAP is definitely associated with autosomal recessive “metachromatic leukodystrophy due to saposin B deficiency”. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases GCEP on July 20, 2023, SOP v9.

Inheritance Pattern: AR

Disease ID:MONDO:0012517

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0012719

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0012720

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0009590

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009590

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0012720

Submitter: G2P