GALNS

Inheritance Pattern: AR

Disease ID:MONDO:0009659

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009659

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009659

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009659

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0009659

Submitter: ClinGen

The relationship between *GALNS* and mucopolysaccharidosis type 4A (MPS IVA, aka Morquio syndrome A), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of June, 2022. *GALNS* encodes N-acetylgalactosamine-6-sulfatase which is a lysosomal exohydrolase required for the degradation of the glycosaminoglycans, keratan sulfate, and chondroitin 6-sulfate. The phenotypic spectrum of mucopolysaccharidosis IVA (MPS IVA) is a continuum that ranges from a severe and rapidly progressive early-onset form to a slowly progressive later-onset form (https://www.ncbi.nlm.nih.gov/books/NBK148668/). The characteristic features include kyphoscoliosis, genu valgum (knock-knee), pectus carinatum, arthritis, respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly. The diagnosis of MPS IVA involves identification of low N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity in cultured fibroblasts. *GALNS* was first reported in relation to autosomal recessive MPS IVA in 1992 (Fukuda et al, PMID: 1522213). More than 200 nonsense, splice site, frameshift, deletion/duplication and missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 8 probands in 2 publications (PMID: 1522213, PMID: 1522213). Several variants are reported to be recurrent and common in affected individuals in specific populations (e.g., Arg386Cys, Ile113Phe, Met391Val). The mechanism for disease is biallelic loss of function. Summary of experimental data (6 points): This gene-disease relationship is supported by in vitro functional studies, model organisms and rescue evidence. Patients with MPS IVA show accumulation of keratan sulfate and chondroitin sulfate in various tissues due to the lack of degradation of GAGs because of GALNS deficiency. *GALNS* overexpression or silencing is experimentally shown to inversely affect chondroitin sulfate content (PMID: 18285341, 32102177). *GALNS* knock-out mouse model recapitulates GALNS deficiency, urinary excretion of GAGs and lysosomal accumulation of keratin sulfate and chondroitin sulfate; however, the skeletal features are absent in KO mice (PMID: 14583446). The mouse phenotype is rescued by administration of recombinant human GALNS enzyme produced in CHO cells (PMID: 18056156). The recombinant enzyme (elosulfase alfa) is also an FDA-approved enzyme replacement therapy in humans and is reported to improve symptoms of MPS IVA (PMID: 24810369). In summary, *GALNS* is definitively associated with autosomal recessive mucopolysaccharidosis type 4A. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. **Data provided by the ClinGen Prenatal GCEP from November 19, 2024 secondary analysis:** Prenatal phenotypes of MPS IVA have been described in affected fetus. A variable degree of isolated single organ fluid accumulations (ascites, pleural effusions, skin edema) or generalized non-immune hydrops fetalis have been reported in fetuses with a biochemically confirmed diagnosis of MPS IVA (PMID: 3130620, 1287637, 15305357, 16865740, 23137060). These may present in the second trimester or later, and can be transient. Only very few reported prenatal cases, however, have a confirmed genetic MPS IVA diagnosis (PMID: 23137060).

Inheritance Pattern: AR

Disease ID:MONDO:0009659

Submitter: Labcorp Genetics (formerly Invitae)