PMID: 32102177

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO:

InheritancePattern: AR

PMID: 30305043

Gene: GALNS

Disease: Mucopolysaccharidosis

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

Case#: Caciotti_Patient1

Demographics:

CasePresentingHPOs: HP:0002655, HP:0000765, HP:0002673, HP:0003311

CaseNotHPOs: HP:0008166

CasePreviousTesting:

CaseMethod1: Total urinary glycosaminoglycan assay - 0.07 nmol/17h/mg vs 40-170 typical

CaseMethod2: CNV analysis by qPCR

CaseGenotypingMethod: Single gene seq by illumina

Variant: NM_000512.4:c.463G > A & NM_000512.4:c.899-167A >G

ClinVar: 93178 & 1048484

CAID: CA221057 & CA915941057

gnomAD: 16-88904133-C-T v2 &

VariantEvidence: single gen seq, RT-PCR from primary lymphocytes shows different transcripts, WT and larger than WT, larger has 53bp insertion from intron8 between exons 8-9

CaseAddInfo:

CasePMIDs:

PMID: 25252036

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

GroupPresentingHPOs: HP:0000768, HP:0002857, HP:0008454, HP:0001382, HP:0007957, HP:0000687, HP:0004630, HP:0002869, HP:0008807, HP:0002673, HP:0003311, HP:0003414, HP:0002656,

GroupNotHPOs:

GroupPreviousTesting:

GroupMethod1: single gene seq of GALNS exons and flanking intronic seqs

GroupMethod2: GALNS enzyme assa from leukocytes as prev described - range was 0 - 8 nmol/17hr/mg protein with ref range being 40 - 170s

GroupGenotypingMethod: single gene seq

NumberMales: 34

NumberFemales: 34

CountryOrigin: India

Ethnicity:

Race:

AgeRange: 1 - 26

TotalNumber: 68

FamilyInfo: Family blood samples were obtained and the authors state a 3 generation pedigree was constructed for each family but that data was not provided in the study.

NoFamily:

VariantCount: 40

NonVariant:

OtherVariant:

PMID: 34387910

Gene: GALNS

Disease: Mucopolysaccharidosis IVA "Morquio A syndrome"

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Review

Variants 1. NM_000512.5:c.1156C>T 2. NM_000512.5:c.901G>T 3. NM_000512.5:c.337A>T 4. NM_000512.5:c.346G>A 5. NM_000512.5:c.120+1G>A[‐] 6. NM_000512.5:c.860C>T 7. NM_000512.5:c.1171A>G 8. NM_000512.5:c.953T>G 9. NM_000512.5:c.1023C>G 10. NM_000512.5:c.415G>A

Variant 1. NM_000512.5:c.901G>T 2. NM_000512.5:c.1156C>T 3. NM_000512.5:c.120+1G>A 4. NM_000512.5:c.346G>A 5. NM_000512.5:c.1171A>G 6. NM_000512.5:c.860C>T 7. NM_000512.5:c.139G>A 8. NM_000512.5:c.280C>T 9. NM_000512.5:c.1019G>A 10. NM_000512.5:c.1168del

Italics highlight common variants with table 2

PMID: 35859948

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Case Report

Case#: Ma_Proband

Demographics: east Asian? referenced in passing in discussion section

CasePresentingHPOs: HP:0003182, HP:0008812, HP:0002655, HP:0003621, HP:0000943, HP:0001498, HP:0003049, HP:0002857, HP:0004689,

CaseNotHPOs: HP:0008445, HP:0002751, HP:0000768, HP:0008445

CasePreviousTesting: Previous diagnosis Developmental dysplasia of the hip (DDH)

CaseMethod1: quantify urinary excretion of glycosaminoglycans using dimethylmethylene blue

CaseMethod2:

CaseGenotypingMethod: Whole exome sequencing

Variant HGVS: 1) NM_000512.5:c.1156C>T 2) NM_000512.5:c.1288C>G

ClinVar: 1) 700 2) N/A

CAID: 1) CA221040 2) CA397096290

gnomAD v2: 1) 16-88891261-G-A 2) N/A

VariantEvidence:

CaseAddInfo: Onset of symptoms age 8, compound het

CasePMIDs:

Family#PresentingHPOs: None

FamilyNotHPOs: Free of clinical phenotypes

CountryOrigin: China

Ethnicity: Chinese

Race: east Asian

Family#GenotypingMethod: Whole exome sequencing

Affected: None reported

Unaffected: mother and maternal grandmother carriers of same allele, father carrier for separate allele

Segregations: 2?

