Case6 14yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001256, HP:0000098

(Mild intellectual disability, Tall stature)

HPOsFreeText Diagnosis was based on tall height and mild intellectual disability. Plasma free homocystine was reduced from >80μmol to <10μmol (nv <60μmol) in response to treatment with folate and pyridoxine. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid.

CaseNotHPOs HP:0001083

(Lens dislocation)

NotHPOsFreeText no other seqeulae

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2(CBS):c.833T>C (p.Ile278Thr), 2. IVS8+1G>A, compound heterozygous

ClinVar 1. 120, 2. n/a

CAID 2. need more info

gnomAD 1. MAF=0.001432(European(non-Finnish)), no homozygotes, 2. n/a

CaseAddInfo n/a

CasePMIDs n/a

FamilyLabel Family 28

Family28PresentingHPOs n/a

HPOsFreeText Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Affected individuals were not responsive to the treatment, plasma homocysteine levels went unchanged. Patients were given additional oral betaine(3g twice per day) with a low protein diet.

FamilyNotHPOs n/a

NotHPOsFreeText no further sequelae

CountryOrigin n/a

Ethnicity Lebanese

Race n/a

Family28PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 34

Variant NM_000071.2(CBS):c.19dupC (p.Gln7Profs), homozygous

ClinVar 371345

gnomAD MAF=0.00005473, no homozygotes

FamilyAddInfo n/a

FamilyPMIDs n/a

the Asn541 from allele registry and mutalyzer confused me.

However, there cannot be an Asn542 as there is no Asn542 in the refseq. Asn542 is created when you insert TGAA, that is true, but the HGVS tracks the most immediate change on the refeq which is actually the Asn541.

It was also weird that mutalyzer and allele registry didn't take insTGAA, but only used insA. I wrote out the refseq, the refseq with TGAA inserted and the refseq with just A inserted. Sure enough, Asn541 is the most immediate change and the frameshift is the same "...LRGRP...stop" whether you insert TGAA or just A. Not too surprising since you are still in-frame after adding 3 bases, but cool to check.

interesting!

FamilyLabel Family 5

Family5PresentingHPOs n/a

HPOsFreeText plasma free homocystine was reduced from >80μmol to <10μmol (nv <60μmol) in response to treatment with folate and pyridoxine. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid.

FamilyNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText n/a

CountryOrigin n/a

Ethnicity Anglo-Celtic

Race n/a

Family5PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 7

Variant 1. NM_000071.2(CBS):c.833T>C (p.Ile278Thr), 2. IVS1+insC, compound heterozygous

ClinVar 1. 120, 2. n/a

CAID 2. need more info

gnomAD 1. MAF=0.001432(European(non-Finnish)), no homozygotes, 2. n/a

FamilyAddInfo n/a

FamilyPMIDs n/a

Case17 4yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083

(Lens dislocation)

HPOsFreeText Diagnosis was based on dislocated lenses. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. This patient was not responsive to the treatment, plasma homocysteine levels went unchanged. This patient was given additional oral betaine(3g twice per day) with a low protein diet.

CaseNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText no other sequelae

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant NM_000071.2(CBS):c.919G>A (p.Gly307Ser), homozygous

ClinVar 117

gnomAD MAF= 0.00041539(Other), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

FamilyLabel Family 15

Family15PresentingHPOs n/a

HPOsFreeText Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Affected individuals were not responsive to the treatment, plasma homocysteine levels went unchanged. Patients were given additional oral betaine(3g twice per day) with a low protein diet.

FamilyNotHPOs n/a

NotHPOsFreeText n/a

CountryOrigin n/a

Ethnicity Anglo-Celtic

Race n/a

Family15PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 18

Variant NM_000071.2(CBS):c.919G>A (p.Gly307Ser), homozygous

ClinVar 117

gnomAD MAF= 0.00041539(Other), no homozygotes

FamilyAddInfo n/a

FamilyPMIDs n/a

Case29 Male, 1yo diagnosis (Family 25)

CasePresentingHPOs HP:0001256, HP:0001263

(Mild intellectual disability, Developmental delay)

HPOsFreeText Diagnosed was on the basis of developmental delay. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet.

