CasePD/VOUS-6: 2 weeks diagnosis

HPOsFreeText: GAA activity 8.26 (nmol · h−1 · mg−1), Mean percentage of normal 11.6%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Variant3: NM_000152.4:c.2302C>T (p.Pro768Ser)

CAID: CA401324897 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3:c.2302C%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Patient has one pseudodeficency allele and one allele of uncertain significance, Nomenclature claims Variant 1 and 2 are in cis

CasePD/Pathogenic-7: 2 weeks diagnosis

HPOsFreeText: GAA activity 3.0 (nmol · h−1 · mg−1), Mean percentage of normal 4.2%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Variant3: NM_000152.4:c.2167G>A (p.Val723Met)

CAID: CA8815635 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3:c.2167G%3EA

gnomAD: East Asian 6.213e-5, Overall 9.462e-6 http://gnomad.broadinstitute.org/variant/17-78087143-G-A

CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis

CasePD/Pathogenic-4: 2 weeks diagnosis

HPOsFreeText: GAA activity 5.0 (nmol · h−1 · mg−1), Mean percentage of normal 7.0%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Variant3: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant4: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis, Nomenclature claims Variant 3 and 4 are in cis

CasePD/Pathogenic-3: 2 weeks diagnosis

HPOsFreeText: GAA activity 4.9 (nmol · h−1 · mg−1), Mean percentage of normal 6.9%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Variant3: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant4: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis, Nomenclature claims Variant 3 and 4 are in cis

Case13: Female, 30 years report

HPOsFreeText: 7 years of ERT completed, 6 Minute Walking Test at 520 meters, Forced Vital Capacity at 50%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.525delT (p.Glu176Argfs*42)

ClinVar: 4033 https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: European (Non-Finnish) 1.880e-4, Overall 9.959e-5 http://gnomad.broadinstitute.org/variant/17-78078909-CT-C

CaseAddInfo: Late Onset Pompe Disease

Case36: Female, 69 years report

HPOsFreeText: ERT not started, 6 Minute Walking Test at 252 meters, Forced Vital Capacity at 87%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.854C>G (p.Pro285Arg)

ClinVar: 225114 https://www.ncbi.nlm.nih.gov/clinvar/variation/225114/

gnomAD: European (Non-Finnish) 1.148e-5, Overall 5.109e-6 http://gnomad.broadinstitute.org/variant/17-78081517-C-G

CaseAddInfo: Late Onset Pompe Disease

Case4: Male, 50 years report

HPOsFreeText: 9 years of ERT completed, 6 Minute Walking Test at 140 meters, Forced Vital Capacity at 34%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Late Onset Pompe Disease, Variant is homozygous for this patient

Case28: Female, 49 years report

HPOsFreeText: 6 years of ERT completed, 6 Minute Walking Test at 251 meters, Forced Vital Capacity at 109%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.799_803delinsA (p.Leu267Serfs)

CAID: CA891862613 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.799_803delinsA

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case24: Female, 48 years report

HPOsFreeText: 9 years of ERT completed, 6 Minute Walking Test at 180 meters, Forced Vital Capacity at 67%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case2: Female, 68 years report

HPOsFreeText: 5 years of ERT completed, 6 Minute Walking Test at 275 meters, Forced Vital Capacity at 116%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1629C>G (p.Tyr543Ter)

CAID: CA401367368 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1629C%3EG

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case38: Male, 75 years report

HPOsFreeText: ERT not started, 6 Minute Walking Test at 246 meters

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1560C>G (p.Asn520Lys)

CAID: CA401367200 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1560C%3EG

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case34: Male, 46 years report

HPOsFreeText: ERT not started, 6 Minute Walking Test at 383 meters, Forced Vital Capacity at 73%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1888+1G>A

CAID: CA8815511 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1888%2B1G%3EA

gnomAD: European (Non-Finnish) 9.843e-6, Overall 4.375e-6 http://gnomad.broadinstitute.org/variant/17-78086511-G-A

CaseAddInfo: Late Onset Pompe Disease

Case8: Male, 54 years report

HPOsFreeText: 8 years of ERT completed, 6 Minute Walking Test at 300 meters, Forced Vital Capacity at 33%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1888+1G>A

CAID: CA8815511 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1888%2B1G%3EA

gnomAD: European (Non-Finnish) 9.843e-6, Overall 4.375e-6 http://gnomad.broadinstitute.org/variant/17-78086511-G-A

CaseAddInfo: Late Onset Pompe Disease

Case14: Female, 69 years report

HPOsFreeText: 9 years of ERT completed, 6 Minute Walking Test at 200 meters, Forced Vital Capacity at 51%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.118C>T (p.Arg40Ter)

ClinVar: 426593 https://www.ncbi.nlm.nih.gov/clinvar/variation/426593/

gnomAD: South Asian 6.561e-5, Overall 1.428e-5 http://gnomad.broadinstitute.org/variant/17-78078503-C-T

CaseAddInfo: Late Onset Pompe Disease

Case3: Female, 72 years report

HPOsFreeText: 4 years of ERT completed, 6 Minute Walking Test at 264 meters, Forced Vital Capacity at 56%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case5: Male, 57 years report

HPOsFreeText: 2 years of ERT completed, 6 Minute Walking Test at 461 meters, Forced Vital Capacity at 49%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.546+1G>T

CAID: CA401361913 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.546%2B1G%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case15: Female, 54 years report

HPOsFreeText: 8 years of ERT completed, 6 Minute Walking Test at 229 meters, Forced Vital Capacity at 39%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1717A>C (p.Asn573His)

CAID: CA401369056 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1717A%3EC

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Case10: Male, 80 years report

HPOsFreeText: 7 years of ERT completed, 6 Minute Walking Test at 220 meters, Forced Vital Capacity at 44%

GenotypingMethod: GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1927G>A (p.Gly643Arg)

ClinVar: 4023 https://www.ncbi.nlm.nih.gov/clinvar/variation/4023/

gnomAD: European (Non-Finnish) 3.667e-5, Overall 2.479e-5 http://gnomad.broadinstitute.org/variant/17-78086713-G-A

CaseAddInfo: Late Onset Pompe Disease

Case4: Female, 40 years onset, 51 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 51, GAA Activity at ~7.5 pmol/min/mg before ERT and ~11 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.525delT (p.Glu176Argfs*45)

ClinVar: 4033 https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: European (Non-Finnish) 1.880e-4, Overall 9.959e-5 http://gnomad.broadinstitute.org/variant/17-78078909-CT-C

CaseAddInfo: Late Onset Pompe Disease

Case6: Male, 25 years onset, 56 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 57, GAA Activity at ~10.5 pmol/min/mg before ERT and ~11 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1655T>C (p.Leu552Pro)

ClinVar: 279811 https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: European (Non-Finnish) 7.053e-5, Overall 3.188e-5 http://gnomad.broadinstitute.org/variant/17-78085800-T-C

CaseAddInfo: Late Onset Pompe Disease

Case16: Female, 37 years onset, 49 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 50, GAA Activity at ~4 pmol/min/mg before ERT and ~11 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1465G>A (p.Asp489Asn)

