GLB1

Inheritance Pattern: AR

Disease ID:MONDO:0009262

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009660

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0009660

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009260

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0009660

Submitter: ClinGen

The relationship between **GLB1** and Mucopolysaccharidosis type IVB (a.k.a. Morquio B disease), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of April, 2023. **GLB1** encodes two proteins by alternative splicing: the hydrolytic enzyme, beta-galactosidase (beta-GAL), and the elastin-binding protein (EBP). β-GAL cleaves β-linked galactose residues from the non-reducing end of glycan moieties found in various glycoconjugates. The primary role of EBP is to chaperone the deposition of elastin fibers in the extracellular matrix. Mucopolysaccharidosis type IVB falls within the spectrum of GLB1-related disorders, but unlike GM1 gangliosidosis, the disease is less severe, with primarily skeletal features, absence of neurological features and accumulation of keratan sulfate. **GLB1** was first reported in relation to autosomal recessive Mucopolysaccharidosis type IVB in 1991 (Oshima et al, PMID: 1928092). At least 10 different missense, and a few nonsense, splice site and frameshift variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. OMIM entities: GM1-gangliosidosis, type I (MIM: 230500); GM1-gangliosidosis, type II (MIM: 230600); GM1-gangliosidosis, type III (MIM: 230650); Mucopolysaccharidosis type IVB (Morquio) (MIM: 253010) Per criteria outlined by the ClinGen Lumping and Splitting Working Group, multiple disease assertions are made in the literature; while the GM1 gangiosidoses phenotypes fall on a spectrum, there are differences in phenotypic variability and potentially molecular mechanism(s) between the GM1 gangliosidosis and Mucopolysaccharidosis type IVB. Therefore, the two entities have been split into separate curations. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 11 probands in 7 publication (PMID: 16941474, 19091613, 7586649, 1928092, 22371915, 33558080, 21497194). Several variants are reported to be recurrent in affected individuals, with the Trp273Leu the most common and likely a founder variant. More evidence is available in the literature, but the maximum score for genetic evidence was reached. 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 and model organisms evidence. Reduction in β-GAL activity leads to the accumulation of keratan sulfates (PMID: 34539759). **GLB1** interacts with **NEU1** and **CTSA** to form the lysosomal multienzyme complex (PMID: 33980489). A knock-in mouse model with the Trp273Leu variant recapitulates the enzyme deficiency but not the clinical phentypes. In summary, **GLB1** is definitively associated with autosomal recessive Mucopolysaccharidosis type IVB. 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 Lysosomal Diseases GCEP on April 28, 2023.

Inheritance Pattern: AR

Disease ID:MONDO:0009262

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009660

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0018149

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009660

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009261

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009262

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0009660

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0018149

Submitter: ClinGen

The relationship between **GLB1** and GM1 gangliosidosis (GM1 gangliosidosis type I, II and III included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of April, 2023. **GLB1** encodes two proteins by alternative splicing: the hydrolytic enzyme, beta-galactosidase (beta-GAL), and the elastin-binding protein (EBP). β-GAL cleaves β-linked galactose residues from the non-reducing end of glycan moieties found in various glycoconjugates. The primary role of EBP is to chaperone the deposition of elastin fibers in the extracellular matrix. The phenotypic spectrum of GM1 gangliosidosis is a continuum that is classified based on age of onset: Type I (infantile), Type II (late-infantile and juvenile) and Type III (adult) (PMID: 34539759, 24156116). The clinical manifestations are variable and may include intellectual disability, cerebral degeneration, developmentla delay, gait disturbance, kyphosis, scoliosis, joint stiffness, hepatomegaly, splenomegaly, facial dysmorphism and/or dwarfism. The diagnosis of GM1 gangliosidosis involves demonstration of low beta-galactosidase enzyme activity in patient fibroblasts. **GLB1** was first reported in relation to autosomal recessive GM1 gangliosidosis in 1991 (Yoshida et al, PMID: 1907800; Nishimoto et al, PMID: 1909089). 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. OMIM entities: GM1-gangliosidosis, type I (MIM: 230500); GM1-gangliosidosis, type II (MIM: 230600); GM1-gangliosidosis, type III (MIM: 230650); Mucopolysaccharidosis type IVB (Morquio) (MIM: 253010) Per criteria outlined by the ClinGen Lumping and Splitting Working Group, multiple disease assertions are made in the literature; while the GM1 gangiosidoses phenotypes fall on a spectrum, there are differences in phenotypic variability and potentially molecular mechanism(s) between the GM1 gangliosidosis and Mucopolysaccharidosis type IVB. Therefore, the two entities have been split into separate curations. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 9 probands in 1 publication (PMID: 16941474). Several variants are reported to be recurrent in affected individuals. Much more evidence is available in the literature, but the maximum score for genetic evidence was reached. 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. Reduction in β-GAL activity leads to the accumulation of GM1 ganglioside and its asialo derivative (PMID: 34539759). **GLB1** interacts with **NEU1** and **CTSA** to form the lysosomal multienzyme complex (PMID: 33980489). Several model organisms, spontaneous and lab-generated have been reported in the literature (knock-out mouse, PMID: 9063740; spontaneous in American black bears, PMID: 24581871; spontaneous in Siamese cats, PMID: 22772479; spontaneous in Alaskan Huskies, PMID: 15944348). Rescue of phenotype by the wild-type gene product has been reported in mouse model and patient cells (PMID: 31481471) and enzyme replacement therapy are under development and refinement (PMID: 26766614). In summary, **GLB1** is definitively associated with autosomal recessive GM1 gangliosidosis. 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 Lysosomal Diseases GCEP on April 28, 2023.

Inheritance Pattern: AR

Disease ID:MONDO:0009261

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0018149

Submitter: Myriad Women's Health

Inheritance Pattern: AR

Disease ID:MONDO:0009262

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009260

Submitter: Orphanet