CaseNotHPOs n/a

NotHPOsFreeText no other sequelae

CasePreviousTesting n/a

Variant 1. NM_000071.2(CBS):c.536_553del18 (p.Asp179_Leu184del), 2. NM_000071.2(CBS):c.325T>C (p.Cys109Arg), comp het

ClinVar 1. 198388, 2. 212878

gnomAD 1. MAF=0.00002683(European(non-Finnish), no homozygotes, 2. MAF= 0.0001631(Other), no homozygotes

CaseAddInfo son of patient 30

CasePMIDs n/a

FamilyLabel Family 26

Family26PresentingHPOs HP:0001083

(Lens dislocation)

HPOsFreeText Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Affected individuals were not responsive to the treatment, plasma homocysteine levels went unchanged. Patients were given additional oral betaine(3g twice per day) with a low protein diet.

FamilyNotHPOs n/a

NotHPOsFreeText n/a

CountryOrigin n/a

Ethnicity Portugese

Race n/a

Family26PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 31

Variant NM_000071.2(CBS):c.374G>A (p.Arg125Gln), homozygous

ClinVar 197625

gnomAD MAF= 0.00002326(European(non-Finnish)), no homozygotes

FamilyAddInfo n/a

FamilyPMIDs n/a

Case25 9yo diagnosis, Australia, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0002342, HP:0000939, HP:0001263, HP:0001369

(Lens dislocation, Moderate intellectual disability, Osteoporosis, Developmental delay, Arthritis)

HPOsFreeText Patient had severe osteoporosis, juvenile arthritis and was diagnosed on the basis of dislocated lenses and developmental delay. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided. (PMID:9156316): Total homocysteine was 252μmol/l before and 34μmol/l after treatment of betaine, folic acid, and low-dose aspirin.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS. (PMID: 9156316): Restriction analysis confirmed the presence of two variants. The variant c.430G>A destroys a TaqI site. Thus, TaqI digestion yielded uncleaved 155bp fragments in both the proband and his father, while the WT was cleaved into 107 and 48bp fragments. The c.1316G>A variant likewise destroys a HapII site. The proband and his father had uncleaved 120bp fragments while the WT had 87 and 33bp fragments on HapII digestion. As both variants were detected in the proband, father, and two paternal aunts, c.1316G>A and c.430G>A were proposed to be in cis.

Variant 1. NM_000071.2:c.892dup (p.Gln298ProfsTer?), 2. NM_000071.2(CBS):c.430G>A (p.Glu144Lys); 3. NM_000071.2(CBS):c.1316G>A (p.Arg439Gln), comp het, 2&3 in cis

ClinVar 1. n/a, 2. 122; 3. 189088

CAID 1. register

gnomAD 1. MAF=0.00001777(European(Non-finnish)), no homozygotes 2. MAF=0.00009799(South Asian), no homozygotes, 3. MAF=0.00005341(African), no homozygotes

CaseAddInfo n/a

CasePMIDs 9156316

Case15 3yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0001256

(Lens dislocation, Mild intellectual disability)

HPOsFreeText Diagnosis was based on dislocated lens and intellectual disability. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. This patient was not responsive to the treatment, plasma homocysteine levels went unchanged. This patient was given additional oral betaine(3g twice per day) with a low protein diet.

CaseNotHPOs n/a

NotHPOsFreeText no other sequelae

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant NM_000071.2(CBS):c.919G>A (p.Gly307Ser), homozygous

ClinVar 117

gnomAD MAF= 0.00041539(Other), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

found c.444dup in allele registry

according to Mutalyzer, for correct HGVS notation, the correct position was 2 nucleotides over. The aa consequence also looked the same as the article reported.

Case22 7yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0001256, HP:0011342

(Lens dislocation, Mild intellectual disability, Mild developmental delay)

HPOsFreeText Patient had marfanoid features and was diagnosed on the basis of dislocated lens and mild developmental delay. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet.