ClinVar: 92465 https://www.ncbi.nlm.nih.gov/clinvar/variation/92465/

gnomAD: European (Finnish) 4.621e-5, Overall 1.195e-5 http://gnomad.broadinstitute.org/variant/17-78084553-G-A

CaseAddInfo: Late Onset Pompe Disease

Case25

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.722_723delTT (p.Phe241Cysfs*88)

CAID: CA658795235 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.722_723delTT

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.1687C>T (p.Gln563*)

ClinVar: 370357 https://www.ncbi.nlm.nih.gov/clinvar/variation/370357/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case79

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.525delT (p.Glu176Argfs*45)

ClinVar: 4033 https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: European (Non-Finnish) 1.880e-4, Overall 9.959e-5 http://gnomad.broadinstitute.org/variant/17-78078909-CT-C

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease, 3 other patients have the same genotype

Case23

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2560C>T (p.Arg854*)

ClinVar: 4034 https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/

gnomAD: African 1.891e-3, Overall 2.090e-4 http://gnomad.broadinstitute.org/variant/17-78092070-C-T

Variant2: NM_000152.4:c.2236T>C (p.Trp746Arg)

ClinVar: 499293 https://www.ncbi.nlm.nih.gov/clinvar/variation/499293/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case44

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.525delT (p.Glu176Argfs*45)

ClinVar: 4033 https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: European (Non-Finnish) 1.880e-4, Overall 9.959e-5 http://gnomad.broadinstitute.org/variant/17-78078909-CT-C

Variant2: NM_000152.4:c.1799G>T (p.Arg600Leu)

CAID: CA401369428 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1799G%3ET

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case26

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant code not given

Variant1: NM_000152.4: [del Exons 15–20]

ClinVar: N/A

gnomAD: N/A

Variant2: NM_000152.4:c.2012T>G (p.Met671Arg)

ClinVar: 92469 https://www.ncbi.nlm.nih.gov/clinvar/variation/92469/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Case41

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant: NM_000152.4:c.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant

Case67

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Significance of this variant is unknown.

Variant1: NM_000152.4:c.1835A>C (p.His612Pro)

CAID: CA401369560 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1835A%3EC

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease

Case2

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant: NM_000152.4:c.1195-19_2190-17del (p.Asp399fs*6)

CAID: CA658795244 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1195-19_2190-17del

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease, Patient is homozygous for this variant

Case22

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2560C>T (p.Arg854*)

ClinVar: 4034 https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/

gnomAD: African 1.891e-3, Overall 2.090e-4 http://gnomad.broadinstitute.org/variant/17-78092070-C-T

Variant2: NM_000152.4:c.1710C>G (p.Asn570Lys)

ClinVar: 555153 https://www.ncbi.nlm.nih.gov/clinvar/variation/555153/

gnomAD: African 1.149e-4, Overall 3.187e-5 http://gnomad.broadinstitute.org/variant/17-78085855-C-G

CaseAddInfo: Infantile Onset Pompe Disease

Case36

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.437delT (p.Met146Argfs*7)

ClinVar: 554096 https://www.ncbi.nlm.nih.gov/clinvar/variation/554096/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

CaseLP2-1: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.54 umol/hr/L, Serum CK at 72 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.424_440del17 (p.Ser142Leufs*29)

CAID: CA658795228 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.424_440del17

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.1840A>G (p.Thr614Ala)

CAID: CA401369588 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1840A%3EG

gnomAD: Not in gnomAD

Variant3: NM_000152.4:c.2647-23delT

ClinVar: 557403 https://www.ncbi.nlm.nih.gov/clinvar/variation/557403/

gnomAD: East Asian 2.005e-3, Overall 1.432e-4 http://gnomad.broadinstitute.org/variant/17-78092425-CT-C

CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates that Variant 2 and 3 are in cis

CaseIP2-5: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.13 umol/hr/L, Serum CK at 443 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1396G>T (p.Val466Phe)

CAID: CA401366509 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1396G%3ET

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.1935C>A (p.Asp645Glu)

ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

CaseAddInfo: Infantile Onset Pompe Disease

CaseOPOPD-51: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.03 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.1822C>T (p.Arg608Ter)

CAID: CA8815488 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1822C%3ET

gnomAD: East Asian 5.103e-5, Overall 1.806e-5 http://gnomad.broadinstitute.org/variant/17-78086444-C-T

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele

CaseOPTPD-4: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.72 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant3: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variants 2 and 3 are in cis with each other and only one copy of 1

CaseIP-3: Female, Taiwan, Birth diagnosis

HPOsFreeText: 4MU enzyme activity at 0.42, MS/MS ennzyme activity at 0.10

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.1935C>A (p.Asp645Glu)

ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

CaseAddInfo: Infantile Onset Pompe Disease, Nomenclature indicates Variant 1 and 2 are in cis and that the patient is homozygous for this allele

CaseOPOPD-48: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.02 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1508_1510del (p.Val503del)

CAID: CA627699576 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.4%3Ac.1508_1510del

gnomAD: East Asian 5.438e-5, Overall 3.980e-6 http://gnomad.broadinstitute.org/variant/17-78084592-ATGG-A

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 1 other has the same genotype

CaseOPOPD-53: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.80 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.1935C>A (p.Asp645Glu)

ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 3 other people have this genotype

CaseOPOPD-75: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.83 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2815_2816delGT (p.Val939Leufs)

ClinVar: 371481 https://www.ncbi.nlm.nih.gov/clinvar/variation/371481/

gnomAD: East Asian 1.631e-4, Overall 1.194e-5 http://gnomad.broadinstitute.org/variant/17-78093082-CTG-C

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 2 other patients have the same genotype

CaseLP2-11: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.46 umol/hr/L, Serum CK at 86 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.752C>T (p.Ser251Leu)

ClinVar: 325781 https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/

gnomAD: East Asian 2.760e-3, Overall 3.540e-4 http://gnomad.broadinstitute.org/variant/17-78081415-C-T

Variant2: NM_000152.4:c.761C>T (p.Ser254Leu)

ClinVar: 325782 https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/

gnomAD: East Asian 2.759e-3, Overall 1.947e-4 http://gnomad.broadinstitute.org/variant/17-78081424-C-T

Variant3: NM_000152.4:c.1935C>A (p.Asp645Glu)

ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

Variant4: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 and Variants 3 and 4 are in cis

Family 5 - Patients 5a and 5b

FamilyPresentingHPOs: HP:0009027, HP:0000467, HP:0003327, HP:0003691, HP:0002650, HP:0040081, HP:0100284

HPOsFreeText: Myotonic discharges in paraspinal, tibialis anterior, first dorsal interosseous, and biceps muscles, Myopathic muscle unit action potentials, 5b muscular pathology with Severe lysosomal vacuolar myopathy with prominent glycogen excess

FamilyNotHPOs: HP:0010628, HP:0002015, HP:0003306

Ethnicity: Iranian

ProbandLabel: 5a, male, 10yo at onset, 12yo at diagnosis

FamilyAddInfo: 5b (female) dx at 15 yo, 5a MRC sum score = 94, 5b MRC sum score = 91

FamilyPreviousTesting: Respiratory Evaluation: 5a FVC = 91%, 5b FVC = 106%, 5a CK = 1,202 U/L, 5b CK = 907 U/L, muscle pathology (examined only in 5b), DBS enzyme activity (with inhibition) for 5a = 0.5 μmol/L/h, for 5b = 0.6 μmol/L/h, NCS, EMG

FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening

Variant: NM_000152.3:c.1837T>G

ClinVar: n/a

CAID: CA401369569, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401369569

gnomAD: n/a

Case5HPOsFreeText: 10 mg/kg GAA treatment, GAA activity at 0.6 pmol/punch/hr, GAA activity at 6% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Unknown variant, likely a typo

Variant2: NM_000152.4:c.193G>T

ClinVar:

gnomAD:

CaseAddInfo:

Case9HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.6 pmol/punch/hr, GAA activity at 5.5% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Patient is homozygous for this variant

Case18HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 2.1 pmol/spot/hr, GAA activity at 35% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.743T>G (p.Leu248Arg)

CAID: CA401363265 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000152.3:c.743T%3EG

gnomAD: Not in gnomAD

CaseAddInfo:

Case19: 1 mo (at biopsy), White

Case 19 (Level 2)

CasePreviousTesting: same as group. found 1.2 nmol/mg protein/18 h propionate incorporation, 1.0 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.655A>T (p.Asn219Tyr)

ClinVar: 1886

CAID: CA249731

gnomAD: 0.0001318 (European non-Finnish)

Variant2: NM_000255.3:c.1332+1delG

ClinVar: 554656

CAID: CA3846920

gnomAD: 0.000008828 (European non-Finnish)

CaseAddInfo: mut0 type, heterozygous mutations, unknown cis or trans

Case18: 2 mo (at biopsy), French Canadian

Case 18 (Level 2)

CasePreviousTesting: same as group. found 0.7 nmol/mg protein/18 h propionate incorporation, 0.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.655A>T (p.Asn219Tyr)

ClinVar: 1886

CAID: CA249731

gnomAD: 0.0001318 (European non-Finnish)

__

Variant2: NM_000255.3:c.1240delG (p.Glu414LysfsTer17)

ClinVar: n/a

CAID: CA3846936

gnomAD: 0.000008796 (European Non-Finnish)

CaseAddInfo: mut0 type. Variant 2 is novel. heterozygous mutations, unknown cis or trans.

Case17: 6 y (at biopsy), Black

Case 17 (Level 2)

CasePreviousTesting: same as group. found 0.6 nmol/mg protein/18 h propionate incorporation, 0.6 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.631_633delGAG (p.Glu211del)

ClinVar: n/a

CAID: CA913187321

gnomAD: n/a

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutations. Variant 1 is novel. MUT mutations are in trans- demonstrated by RT-PCR of mRNA. Additional variant found in MCEE gene (NM_032601.3:c.428G>A, ClinVar: 336936, CAID: CA1702575, gnomAD: 0.08102 (Latino)) MCEE variant is unlikely to be associated with patient's MMA.

Case16: 5 days (at biopsy), Lao/Thai/Mexican/Portugese

Case 16 (Level 2)

CasePreviousTesting: same as group. found 0.6 nmol/mg protein/18 h propionate incorporation, 0.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.581C>T (p.Pro194Leu)

ClinVar: n/a

CAID: CA364404418

gnomAD: n/a

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutation, unknown cis or trans

Case15: 3 wks (at biopsy), white

Case (Level 2)

CasePreviousTesting: same as group. found 0.5 nmol/mg protein/18 h propionate incorporation, 0.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.572C>A (p.Ala191Glu)

ClinVar: 203854

CAID: CA312777

gnomAD: 0.00006976 (European non-FInnish)

Variant2: NM_000255.3:c.754-2A>G

ClinVar: 552691

CAID: CA364402853

gnomAD: n/a

CaseAddInfo: variant 2 is a novel, splice site mutation. Heterozygous mutations, unknown cis or trans.

Case13: 21 y (at biopsy), English/Irish

Case (Level 2)

CasePreviousTesting: same as group. found 1.5 nmol/mg protein/18 h propionate incorporation, 1.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.572C>A (p.Ala191Glu)

ClinVar: 203854

CAID: CA312777

gnomAD: 0.00006976 (European non-FInnish)

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutation, unknown cis or trans

Case12: 6y (at biopsy), no ethnicity recorded

Case (Level 2)

CasePreviousTesting: same as group. found 0.5 nmol/mg protein/18 h propionate incorporation, 1.3 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.556A>G (p.Met186Val)

ClinVar: 551460

CAID: CA3847093

gnomAD: 0.00001760 (European Non-Finnish)

Variant2: NM_000255.3:c.1106G>A (p.Arg369His)

ClinVar: 203846

CAID: CA312764

gnomAD: 0.0001504 (East Asian)

CaseAddInfo: mut- type, heterozygous mutations, unknown cis or trans

Case11: 6y (at biopsy), White/Hispanic

Case (Level 2)

CasePreviousTesting: same as group. found 2.6 nmol/mg protein/18 h propionate incorporation, 7.0 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.566A>T (p.Asn189Ille)

ClinVar: 222915

CAID: CA3847091

gnomAD: 0.000008804 (European Non-Finnish)

Variant2: NM_000255.3:c.655A>T (p.Asn219Tyr)

ClinVar: 1886

CAID: CA249731

gnomAD: 0.0001318 (European non-Finnish)

CaseAddInfo: Variant 1 is novel, unknown cis or trans. mut- type.

Case14: 3 mo (at biopsy), White/Australian

Case (Level 2)

CasePreviousTesting: same as group. found 0.5 nmol/mg protein/18 h propionate incorporation, 0.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.572C>A (p.Ala191Glu)

ClinVar: 203854

CAID: CA312777

gnomAD: 0.00006976 (European non-FInnish)

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutation, unknown cis or trans

Case10: 6 days (at biopsy), Northern European/Filipino

Case (Level 2)

CasePreviousTesting: same as group. found 0.8 nmol/mg protein/18 h propionate incorporation, 1.2 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.322C>T (p.Arg108Cys)

ClinVar: 1887

CAID: CA249732

gnomAD: 0.0008393 (Latino)

Variant2: NM_000255.3:c.682C>T (p.Arg228Ter)

ClinVar: 203855

CAID: CA312778

gnomAD: 0.0002615 (Latino)

CaseAddInfo: mut0 type, heterozygous mutations, unknown cis or trans.

Case9: 46 days (at biopsy), Hispanic

Case (Level 2)

CasePreviousTesting: same as group. found 0.8 nmol/mg protein/18 h propionate incorporation, 1.2 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.322C>T (p.Arg108Cys)

ClinVar: 1887

CAID: CA249732

gnomAD: 0.0008393 (Latino)

Variant2: NM_000255.3:c.654A>C (p.Gln218His)

ClinVar: 551243

CAID: CA364404273

gnomAD: 0.000008809 (European non-Finnish)

CaseAddInfo: mut0 class, heterozygous mutations, unknown cis or trans.

Case8: 12 days (at biopsy), White/Mexican

Case (Level 2)

CasePreviousTesting: same as group. found 0.8 nmol/mg protein/18 h propionate incorporation, 1.0 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.322C>T (p.Arg108Cys)

ClinVar: 1887

CAID: CA249732

gnomAD: 0.0008393 (Latino)

Variant2: NM_000255.3:c.654A>C (p.Gln218His)

ClinVar: 551243

CAID: CA364404273

gnomAD: 0.000008809 (European non-Finnish)

CaseAddInfo: mut0 class, heterozygous mutations, unknown cis or trans.