PublishedLOD: N/A

eLOD: too few segregations

AddSegregationInfo:

ProbandLabel: Ma_Proband

Variant: Maternal - NM_000512.5:c.1288C>G Paternal - NM_000512.5:c.1156C>T

ClinVar:

CAID:

gnomAD:

FamilyAddInfo: paternal allele is previously reported as pathogenic, maternal allele and has only been reported in one proband/family

FamilyPMIDs: 34557487

Case#: He_12

CasePresentingHPOs: skeletal deformities: HP:0000924, HP:0012069, reduced GALNS activity in leukocytes (0.8 pmol/g protein/17hr)

CaseGenotypingMethod: Sanger of GALNS exons

Variant: p.R386C & p.W403_T404delinsCS

ClinVar: 700 & 1048331

CAID: CA221040 & CA916079760

gnomAD: 16-88891261-G-A & n/a

Case#: He_21

CasePresentingHPOs: HP:0000924, HP:0012069, GALNS activity in leukocytes 0 pmol/g protein/17hr

CaseGenotypingMethod: Sanger of PCR amplified GALNS exons 1-14

Variant: p.W520X & p.G290R

ClinVar: 1048427 & 93171

CAID: CA397076034 & CA221049

gnomAD: n/a & 16-88880857-C-T

PMID: 24035930

Gene: GALNS

Disease: Mucopolysaccharidosis type IVA

MonDO: MONDO:0009659

InheritancePattern: AR

GroupPresentingHPOs: only shared phenotype was reduced GALNS activity in leukocytes

GroupGenotypingMethod: Sanger seq of amplified exons

NumberMales: 15

NumberFemales: 6

NumberFamilies: 19

CountryOrigin: China

AgeRange: 1yo to 7.8yo

TotalNumber: 21

FamilyInfo:19 families, siblings P1 and P2, P3 and P4, parents were studied for segregation info

VariantCount: 15

PMID: 14583446

Gene: GALNS

Disease: mucopolysaccharidosis IVA/Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

NonHumanModel: Murine

GeneAlteration: murine Galns portions of intron 1 and exon 2 were deleted via homologous recombination of a cre-neomycin resistance-cre cassette and mated with a cre recombinase strain to remove the cassette and complete the deletion

ModelPhenotype: No outward phenotypes but biochemically there was up to a 6 fold increase in GAG excretion in urine, chondroitin-6-sulfate specifically and not keratan sulfate, consistent with the human phenotype

HumanPhenotype: in severe cases there are obvious skeletal deformations, increase of GAG's chondroitin-6-sulfate and keratan sulfate in urine and decreased or absent GALNS activity

ModelEvidence: X-rays of mice and multiple life stages, GAG assays in urine, immunohistochemistry images of tissues with labeled chondoritin-6-sulfate and keratan sulfate to show distribution in multiple tissue types and

ModelVariant: large deletion of portion of intron 1 and exon 2

WhereInPaper:

Case#: V:3

Demographics: Pakistani

CasePresentingHPOs: HP:0004322, HP:0000768, HP:0000470, HP:0002857, HP:0002650, HP:0002007, HP:0000431, HP:0010674, HP:0002515, HP:0009803, HP:0006119, HP:0001216, HP:0002986, HP:0003027, HP:0008802, HP:0030299, HP:0000926, HP:0004568

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: Proband whole exome seq

Variant: NM_000512.5:c.697G>A

ClinVar: 1048200

CAID: CA8235027

gnomAD: 16-88902194-C-T

VariantEvidence: previous pub as pathogenic, and in silico data suggesting damage to catalytic domain

CaseAddInfo: Family was tested via single gene sanger seq., consanguineous parents both carriers, two affected siblings and three unaffected siblings

CasePMIDs:

PMID: 36292628

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Case report

PMID: 8829629

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

NonHumanModel: Mus musculus

GeneAlteration: p.Arg386Cys the most frequently reported missense variant linked as a causal pathogenic allele in mucopolysaccharidosis IVA patients

ModelPhenotype: In addition to undetectable GALNS enzyme activity in any assayed tissue, increased keratan sulfate detection in liver tissue and blood serum, the boney deformations missing from previous models were present in this mouse model HP:0004325, MP:0001258, HP:0005736

HumanPhenotype: HP:4000197, HP:0012069, HP:0004322, HP:0005736

ModelEvidence: CRISPR/Cas9 directed site mutagenesis of murine Galns coding sequence at codon homologous to the human p.Arg388Cys mutation cited in human MPSIVA patients. Mouse model showed increased keratan sulfate accumulation in liver and blood serum, undetectable n-acetylgalactosamine-6-sulfatase activity in any body tissue assayed as well as skeletal deformities consistent with human MPSIVA patients

ModelVariant: p.Arg388Cys

WhereInPaper:

PMID: 34504088

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

RescueModel: Rescue WT CAG::GALNS in murine model by ovexpression in a Galns variant frequently found in human's affected with MPSIVA

GeneAlteration: transduction by AAV9 of CAG promoted WT murine optimized Galns coding sequence. Widespread tissue transduction was visualized with a CAG promoted GFP cassette delivered by AAV9, subsequently GFP production was widespread and found in all relevant tissue including osteoblast rich areas.

RescueVariant: AAV9-Galns with the coding sequence under the control of a CAG promoter element

RescuePhenotype: HP:0004325, MP:0001258, HP:0005736

RescueMethod: p.Arg386Cys (MPSIVA) mice were first transducted with CAG::GFP via AAV9 to verify efficiency of delivering the coding sequence to target tissue like bone. Then a CAG::Galns (optimized WT) was transducted in to MPSIVA mice (Galns -/-) via AAV9 by 4 weeks of age to avoid the high mortality in the Galns homozygote starting at 2 months.