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2(CBS):c.919G>A (p.Gly307Ser), 2. NM_000071.2(CBS):c.536_553del18 (p.Asp179_Leu184del), comp het

ClinVar 1. 117, 2. 198388

gnomAD 1. MAF=0.00041539(Other), no homozygotes, 2. MAF= 0.00002683(European(non-Finnish)), no homozygotes

CaseAddInfo patient also carries a common 68bp insertion, 88ins68, variant that does not cause hyperhomocysteinemia.

CasePMIDs n/a

Case16 3yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0001256

(Lens dislocation, Mild intellectual disability)

HPOsFreeText Diagnosis was based on dislocated lens and marfanoid features. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. This patient was not responsive to the treatment, plasma homocysteine levels went unchanged. This patient was given additional oral betaine(3g twice per day) with a low protein diet.

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant NM_000071.2(CBS):c.919G>A (p.Gly307Ser), homozygous

ClinVar 117

gnomAD MAF= 0.00041539(Other), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

Case5 14yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083

(Lens dislocation)

HPOsFreeText Diagnosis was based on dislocated lenses. Plasma free homocystine was reduced from >80μmol to <10μmol (nv <60μmol) in response to treatment with folate and pyridoxine. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid.

CaseNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText no other sequelae

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2(CBS):c.833T>C (p.Ile278Thr), 2. NM_000071.2(CBS):c.325T>C (p.Cys109Arg), compound heterozygous

ClinVar 1. 120, 2. 212878

gnomAD 1. MAF=0.001432(European(non-Finnish)), no homozygotes, 2. MAF=0.0001631(Other), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

Case23 5yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0001256, HP:0002751, HP:0000766

(Lens dislocation, Mild intellectual disability, Kyphoscoliosis, Abnormality of the sternum)

HPOsFreeText Patient was diagnosed on the basis of dislocated lenses. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2(CBS):c.430G>A (p.Glu144Lys), 2. IVS1+1G>A, compound heterozygous

ClinVar 1. 122, 2. n/a

CAID 2. need more info

gnomAD 1. MAF=0.00009799(South Asian), no homozygotes, 2. n/a

CaseAddInfo n/a

CasePMIDs n/a

FamilyLabel Family 1

Family1PresentingHPOs n/a

HPOsFreeText plasma free homocystine was reduced from >80μmol to <10μmol (nv <60μmol) in response to treatment with folate and pyridoxine. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid.

FamilyNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText n/a

CountryOrigin n/a

Ethnicity Anglo-Celtic

Race n/a

Family1PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 1

Variant NM_000071.2(CBS):c.833T>C (p.Ile278Thr), homozygous

ClinVar 120

gnomAD MAF=0.001432(European(non-Finnish)), no homozygotes

FamilyAddInfo n/a

FamilyPMIDs n/a

Case13 8yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0000767

(Lens dislocation, Pectus excavatum)

HPOsFreeText borderline intellectual disability. Diagnosis was based on dislocated lenses. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. This patient had a partial response to the treatment. Homocystine levels were sharply reduced on pyridoxine and folate treatment, but did not levels did not fall below 20μmol (nv <60μmol) on this treatment alone.

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2(CBS):c.430G>A (p.Glu144Lys), 2. NM_000071.2(CBS):c.1111G>A (p.Val371Met), compound heterozygous

ClinVar 1. 122, 2. 212862

gnomAD 1. MAF=0.00009799(South Asian), no homozygotes, 2. MAF= 0.00006219(African), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

FamilyLabel Family 2

Family2PresentingHPOs n/a

HPOsFreeText plasma free homocystine was reduced from >80μmol to <10μmol (nv <60μmol) in response to treatment with folate and pyridoxine. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid.

FamilyNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText no other sequelae

CountryOrigin n/a

Ethnicity Anglo-Celtic

Race n/a

Family2PreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

ProbandLabel Case 3

Variant 1. NM_000071.2(CBS):c.833T>C (p.Ile278Thr), 2. NM_000071.2(CBS):c.302T>C (p.Leu101Pro), compound heterozygous

ClinVar 1. 120, 2. 189185

gnomAD 1. MAF=0.001432(European(non-Finnish)), no homozygotes, 2. not in gnomAD

FamilyAddInfo n/a

FamilyPMIDs n/a

Case27 6yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0001256, HP:0002616, HP:0006280, HP:0002583

(Lens dislocation, Mild intellectual disability, Aortic root dilation, Chronic pancreatitis, Colitis)

HPOsFreeText Patient diagnosed on the basis of presenting marfanoid features. Patient had chronic pancreatitis requiring TPN and colitis requiring colostomy. Final CT scan of patient looking like multi-infarct dementia. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2:c.684C>A (p.Asn228Lys), 2. IVS11+1G>A, comp het

ClinVar 1. n/a, 2 n/a

CAID 1. CA410600617, 2. not enough info

gnomAD 1. MAF=0.00001759(European(non-Finnish)), no homozygotes, 2. n/a

CaseAddInfo n/a

CasePMIDs n/a

Case30 Female, 24yo diagnosis (Family 25)

CasePresentingHPOs HP:0001083, HP:0001256, HP:0001263, HP:0002625, HP:0002204

(Lens dislocation, Mild intellectual disability, Developmental delay, Deep vein thrombosis, Pulmonary embolism)

HPOsFreeText Presented with a pulmonary embolus at 23yo after birth of son, presumably secondary to deep vein thrombosis. Patient's plasma free homocystine was reduced from >80μmol to <10μmol (nv <60μmol) in response to treatment with folate and pyridoxine.

CaseNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText n/a

CasePreviousTesting Diagnosed by family screen and deep vein thrombosis.

Variant 1. NM_000071.2(CBS):c.536_553del18 (p.Asp179_Leu184del), 2. NM_000071.2(CBS):c.1105C>T (p.Arg369Cys), comp het

ClinVar 1. 198388, 2. 212860

gnomAD 1. MAF=0.00002683(European(non-Finnish), no homozygotes, 2. MAF= 0.006796(Ashkenazi Jewish), 5 homozygotes

CaseAddInfo mother of patient 29

CasePMIDs n/a

Case12 4yo diagnosis, Anglo-Celtic

CasePresentingHPOs n/a

HPOsFreeText Plasma free homocystine was reduced from >80μmol to <10μmol (nv <60μmol) in response to treatment with folate and pyridoxine. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid.

CaseNotHPOs HP:0001249, HP:0001083

(Intellectual disability, Lens dislocation)

NotHPOsFreeText no other sequelae

CasePreviousTesting Diagnosis was based on family screen. Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2(CBS):c.430G>A (p.Glu144Lys), 2. NM_000071.2(CBS):c.146C>T (p.Pro49Leu), compound heterozygous

ClinVar 1. 122, 2. 212872

gnomAD 1. MAF=0.00009799(South Asian), no homozygotes, 2. MAF=0.0003116(European(non-Finnish)), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

Case33 41yo diagnosis, South African

CasePresentingHPOs HP:0001083

(Lens dislocation)

HPOsFreeText Diagnosis was based on dislocated lens and skeletal deformities. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet

CaseNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2(CBS):c.494G>A (p.Cys165Tyr), 2. NM_000071.2:c.1622dup (p.Asn541LysfsTer?), comp het

ClinVar 1. 495531

CAID 2. register

gnomAD 1. MAF=0.00001308(European(non-Finnish)), no homozygotes, 2. not in gnomAD

CaseAddInfo n/a

CasePMIDs n/a

Case26 2yo diagnosis, Australia, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0010864, HP:0000939, HP:0001263

(Lens dislocation, Severe intellectual disability, Osteoporosis, Developmental delay)

HPOsFreeText Patient had severe osteoporosis and was diagnosed on the basis of developmental delay and osteogenesis impefecta type IV. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided. (PMID:9156316): Urinary homocysteine was 42μmol/l before and 14μmol/l after treatment with betaine, folic acid, and aspirin.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS. (PMID:9156316): c.992C>A variant was also confirmed with HinfI restriction digest. A G mismatch was introduced to the 3' end of the antisense primer used to amplify the region in order to create the Hinfl restriction site as c.992C>A does not do so on its own. While the father and control sample had only an uncleaved 105bp band, both a 73bp and 32bp fragment were detected on HinfI restriction digestion analysis of the mother and proband.