Case7: 10 days (at biopsy), White

Case (Level 2)

CasePreviousTesting: same as group. found 0.4 nmol/mg protein/18 h propionate incorporation, 0.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.146_147ins279

ClinVar: n/a

CAID: n/a- could not register

gnomAD: n/a

Variant2: NM_000255.3:c.372_374dupGA (p.Lys124_Asp125insGlu)

ClinVar: 203861

CAID: CA312788

gnomAD: 0.000008799

CaseAddInfo: mut0 class. heterozygous mutations. identified to be in trans through cDNA analysis. variant 1 is novel and consists of a 279 base pair insertion.

Case6 2 mo (at biopsy), White

Case (Level 2)

CasePreviousTesting: same as group. found 1.1 nmol/mg protein/18 h propionate incorporation, 3.0 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.129G>A (p.Trp43Ter)

ClinVar: 222908

CAID: CA10575886

gnomAD: n/a

Variant2: NM_000255.3:c.299A>G (p.Tyr100Cys)

ClinVar: 218991

CAID: CA347866

gnomAD: 0.000008793 (European non-Finnish)

CaseAddInfo: mut- class. heterozygous mutations. unknown cis or trans. variant 1 is novel.

Case5: 1y 9 mo (at biopsy), Korean

Case (Level 2)

CasePreviousTesting: same as group. found 0.7 nmol/mg protein/18 h propionate incorporation, 0.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.91C>T (p.Arg31Ter)

ClinVar: 92688

CAID: CA249743

gnomAD: 0.00008013 (African)

Variant2: NM_000255.3:c.349G>T (p.Glu117Ter)

ClinVar: 1882

CAID: CA115264

gnomAD: n/a

CaseAddInfo: mut0 class. heterozygous mutations. unknown cis or trans.

Case4: 2 y (at biopsy), Black

Case (Level 2)

CasePreviousTesting: same as group. found 2.1 nmol/mg protein/18 h propionate incorporation, 3.1 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.91C>T (p.Arg31Ter)

ClinVar: 92688

CAID: CA249743

gnomAD: 0.00008013 (African)

Variant2: NM_000255.3:c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

CaseAddInfo: mut- class. heterozygous mutations. unknown cis or trans. Third variant in TCN2 gene (NM_000355.3:c.89T>G p.Leu30Arg, CAID: CA10184491, ClinVar: 529781, gnomAD: 0.01329 (African))

Case3: 19y (at biopsy), Irish/Scottish/Polish

Case (Level 2)

CasePreviousTesting: same as group. found 1.2 nmol/mg protein/18 h propionate incorporation, 1.2 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.29dupT (p.Leu10PhefsTer39)

ClinVar: 553287

CAID: CA567155988

gnomAD: 0.00003269 (South Asian)

Variant2: NM_000255.3:c.1658delT (p.Val553GlyfsTer17)

ClinVar: n/a

CAID: CA450397348

gnomAD: 0.000008808 (European non-Finnish)

CaseAddInfo: mut0 class. heterozygous mutations. variant 1 is novel. unknown cis or trans.

Case2: 1 mo (at biopsy), Palestinian

Case (Level 2)

CasePreviousTesting: same as group. found 1.5 nmol/mg protein/18 h propionate incorporation, 1.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.2T>C (p.Met1Thr)

ClinVar: 222903

CAID: CA10575890

gnomAD: n/a

Variant2: NM_000255.3:c.1630_1631delGGinsTA (p.Gly544Ter)

ClinVar: 203860

CAID: CA312786

gnomAD: 0.0001088 (East Asian)

CaseAddInfo: mut0 class. heterozygous mutations- unknown cis or trans. 3rd mutation in CD320 gene (NM_016579.3:c.658G>A p.Gly220Arg, ClinVar: 136684, CAID: CA289989, gnomAD: 0.3086 (African) )

Case1: 13 mo (at biopsy), no recorded ethnicity

Case (Level 2)

CasePreviousTesting: same as group. found 2.4 nmol/mg protein/18 h propionate incorporation, 4.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1A>G (p.M1?)

ClinVar: n/a

CAID: CA364406084

gnomAD: n/a

Variant2: NM_000255.3:c.2150G>T (p.Gly717Val)

ClinVar: 1881

CAID: CA249729

gnomAD: 0.0006810 (African)

CaseAddInfo: mut- class. heterozygous mutations. unknown cis or trans

Case2: Female

CasePresentingHPOs: HP:0000252, HP:0001270, HP:0000750, HP:0001252 (Microcephaly, Motor delay, Delayed speech and language development, Muscular hypotonia)

HPOsFreeText: N/A

CaseNotHPOs: HP:0000407 (Sensorineural hearing impairment)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous, Compound heterozyosity was confirmed in trans via parental testing

CasePreviousTesting: At 2 yrs levels were at 2-oxoadipate, 520–970 mmol/mol creatinine; 2-hydroxyadipate, 100–150 mmol/mol creatinine; 2-aminoadipate, elevated; Moderate protein restriction did not influence disease course; IQ of 87

CaseGenotypingMethod: After confirmation of the DHTKD1 mutations in Individual 1, Sanger sequencing confirmed compound heterozygous mutations in the same gene here.

Variant1: NM_018706.7(DHTKD1):c.1228C>T (p.Arg410Ter)

ClinVar: 39565 https://www.ncbi.nlm.nih.gov/clinvar/variation/39565/

gnomAD: 0.00005437, https://gnomad.broadinstitute.org/variant/10-12136140-C-T

Variant2: NM_018706.5(DHTKD1):c.2185G>A (p.Gly729Arg)

ClinVar: 39564 https://www.ncbi.nlm.nih.gov/clinvar/variation/39564/

gnomAD: 0.002748, https://gnomad.broadinstitute.org/variant/10-12154929-G-A

Case39: Female, Chinese, 3.4y (end of study)

HPOsFreeText: 1y onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case39 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1741C>T (p.Arg581Ter)

ClinVar: 554675

CAID: CA364395893

gnomAD: n/a

CaseAddInfo: one variant, not homozygous.

Case40: Female, Chinese, 2.1y (end of study)

HPOsFreeText: 8 mo onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case40 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1777G>T (p.Glu593Ter)

ClinVar: 558328

CAID: CA364395728

gnomAD: n/a

Variant2: NM_000255.3:c.2179C>T (p.Arg727Ter)

ClinVar: 218998

CAID: CA347913

gnomAD: 0.0001504 (East Asian)

CaseAddInfo: variant 1 is novel. heterozygous mutations in trans

Case38: Male, Chinese, 1.5y (end of study)

HPOsFreeText: neonatal onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case38 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1741C>T (p.Arg581Ter)

ClinVar: 554675

CAID: CA364395893

gnomAD: n/a

CaseAddInfo: one variant, not homozygous.