RescueEvidence: Early transduction of Galns -/- mice recovered higher than WT enzyme activity and WT levels of keratan sulfate detected in liver tissue. Abnormalities in the growth plate in Galns -/- mice were absent in those treated with AAV9-Galns resulting from a return to WT levels of enzyme activity and keratan sulfate in all bone tissue sampled. GALNS activity recovered in lung and heart tissue with the elevated heart rate in MPSIVA mice returned to WT.

ModelVariant: p.Arg386Cys

PMID: 33390680

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Case report

No genetic or enzymatic confirmation of MPSIVA

Family#PresentingHPOs: P1: HP:0000943, HP:0008922, HP:0002650, HP:0001537, HP:0020152, HP:0002515, HP:0002808, HP:0007957, HP:0008480, HP:0005180, HP:0002857,HP:0012069, HP:0002870 P2:HP:0001537, HP:0002857, HP:0007957, HP:0005180, HP:6000342, HP:0001385, HP:0000768, HP:0100559, HP:0012069 occipitocervical stenosis, myelomalacia

FamilyNotHPOs:

CountryOrigin:

Ethnicity:

Race:

Family#PreviousTesting:

Family#Method1:

Family#Method2:

Family#GenotypingMethod: unspecified NGS technique followed by GALNS specific Sanger seq of exons and targeted intronic regions

Affected: 2

Unaffected: 2

Segregations:

PublishedLOD:

eLOD:

AddSegregationInfo:

ProbandLabel: DeLong_P1, DeLong_P2

Variant: NM_000512.5(GALNS):c.899-397_1003-1862del

ClinVar: 1048483

CAID: CA2499223751

gnomAD: n/a

FamilyAddInfo:

FamilyPMIDs:

PMID: 36245961

Gene: GALNS

Disease: Mucopolysaccharidosis IVA/ Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

PMID: 27825773

Gene: GALNS

Disease: Mucopolysaccharidosis IVA/Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

Case#: Fateen_P4

Demographics: Egyptian

CasePresentingHPOs: HP:0000768, HP:0000943, HP:0002857, HP:0000256, HP:0002808, HP:0001382, HP:0005072, HP:0009769 prominent proximal metaphyses

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: single gene seq by Sanger of all 14 exons and restriction digest confirmation/ screening of parents and controls

Variant: NM_000512.5(GALNS):c.119A>G (p.Asp40Gly)

ClinVar: 1048369

CAID: CA397100962

gnomAD: n/a

VariantEvidence: hydrophillic>hydrophobic substitution in putative active site and enzyme activity data shows low enzyme function compared to reference range

CaseAddInfo:

CasePMIDs:

PMID: 9660054

Gene: GALNS

Disease: Mucopolysaccharidosis IVA/Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Family#PresentingHPOs: HP:0000884, HP:0005619, HP:0002761, HP:0012069

CountryOrigin: Poland

Family#Method1: SSCP

Family#Method2: Sanger

Family#GenotypingMethod: SSCP followed by sanger sequencing of mobility variants

Affected: 3

Unaffected: 2

Segregations: 3

eLOD: 1.45

AddSegregationInfo: II:2 and II:7 were not genotyped and not counted, III:1 and III:2 had a greater than 0.25 chance since mother was homozygous so they can not be counted

ProbandLabel: TM

Variant: R259Q and R94G

ClinVar: 706 & 705

CAID: CA251569 & CA251568

gnomAD: 16-88901743-C-T & n/a

PMID: 12721840

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

PMID: 35729508

Gene: GALNS

Disease: Mucopolysaccharidosis Type IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Case Study - 23 probands

PMID: 35782621

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

PMID: 1522213

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

ExperimentName: Expression of variant carrying cDNA in GALNS deficient fibroblasts

FunctionalEvidence: cDNA encoding each of the 15 variants identified in the study were transfected into a GALNS deficient fibroblast cell line. 14 of the 15 altered cDNA's showed no increase in GALNS activity when the cells were assayed, confirming a lack of enzymatic activity.

HGNC:

GeneEvidence:

SharedGeneImplication:

PMID 33407246

Disease Mucopolysaccharidosis IVA

Gene GALNS

PMID: 7668283

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

PMID: 27979613

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Review

ExperimentName: Accumulation of glycosaminoglycans

GOterm:

FunctionalEvidence: Patient cells assayed with artificial substrates for the N-acetylgalactosamine-6-sulfate sulfatase encoded by GALNS, depending on the severity of the coding sequence alteration, are either unable to break down the substrate or are hindered. Further, in mucopolysaccharidosis IVA patients with known variants, elevated levels of keratan sulfate and chondroitin-6-sulfate can be found in their urine where levels in unaffected individuals are much lower.

HGNC:

GeneEvidence:

SharedGeneImplication: