FamilyBI1: N/A

FamilyPresentingHPOs: HP:0001635, HP:0001875, HP:0001644, HP:0003756 (Congestive heart failure, Neutropenia, Dilated cardiomyopathy, Skeletal myopathy)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: The family was investigated for linkage analysis via chromosomal DNA extraction from white blood cells and fibroblasts. These were tested with 28 x-chromosomal probes for heterozygosity in carriers, leading to an identified area near Xq28. The 30 genes in this region were identified and five were noted to have high heart and skeletal muscle expression. All five were sequenced and ORFs created. After PCR amplification and direct sequencing of the TAZ gene (G4.5.), each family was seen to have a unique variant that segregated with the disease.

FamilyPreviousTesting: N/A

FamilyPMIDs: 1998334, 6142097

FamilyAddInfo: N/A

Variant: NM_000116.5(TAZ):c.153C>G (p.Tyr51Ter)

ClinVar: 11101, https://www.ncbi.nlm.nih.gov/clinvar/variation/11101/

gnomAD: Not in gnomAD

Affected: 3

Unaffected: 6

Segregations: 9

pLOD: 5.24 at DXS305 multipoint LOD score

AddSegregationInfo: Pedigree in PMID: 6142097 Figure 1

FamilyBI3: N/A

FamilyPresentingHPOs: HP:0001875, HP:0001644, HP:0003756 (Neutropenia, Dilated cardiomyopathy, Skeletal myopathy)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Five genes noted to have high heart and skeletal muscle expression were sequenced and ORFs created. After PCR amplification and direct sequencing of the TAZ gene (G4.5.), each family was seen to have a unique variant that segregated with the disease.

FamilyPreviousTesting: N/A

FamilyAddInfo: N/A

Variant: NM_000116.5(TAZ):c.239-1G>A

ClinVar: 11100, https://www.ncbi.nlm.nih.gov/clinvar/variation/11100/

gnomAD: Not in gnomAD

Affected: 2

Unaffected: 3

Segregations: 4

AddSegregationInfo: Candidate gene sequencing

CaseBI2K: N/A

CasePresentingHPOs: HP:0001875, HP:0001644, HP:0003756 (Neutropenia, Dilated cardiomyopathy, Skeletal myopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseGenotypingMethod: Five genes noted to have high heart and skeletal muscle expression were sequenced and ORFs created. After PCR amplification and direct sequencing of the TAZ gene (G4.5.), a unique missense variant was found in this proband.

CasePreviousTesting: N/A

CaseAddInfo: N/A

Variant: NM_000116.5(TAZ):c.239-1G>C

ClinVar: 11102, https://www.ncbi.nlm.nih.gov/clinvar/variation/11102/

gnomAD: Not in gnomAD

CaseCA2: Male, 17 months death

CasePresentingHPOs: HP:0001644, HP:0001875, HP:0001508, HP:0003535 (Dilated cardiomyopathy, Neutropenia, Failure to thrive, 3-Methylglutaconic aciduria)

HPOsFreeText: N/A

CaseNotHPOs: HP:0003107 (Abnormal circulating cholesterol concentration)

NotHPOsFreeText: N/A

CaseAddInfo: Family history of high urinary 3-MGC

CasePreviousTesting: N/A

CaseGenotypingMethod: The TAZ gene was PCR amplified in three fragments and directly sequenced in the mother and proband.

Variant: NM_000116.4:c.548T>G (p.Val183Gly)

CAID: CA415183843, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA415183843

gnomAD: Not in gnomAD

CaseCA4: Male, 6 months death

CasePresentingHPOs: HP:0001644, HP:0001508 (Dilated cardiomyopathy, Failure to thrive)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Cardiac transplant 11 months after presentation; Variant also found in mother and grandmother

CasePreviousTesting: N/A

CaseGenotypingMethod: The TAZ gene was PCR amplified in three fragments and directly sequenced in obligate heterozygotes, III.2, a heterozygous carrier, and III.4.

Variant: NM_000116.5(TAZ):c.589G>A (p.Gly197Arg)

ClinVar: 11105, https://www.ncbi.nlm.nih.gov/clinvar/variation/11105/

gnomAD: Not in gnomAD

CaseCA5: Male, 9 months death

CasePresentingHPOs: HP:0001644, HP:0001875, HP:0001508, HP:0003535, HP:0002014, HP:0008872, HP:0003146 (Dilated cardiomyopathy, Neutropenia, Failure to thrive, 3-Methylglutaconic aciduria, Diarrhea, Feeding difficulties in infancy, Hypocholesterolemia)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: The TAZ gene was PCR amplified in three fragments and directly sequenced in the mother and proband.

Variant: NM_000116.4:c.629T>G (p.Leu210Arg)

CAID: CA415184340, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA415184340

gnomAD: Not in gnomAD

CaseCA3: Male, 6 months diagnosis

CasePresentingHPOs: HP:0001644, HP:0001875, HP:0001508, HP:0003535, HP:0003756, HP:0030319, HP:0003551 (Dilated cardiomyopathy, Neutropenia, Failure to thrive, 3-Methylglutaconic aciduria, Skeletal myopathy, Facial weakness, Difficulty climbing stairs)

HPOsFreeText: N/A

CaseNotHPOs: HP:0003107 (Abnormal circulating cholesterol concentration)

NotHPOsFreeText: N/A

CaseAddInfo: Cardiac transplant 11 months after presentation; Variant also found in mother and grandmother

CasePreviousTesting: N/A

CaseGenotypingMethod: The TAZ gene was PCR amplified in three fragments and directly sequenced in the mother and proband.

Variant: NM_000116.5(TAZ):c.589G>A (p.Gly197Arg)

ClinVar: 11105, https://www.ncbi.nlm.nih.gov/clinvar/variation/11105/

gnomAD: Not in gnomAD

ExperimentName: TAZ Function in Patient Fibroblasts

PatientCell: CL:0000057 (Fibroblast)

GeneFunction: GO:0003841 (1-acylglycerol-3-phosphate O-acyltransferase activity)

GeneAlteration: Fibroblasts were utilized from frozen tissue samples that were taken from 14 Barth Syndrome probands and compared to age-matched controls.

FunctionalEvidence: Several relevant tafazzin slice variants (full transcript, -ex5, and -ex7) were expressed in human BTHS fibroblasts and the MLCL/CL ratio was compared to age-matched controls and the previous results from the fibroblasts themselves. This ratio is important as the amount of cardiolipin (CL) conversion by tafazzin is crucial to the disease progress and observable phenotypes. Overall, the ratio observed in fibroblasts alone was significantly higher than controls (~1.1, reference 0.12). The expression of tafazzin splice variants did rescue some of the ratio, although only the preumed active variant lacking exon 5 showed significant decrease of the ratio (~0.5).

FAVariant1: NM_000116.5(TAZ):c.153C>G (p.Tyr51Ter)

ClinVar: 11101, https://www.ncbi.nlm.nih.gov/clinvar/variation/11101/

FAVariant2: NM_000116.4:c.170G>T (p.Arg57Leu)

CAID: CA415179752, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA415179752

FAVariant3: NM_000116.4:c.590G>T (p.Gly197Val)

CAID: CA415184091, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA415184091

FAVariant4: NM_000116.5(TAZ):c.280C>T (p.Arg94Cys)

ClinVar: 202092, https://www.ncbi.nlm.nih.gov/clinvar/variation/202092/

FamilyRO: N/A

FamilyPresentingHPOs: HP:0001252, HP:0001635, HP:0012664, HP:0001875, HP:0001640, HP:0001324 (Muscular hypotonia, Congestive heart failure, Reduced ejection fraction, Neutropenia, Cardiomegaly, Muscle weakness)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: DNA was extracted from salavia and buccal swabs. DNA sequencing for all 11 exons of the TAZ gene was performed via PCR amplification and direct sequencing. Once the mutation was located, site-specific DNA sequencing was used on four unaffected family members to confirm segregation.

FamilyPreviousTesting: N/A

FamilyAddInfo: N/A

Variant: NM_000116.5(TAZ):c.583G>T (p.Gly195Ter)

ClinVar: 559336, https://www.ncbi.nlm.nih.gov/clinvar/variation/559336/

gnomAD: Not in gnomAD

Affected: 2

Unaffected: 2

Segregations: 4

AddSegregationInfo: Not enough info to count, pedigree in Figure 1

CaseDO2: Male, Italy, 1 day onset

CasePresentingHPOs: HP:0001252, HP:0002045, HP:0002033, HP:0001958, HP:0001987, HP:0002151, HP:0001942, HP:0003648, HP:0001640, HP:0001644, HP:0001667, HP:0003324, HP:0001270, HP:0001510, HP:0001875, HP:0002098, HP:0001649, HP:0000969, HP:0001712, HP:0012666, HP:0003535, HP:0001397, HP:0001706 (Muscular hypotonia, Hypothermia, Poor suck, Nonketotic hypoglycemia, Hyperammonemia, Increased serum lactate, Metabolic acidosis, Lacticaciduria, Cardiomegaly, Dilated cardiomyopathy, Right ventricular hypertrophy, Generalized muscle weakness, Motor delay, Growth delay, Neutropenia, Respiratory distress, Tachycardia, Edema, Left ventricular hypertrophy, Severely reduced ejection fraction, 3-Methylglutaconic aciduria, Hepatic steatosis, Endocardial fibroelastosis)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001875 (Neutropenia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Birth weight of 2830 g; Unremarkable family history; See "Results" for exact metabolic values

CaseGenotypingMethod: Genomic DNA was isolated from whole blood and the TAZ gene was amplified and directly sequenced.

Variant: NM_000116.4:c.541+1G>A

CAID: CA415183775, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA415183775

gnomAD: Not in gnomAD

CaseDO1: Male, Italy, 3 days onset

CasePresentingHPOs: HP:0011968, HP:0001254, HP:0001252, HP:0002045, HP:0001640, HP:0012664, HP:0002119, HP:0001943, HP:0002910, HP:0003236, HP:0001942, HP:0002151, HP:0003542, HP:0100493, HP:0008315, HP:0011936, HP:0003648, HP:0003344, HP:0003535, HP:0001508, HP:0001270, HP:0001649, HP:0001875, HP:0001644, HP:0002375, HP:0001706, HP:0001397 (Poor feeding, Lethargy, Muscular hypotonia, Hypothermia, Cardiomegaly, Reduced ejection fraction, Ventriculomegaly, Hypoglycemia, Elevated hepatic transaminase, Elevated serum creatine kinase, Metabolic acidosis, Increased serum lactate, Increased serum pyruvate, Hypoammonemia, Decreased plasma free carnitine, Decreased plasma total carnitine, Lacticaciduria, 3-Methylglutaric aciduria, 3-Methylglutaconic aciduria, Failure to thrive, Motor delay, Tachycardia, Neutropenia, Dilated cardiomyopathy, Hypokinesia, Endocardial fibroelastosis, Hepatic steatosis)

HPOsFreeText: N/A

CaseNotHPOs: HP:0002240, HP:0002919 (Hepatomegaly, Ketonuria)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Birth weight of 2780 g; Three maternal great-uncles and two maternal second cousins died in the first years of life; See "Results" for exact metabolic values;

CaseGenotypingMethod: Genomic DNA was isolated from whole blood and the TAZ gene was amplified and directly sequenced.

Variant: NM_000116.5(TAZ):c.589G>A (p.Gly197Arg)

ClinVar: 11105, https://www.ncbi.nlm.nih.gov/clinvar/variation/11105/

gnomAD: Not in gnomAD