FamilyLabel: Family 1

Family1PresentingHPOs: HP:0001987, HP:0001942, HP:0003128, HP:0002912 (hyperammonemia, metabolic acidosis, lactic acidosis, methylmalonic acidemia)

NotHPOsFreeText: normal plasma total homocysteine

CountryOrigin: China

Ethnicity: Chinese

ProbandLabel: Case35, Case36

Family1 (Level 2)

FamilyPreviousTesting: tandem mass spectrometry for blood levels, gas chromatography-mass spectrometry for urine, NBS

FamilyMethod1: PCR

FamilyGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes from patients and their parents. Exonic ad flanking intronic regions of the MUT gene were amplified through PCR. PCR products were sequenced directly using forward and reverse primers on ABI 3700 sequencer. Mutation analysis using MUT reference NM_000255.3. Nucleotide numbering reflects cDNA numbering (initiation codon= codon1). All detected mutations were confirmed in the patients' parents. Novel variants were screened in 100 alleles from 50 control children. Novel variants were considered pathogenic when predicted to be deleterious by two algorithms.

FamilyAddInfo: counted in group annotation also. identical twins. mut- and mut0 mutation together may explain relatively good clinical condition.

Case37: Female, Chinese, 5.8y (end of study)

HPOsFreeText: 3y onset

NotHPOsFreeText: normal cognitive and motor development without further episodes of metabolic decompensation, not responsive to vitamin B12

Case37 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1677-1G>A (p.=)

ClinVar: 550012

CAID: CA3846767

gnomAD: 0.0003511 (East Asian)

CaseAddInfo: one variant, not homozygous

Case36: Female, Chinese, 9.3(end of study)

NotHPOsFreeText: asymptomatic, no onset

Case36 (Level 2)

CasePreviousTesting: NBS

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1630_1631delGGinsTA (p.Gly544Ter)

ClinVar: 203860

CAID: CA312786

gnomAD: 0.0001088 (East Asian)

Variant2: NM_000255.3:c.1943G>A (p.Gly648Asp)

ClinVar: n/a

CAID: CA3846709

gnomAD: 0.0001087 (East Asian)

CaseAddInfo: heterozygous mutations in trans, but no symptoms. identical twin to Case35/P35.

Case35: Female, Chinese, 9.3y (end of study)

NotHPOsFreeText: asymptomatic, no onset

Case35 (Level 2)

CasePreviousTesting: NBS

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1630_1631delGGinsTA (p.Gly544Ter)

ClinVar: 203860

CAID: CA312786

gnomAD: 0.0001088 (East Asian)

Variant2: NM_000255.3:c.1943G>A (p.Gly648Asp)

ClinVar: n/a

CAID: CA3846709

gnomAD: 0.0001087 (East Asian)

CaseAddInfo: heterozygous mutations in trans, but no symptoms. identical twin to Case36/P36.

Case34: Male, Chinese, 5.5y (end of study)

HPOsFreeText: 2 mo onset, poor neurologic outcome

NotHPOsFreeText: not responsive to vitamin B12

Case34 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1630_1631delGGinsTA (p.Gly544Ter)

ClinVar: 203860

CAID: CA312786

gnomAD: 0.0001088 (East Asian)

Variant2: NM_000255.3:c.1880A>G (p.His627Arg)

ClinVar: 551830

CAID: CA3846719

gnomAD: 0.00002639 (European non-Finnish)

CaseAddInfo: heterozygous mutations in trans

Case33: Male, Chinese, 1.8y (end of study)

HPOsFreeText: Neonatal development

NotHPOsFreeText: normal cognitive and motor development without further episodes of metabolic decompensation, not responsive to vitamin B12

Case33 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1280G>A (p.

ClinVar: 218990

CAID: CA347873

gnomAD: 0.0004011 (East Asian)

CaseAddInfo: one variant, not homozygous

Case31: Male, Chinese, 3.7y (end of study)

HPOsFreeText: neonatal onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case31 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1106G>A (p.Arg369His)

ClinVar: 203846

CAID: CA312764

gnomAD: 0.0001504 (East Asian)

CaseAddInfo: one variant, not homozygous.

Case30: Male, Chinese, 1 mo (age at death)

HPOsFreeText: neonatal onset

NotHPOsFreeText: not responsive to vitamin B12

Case30 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.925T>G (p.Trp309Gly)

ClinVar: n/a

CAID: CA364401026

gnomAD: n/a

Variant2: NM_000255.3:c.1630_1631delGGinsTA (p.Gly544Ter)

ClinVar: 203860

CAID: CA312786

gnomAD: 0.0001088 (East Asian)

CaseAddInfo: heterozygous mutations in trans, died at 1 mo

Case32: Male, Chinese, 1.8y (end of study)

HPOsFreeText: neonatal onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case32 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1280G>A (p.

ClinVar: 218990

CAID: CA347873

gnomAD: 0.0004011 (East Asian)

Variant2: NM_000255.3:c.1677-1G>A (p.=)

ClinVar: 550012

CAID: CA3846767

gnomAD: 0.0003511 (East Asian)

CaseAddInfo: heterozygous mutations in trans

Case29: Male, Chinese, 3.2 y (end of study)

HPOsFreeText: neonatal onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case29 (Level 2)

CasePreviousTesting: NBS

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.755dupA (p.His252GlinfsTer6)

ClinVar: n/a

CAID: CA3847037

gnomAD: 0.0001090 (East Asian)

Variant2: NM_000255.3:c.1741C>T (p.Arg581Ter)

ClinVar: 554675

CAID: CA364395893

gnomAD: n/a

CaseAddInfo: heterozygous mutations in trans

Case28: Male, Chinese, 6.8y (end of study)

HPOsFreeText: neonatal onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case28 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.754-1G>A (p.=)

ClinVar: n/a

CAID: CA364402849

gnomAD: n/a

Variant2: NM_000255.3:c.1061C>T (p.Ser354Phe)

ClinVar: n/a

CAID: CA364400211

gnomAD: n/a

CaseAddInfo: heterozygous mutations in trans.

Case27: Male, Chinese, 1.8y (end of study)

HPOsFreeText: neonatal onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case27 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

CaseAddInfo: one variant, not homozygous.

Case26: Female, Chinese, 6.6y (end of study)

HPOsFreeText: responsive to vitamin B12

NotHPOSFreeText: asymptomatic, no onset

Case26 (Level 2)

CasePreviousTesting: NBS

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

CaseAddInfo: one variant, not homozygous. asymptomatic.

Case25: Male, Chinese, 3 mo (age at death)

HPOsFreeText: neonatal onset

NotHPOsFreeText: not responsive to vitamin B12

Case25 (Level 2)

CasePreviousTesting: NBS

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

Variant2: NM_000255.3:c.1630_1631delGGinsTA (p.Gly544Ter)

ClinVar: 203860

CAID: CA312786

gnomAD: 0.0001088 (East Asian)

CaseAddInfo: heterozygous mutations in trans. died at 3 mo.

Case24: Male, Chinese, 6.5y (end of study)

HPOsFreeText: neonatal onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case24 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

Variant2: NM_000255.3:c.1540C>A (p.Gln514Lys)

ClinVar: n/a

CAID: CA364397122

gnomAD: n/a

CaseAddInfo: heterozygous mutations in trans. Variant 2 is novel

Case23: Female, Chinese, 3y (end of study)

HPOsFreeText: 1.8y onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case23 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

Variant2: NM_000255.3:c.1295A>C (p.Glu432Ala)

ClinVar: n/a

CAID: CA364398703

gnomAD: n/a

CaseAddInfo: heterozygous mutations in trans

Case22: Female, Chinese, 1.3y (end of study)

HPOsFreeText: 11 mo onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case22 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

Variant2: NM_000255.3:c.1106G>A (p.Arg369His)

ClinVar: 203846

CAID: CA312764

gnomAD: 0.0001504 (East Asian)

CaseAddInfo: heterozygous mutations in trans

Case21: Male, Chinese, 9 mo (age at death)

HPOsFreeText: neonatal onset

NotHPOsFreeText: not responsive to vitamin B12

Case21 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

Variant2: NM_000255.3:c.1106G>A (p.Arg369His)

ClinVar: 203846

CAID: CA312764

gnomAD: 0.0001504 (East Asian)

CaseAddInfo: heterozygous mutations in trans, died at 9 mo

Case20: Female, Chinese, 1 y (end of study)

HPOsFreeText: neonatal onset, poor neruological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case20 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

Variant2: NM_000255.3:c.1105C>T (p.Arg369Cys)

ClinVar: 218989

CAID: CA347895

gnomAD: 0.00006536 (South Asian)

CaseAddInfo: heterozygous mutations in trans

Case19: Female, Chinese, 2.4 y (end of study)

HPOsFreeText: 1.8 y onset

NotHPOsFreeText: normal cognitive and motor development without further episodes of metabolic decompensation, not responsive to vitamin B12

Case19 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.655A>G (p.Asn219Asp)

ClinVar: n/a

CAID: CA364404270

gnomAD: n/a

Variant2: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

CaseAddInfo: heterozygous mutations in trans

Case17: Male, Chinese, 6.5y (end of study)

HPOsFreeText: neonatal onset

NotHPOsFreeText: not responsive to vitamin B12, normal cognitive and motor development without further episodes of metabolic decompensation

Case17 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.554C>T (p.Ser185Phe)

ClinVar: n/a

CAID: CA364404475

gnomAD: n/a

Variant2: NM_000255.3:c.2062G>T (p.Glu688Ter)

ClinVar: n/a

CAID: CA3846672

gnomAD: 0.00006152 (African)

CaseAddInfo: heterozygous mutations in trans.

Case16: Male, Chinese, 2.4 y (end of study)

HPOsFreeText: neonatal onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case16 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.454C>T (p.Arg152Ter)

ClinVar: 426467

CAID: CA3847107

gnomAD: 0.00009813 (South Asian)

Variant2: NM_000255.3:c.1280G>A (p.Gly427Asp)

ClinVar: 218990

CAID: CA347873

gnomAD: 0.0004011 (East Asian)

CaseAddInfo: heterozygous mutations in trans.

Case18: Male, Chinese, 5 mo (age at death)

HPOsFreeText: neonatal onset

NotHPOsFreeText: not responsive to vitamin B12

Case18 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.626dupC

ClinVar: n/a

CAID: CA825482501

gnomAD: n/a

Variant2: NM_000255.3:c.1531C>T (p.Arg511Ter)

ClinVar: 556124

CAID: CA3846855

gnomAD: 0.00003270 (South Asian)

CaseAddInfo: variant 1 is novel. Heterozygous mutations in trans.

Case15: Male, Chinese, 6 mo (age at death)

HPOsFreeText: neonatal onset

NotHPOsFreeText: not responsive to vitamin B12

Case15 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.433G>A (p.Gly145Ser)

ClinVar: n/a

CAID: CA364404739

gnomAD: n/a

Variant2: NM_000255.3:c.1677-1G>A (p.=)

ClinVar: 550012

CAID: CA3846767

gnomAD: 0.0003511 (East Asian)

CaseAddInfo: heterozygous mutations in trans. Died at 6 mo.

Case14: Male, Chinese, 2.4 y (onset)

HPOsFreeText: 2.4 y onset

NotHPOsFreeText: not responsive to vitamin B12

Case14 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.421G>A (p.Ala141Thr)

ClinVar: 557678

CAID: CA364404763

gnomAD: n/a

Variant2: NM_000255.3:c.810_811dupGG (p.?)

ClinVar: n/a

CAID: CA3847032

gnomAD: n/a

CaseAddInfo: lost to follow up. heterozygous mutations in trans. both novel mutations

Case12: Female, Chinese, 1.5 y (end of study)

HPOsFreeText: 11 mo onset, poor neruological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case 12 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

Variant2: NM_000255.3:c.2179C>T (p.Arg727Ter)

ClinVar: 218998

CAID: CA347913

gnomAD: 0.0001504 (East Asian)

CaseAddInfo: heterozygous mutations in trans

Case11: Female, Chinese, 2 y (age at death)

HPOsFreeText: 9 mo onset, responsive to vitamin B12

Case11 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3(MMUT):c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

Variant2: NM_000255.3:c.1514T>C (p.!le505Thr)

ClinVar: n/a

CAID: CA364397174

gnomAD: n/a

CaseAddInfo: heterozygous mutations in trans, died at 2 y

Case10: Male, Chinese, 6.4 y (onset)

HPOsFreeText: 6.4 y onset

NotHPOsFreeText: not responsive to vitamin B12

Case10 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3(MMUT):c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

Variant2: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

CaseAddInfo: lost to follow up, heterozygous mutations in trans

Case13: Female, Chinese, 7 mo (onset)

HPOsFreeText: 7 mo onset

NotHPOsFreeText: not responsive to vitamin B12

Case13 (Level 2):

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.419T>C (p.Leu140Pro)

ClinVar: n/a

CAID: CA364404765

gnomAD: n/a

Variant2: NM_000255.3:c.424A>G (p.Thr142Ala)

ClinVar: n/a

CAID: CA364404758

gnomAD: n/a

CaseAddInfo: Variant 1 is novel. Heterozygous mutations in trans. lost to follow up.

Case1: Male, Chinese, 1.8 y (end of study)

HPOsFreeText: neonatal onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case9 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.322C>T (p.Arg108Cys)

ClinVar: 1887

CAID: CA249732

gnomAD: 0.0008393 (Latino)

Variant2: NM_000255.3(MMUT):c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

Variant3: NM_000255.3:c.2168G>A (p.Gly723Asp)

ClinVar: n/a

CAID: CA3846630

gnomAD: 0.00006533 (South Asian)

CaseAddInfo: Variant 1 in trans to Variants 2 and 3 (cis). Variant 3 is novel

Case8: Male, Chinese, 8 mo (onset)

HPOsFreeText 8 mo onset, responsive to vitamin B12

Case8 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.278G>A (p.Arg93His)

ClinVar: 1880

CAID: CA249728

gnomAD: 0.0004777 (European-Finnish)

Variant2: NM_000255.3:c.567T>G (p.Asn189Lys)

ClinVar: 618734

CAID: CA364404447

gnomAD: n/a

CaseAddInfo: lost to follow up, heterozygous mutations in trans

Case7: Male, Chinese, 33 d (age at death)

HPOsFreeText: Neonatal onset

NotHPOsFreeText: Not responsive to vitamin B12

Case7 (Level 2)

CasePreviousTesting: Same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.103C>T (p.Gln35Ter)

ClinVar: n/a

CAID: CA364405751

gnomAD: 0.00009950 (Ashkenazi Jewish)

Variant2: NM_000255.3:c.494A>G (p.Asp165Gly)

ClinVar: n/a

CAID: CA138799926

gnomAD: 0.00005443 (East Asian)

CaseAddInfo: died at 33d, heterozygous mutations in trans

Case6: Female, Chinese, 1 mo (onset)

HPOsFreeText: not responsive to vitamin B12

Case6 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.68C>G (p.Ser23Ter)

ClinVar: n/a

CAID: CA364405860

gnomAD: n/a

Variant2: NM_000255.3:c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

CaseAddInfo: lost to follow up, heterozygous mutations in trans

CaseBII-1: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 890 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband for Family B

Variant1: NM_000277.3(PAH):c.1222C>T (p.Arg408Trp)

ClinVar: 577 https://www.ncbi.nlm.nih.gov/clinvar/variation/577/

gnomAD: 0.001766, https://gnomad.broadinstitute.org/variant/12-102840493-G-A?dataset=gnomad_r3

Variant2: NM_000277.3(PAH):c.1241A>G (p.Tyr414Cys)

ClinVar: 593 https://www.ncbi.nlm.nih.gov/clinvar/variation/593/

gnomAD: 0.0005264, https://gnomad.broadinstitute.org/variant/12-102840474-T-C?dataset=gnomad_r3

CaseEII-2: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 320 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

Variant1: NM_000277.3(PAH):c.1222C>T (p.Arg408Trp)

ClinVar: 577 https://www.ncbi.nlm.nih.gov/clinvar/variation/577/

gnomAD: 0.001766, https://gnomad.broadinstitute.org/variant/12-102840493-G-A?dataset=gnomad_r3

Variant2: NM_000277.3(PAH):c.533A>G (p.Glu178Gly)

ClinVar: 92746 https://www.ncbi.nlm.nih.gov/clinvar/variation/92746/

gnomAD: 0.0001473, https://gnomad.broadinstitute.org/variant/12-103249087-T-C

CaseCI-1: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 365 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

Variant1: NM_000277.3(PAH):c.194T>C (p.Ile65Thr)

ClinVar: 636 https://www.ncbi.nlm.nih.gov/clinvar/variation/636/

gnomAD: 0.0005574, https://gnomad.broadinstitute.org/variant/12-102894893-A-G?dataset=gnomad_r3

Variant2: NM_000277.3(PAH):c.261C>A (p.Ser87Arg)

ClinVar: 583 https://www.ncbi.nlm.nih.gov/clinvar/variation/583/

gnomAD: 0.00009294, https://gnomad.broadinstitute.org/variant/12-102894826-G-T?dataset=gnomad_r3

CaseDII-3: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 725 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

Variant1: NM_000277.3(PAH):c.561G>A (p.Trp187Ter)

ClinVar: 102736 https://www.ncbi.nlm.nih.gov/clinvar/variation/102736/

gnomAD: 0.00001760, https://gnomad.broadinstitute.org/variant/12-103249059-C-T

Variant2: NM_000277.3(PAH):c.782G>C (p.Arg261Pro)

ClinVar: 102832 https://www.ncbi.nlm.nih.gov/clinvar/variation/102832/

gnomAD: Not in gnomAD

CaseFZ8: Male, United States, 3 yrs report

CasePresentingHPOs: HP:0001511, HP:0008897, HP:0001999, HP:0000973, HP:0100678, HP:0000963, HP:0010648, HP:0001388, HP:0001374, HP:0001181, HP:0000938, HP:0000270, HP:0025356, HP:0001252, HP:0000518, HP:0000325, HP:0011220, HP:0000337, HP:0000411, HP:0000369, HP:0100790, HP:0005116, HP:0000717, HP:0008872, HP:0000486, HP:0500163, HP:0003572, HP:0500139 (Intrauterine growth retardation, Postnatal growth retardation, Abnormal facial shape, Cutis laxa, Premature skin wrinkling, Thin skin, Dermal translucency, Joint laxity, Congenital hip dislocation, Adducted thumb, Osteopenia, Delayed cranial suture closure, Psychomotor retardation, Muscular hypotonia, Cataract, Triangular face, Prominent forehead, Broad forehead, Protruding ear, Low-set ears, Hernias, Arterial tortuosity, Autism, Feeding difficulties in infancy, Strabismus, Hypoornithinemia, Low plasma citrulline, Hypoprolinemia)

HPOsFreeText: Typical facial gestalt

CaseNotHPOs: HP:0002645, HP:0012443, HP:0001762, HP:0002650, HP:0000252, HP:0001348 (Wormian bones, Abnormality of brain morphology, Talipes equinovarus, Scoliosis, Microcephaly, Brisk reflexes)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed de novo in this case with one other confirmed and one non-confirmed case with the same variant and similar presentation, No family history

CasePreviousTesting: N/A

CaseGenotypingMethod: ALDH18A1 and PYRC1 were investigated by Sanger sequencing, with the latter revealing no abnormalities and the former showing a heterozygous change at the Arg138 residue.Investigation revealed no further variants in the coding regions. Familial sequencing revealed the inheritance was de novo with no variants in the parents.

Variant: NM_002860.4(ALDH18A1):c.413G>A (p.Arg138Gln)

ClinVar: 217260 https://www.ncbi.nlm.nih.gov/clinvar/variation/217260/

gnomAD: Not in gnomAD

Method 1: Sanger

GenotypingMethod: Coding regions as well as exon–intron boundaries PCCA and PCCB amplified by PCR then analyzed with bidirectional sequencing. Variants were blasted against references genomes PCCA (NM_000282.3) and PCCB (NM_000532.4).

Case6: Female, 16 days at initiation of follow up, European ancestry

HPOsFreeText: NBS C4-acylcarnitine 2.0 umol/L, Plasma C4-acylcarnitine 1.36 umol/L, in vitro probe isoC4-acylcarnitine 0.160 umol/g protein, in vitro probe C4-acylcarnitine 0.150 umol/g protein, urine c4 acylcarnitine 19.13 mmol/mol creatinine, urine C4/C3 ratio 101

CaseNotHPOs: normal urine isobutyryglycine

CaseAddInfo: no data for clinical condition or SCAD gene variants

Case6 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2(ACAD8):c.958G>A (p.Ala320Thr)

ClinVar: 372297

CAID: CA6373180

gnomAD: 0.001725 (European Finnish)

Variant2: NM_014384.2(ACAD8):c.1129G>A (p.Gly377Ser)

ClinVar: 5356

CAID: CA117435

gnomAD: 0.0001551 (European non-Finnish)

CaseAddInfo: compound heterozygote, specified allele 1 and 2 but not maternal and paternal. no potential splice site alteration

Case7a: Male, 7 days at initiation of follow up, Hispanic ancestry

HPOsFreeText: NBS C4-acylcarnitine 2.2 umol/L, plasma C4-acylcarnitine 2.09 umol/L, in vitro probe isoC4-acylcarnitine 0.070 umol/g protein, urine C4-acylcarnitine 3.58 mmol/mol creatinine, Urine C4/C3 ratio 130.

CaseNotHPOs: normal in vitro probe C4-acylcarnitine, normal urine isobutyrylglycine,

CaseAddInfo: younger brother of patient 7b, part of Family2, unremarkable clinical condition

Case7a (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2:c.687T>G (p.Phe229Leu)

ClinVar: n/a

CAID: CA6373030

gnomAD: 0.00008673 (Latino)

Variant2: NM_014384.2(ACAD8):c.1129G>A (p.Gly377Ser)

ClinVar: 5356

CAID: CA117435

gnomAD: 0.0001551 (European non-Finnish)

CaseAddInfo: no potential splice site alteration, no data for SCAD gene variants

Case1: Female, 9 days at follow up, North African ancestry

CasePresentingHPOs: HP:0002013, HP:0001944,HP:0031123, HP:0000388 (emesis, dehydration, recurrent gastroenteritis, otitis media)

HPOsFreeText: NBS C4-acylcarnitine 2.9 umol/L, plasma C4 acylcarnitine 1.35 umol/L, isoC4-acylcarnitine 0.090 umol/g protein,

CaseNotHPOs:

NotHPOsFreeText: normal urine isobutyrylglycine

CaseAddInfo: repeatedly hospitalized during first 2 years of life.

CasePMIDs:

Case (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2(ACAD8):c.988C>T (p.Arg330Trp)

ClinVar: 5357

CAID: CA117438

gnomAD: 0.00006155 (African)

CaseAddInfo: homozygous mutations

CaseAHN3.4: Australia, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease

CasePMIDs: 15286788

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3:c.719G>A (p.Arg240Gln)

CAID: CA3182844, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182844

gnomAD: 0.0001307, https://gnomad.broadinstitute.org/variant/5-1213633-G-A

Variant2: NM_001003841.3(SLC6A19):c.1701+1G>A

ClinVar: 623442, https://www.ncbi.nlm.nih.gov/clinvar/variation/623442/

gnomAD: 0.00005286, https://gnomad.broadinstitute.org/variant/5-1221429-G-A

CaseAHN5.1: Australia, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variant 1 is in-trans with Variants 2 and 3, which are in cis; Variant segregates with the disease

CasePMIDs: 17555458

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography;

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3:c.196G>A (p.Gly66Arg)

CAID: CA359061114 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA359061114

gnomAD: Not in gnomAD

Variant2: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A

Variant3: NM_001003841.3(SLC6A19):c.718C>T (p.Arg240Ter)

ClinVar: 2020 https://www.ncbi.nlm.nih.gov/clinvar/variation/2020/

gnomAD: 0.0001960, https://gnomad.broadinstitute.org/variant/5-1213632-C-T

CaseAHN9.2: Australia, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography;

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A

Variant2: NM_001003841.3:c.1550A>G (p.Asp517Gly)

CAID: CA3183226, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3183226

gnomAD: 0.00004675, https://gnomad.broadinstitute.org/variant/5-1221277-A-G

CaseF3P: 4 yrs report, India

CasePresentingHPOs: HP:0001010, HP:0000750, HP:0001249, HP:0006801, HP:0004923 (Hypopigmentation of the skin, Delayed speech and language development, Intellectual disability, Brisk deep tendon reflexes, Hyperphenylalaninemia)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Family is consanguinous, Parents were confirmed heterozygous, Variant may not undergo NMD however would be missing essential domains (but PAH level supports some residual function)

CasePreviousTesting: Blood phenylalanine before treatment was 439 μmol/l, Blood tyrosine before treatment was 121 μmol/l, PKU diagnosis was based on ferric chloride test on patient urine samples and detection of elevated Phenylalanine levels in blood samples by using HPLC, in addition to analysis of clinical features.

CaseGenotypingMethod: Genomic DNA was isolated from blood samples of proband and family members. PCR amplification and sequencing was used to screen for mutations. Each mutation was confirmed by bi-directional DNA sequencing.

Variant: NM_000277.3:c.976del (p.Trp326Glyfs*15)

CAID: CA16020912 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA16020912

gnomAD: Not in gnomAD

CaseAM7162: Female, 6 yrs report

CasePresentingHPOs: HP:0001992, HP:0002179, HP:0010864, HP:0008936, HP:0002509, HP:0000750, HP:0011968, HP:0008872, HP:0100247, HP:0002373, HP:0001347, HP:0011449 (Organic aciduria, Opisthotonus, Severe Intellectual disability, Muscular hypotonia of the trunk, Limb hypertonia, Delayed speech and language development, Feeding difficulties, Feeding difficulties in infancy, Recurrent singultus, Febrile seizure, Hyperreflexia, Knee clonus)

HPOsFreeText: Birth weight 2.86 kg, Cranial circumference is 49 cm (3rd percentile), weight 18.6 kg (25th percentile) and height 115 cm (50th percentile) at 6 yrs of age

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are first cousin consanguineous; Proband is confirmed homozygous for this variant via a QFM‐PCR assay for the dosage of ACY1 exons 12 and 13; Variant leads to skipping of Exon 13 and a resulting frameshift with a premature termination

CasePreviousTesting: Urinary organic acid analysis confirmed by enzyme assay showed elevated levels of N ‐acetylated derivatives of glutamic acid, leucine, valine and isoleucine; Several genetic investigations, such as karyotyping, ring 15 chromosome analysis and mutational analysis of MECP5 and STXBP1 genes, were performed and were found to be normal; MRI showed dilatation of the left temporal horn at the age of 13 months;

CaseGenotypingMethod: Genomic DNA was isolated and the ACY1 gene was PCR-amplified and sequenced. PCR analysis of retrotranscribed RNA was performed to analyze the effect of this variant on splicing.

Variant: NM_000666.3(ACY1):c.1001_1001+5del

ClinVar: 162019, https://www.ncbi.nlm.nih.gov/clinvar/variation/162019/

gnomAD: 0.00001758, https://gnomad.broadinstitute.org/variant/3-52022618-ATGTGAG-A

CaseWA: Male, 2 yrs onset, Germany

CasePresentingHPOs: HP:0002013, HP:0012470, HP:0004372, HP:0002069, HP:0010819, HP:0007359, HP:0010845, HP:0002133, HP:0007979, HP:0000572, HP:0000577, HP:0000543, HP:0001263, HP:0001310, HP:0002075, HP:0002317, HP:0002188 (Vomiting, Setting-sun eye phenomenon, Lowered consciousness, Bilateral tonic-clonic seizure, Atonic seizure, Focal-onset seizure, EEG with generalised slow activity, Status epilepticus, Gaze-evoked horizontal nystagmus, Visual loss, Exotropia, Optic disc pallor, Global developmental delay, Dysmetria, Dysdiadochokinesis, Unsteady gait, Delayed CNS myelination)

HPOsFreeText: Tonic flexion of the right limbs, The right hemisphere showed continuous spike and slow-spike waves with a temporo-occipital maximum

CaseNotHPOs: HP:0010841 (Multifocal epileptiform discharges)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are nonconsanguineous, Proband is confirmed homozygous via parental testing

CasePreviousTesting: EEG showed severe cerebral dysfunction of the right hemisphere (continuous subdelta and delta activity); Antiepileptic treatment with phenobarbital was initiated after the first seizure but was replaced by levetiracetam after the second seizure