Variant 1. NM_000071.2(CBS):c.992C>A (p.Ala331Glu), 2. NM_000071.2:c.444dup, comp het

ClinVar 1. 212857

CAID 2. register

gnomAD 1. MAF=0.000008824(European(non-Finnish), no homozygotes, 2. not in gnomAD

CaseAddInfo n/a

CasePMIDs 9156316

Case20 7yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0002650

(Lens dislocation, Scoliosis)

HPOsFreeText Diagnosis based on lens dislocation. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet

CaseNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2(CBS):c.919G>A (p.Gly307Ser), 2. NM_000071.2(CBS):c.494G>A (p.Cys165Tyr), comp het

ClinVar 1. 117, 2. 495531

gnomAD 1. MAF=0.00041539(Other), no homozygotes, 2. MAF= 0.00001308(European(non-Finnish)), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

Case9 11yo diagnosis, Anglo-Celtic

CasePresentingHPOs n/a

HPOsFreeText Plasma free homocystine was reduced from >80μmol to <10μmol (nv <60μmol) in response to treatment with folate and pyridoxine. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid.

CaseNotHPOs HP:0001249, HP:0001083

(Intellectual disability, Lens dislocation)

NotHPOsFreeText no other sequelae

CasePreviousTesting Diagnosis was based on family screen. Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2(CBS):c.833T>C (p.Ile278Thr), 2. NM_000071.2(CBS):c.1221delC (p.Trp408Glyfs), compound heterozygous

ClinVar 1. 120, 2. 495530

gnomAD 1. MAF=0.001432(European(non-Finnish)), no homozygotes, 2. MAF=0.000008802(European(non-Finnish), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

Case14 29yo diagnosis, Australia, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0002751, HP:0000939

(Lens dislocation, Kyphoscoliosis, Osteoporosis)

HPOsFreeText Diagnosis was based on dislocated lens and skeletal deformity. Patient has severe kyphoscoliosis. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. This patient had a partial response to the treatment. Homocystine levels were sharply reduced on pyridoxine and folate treatment, but levels did not fall below 20μmol (nv <60μmol) on this treatment alone. (PMID:9156316:): In this study, patient was found to have mild intellectual disability and osteoporosis at 50yo.

CaseNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided. (PMID:9156316): Serum homocysteine was 100μmol/l and methionine was 18μmol/l after five years of treatment. Addition of betaine(3g twice per day) lowered homocysteine to 18μmol/l which remained <50μmol for years.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2(CBS):c.833T>C (p.Ile278Thr), 2. NM_000071.2(CBS):c.1058C>T (p.Thr353Met), comp het

ClinVar 1. 120, 2. 131

gnomAD 1. MAF=0.001432(European(non-Finnish)), no homozygotes, 2. MAF=0.0002916(African), no homozygotes

CaseAddInfo Patient carries a common 68bp insertion, 88ins68, variant that does not cause hyperhomocysteinemia. (PMID:9156316): Additionally is heterozygous for a c.699C>T(Y233Y) synonymous variant as well as homozygous c.1080T>C(A360A) synonymous variants.

CasePMIDs 9156316

Case24 6yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083

(Lens dislocation)

HPOsFreeText Patient had marfanoid features and was diagnosed on the basis of dislocated lenses. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet

CaseNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2(CBS):c.904G>A (p.Glu302Lys), 2. NM_000071.2(CBS):c.430G>A (p.Glu144Lys); 3. NM_000071.2(CBS):c.1316G>A (p.Arg439Gln), comp het, 2&3 in cis

ClinVar 1. 496864, 2. 122; 3. 189088

gnomAD 1. MAF=0.00006153(African), no homozygotes 2. MAF=0.00009799(South Asian), no homozygotes, 3. MAF=0.00005341(African), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

Case1874(T.C.) Female, 5yo diagnosis, Irish

CasePresentingHPOs HP:0010864, HP:0000939, HP:0002942, HP:0000766, HP:0000276, HP:0000275, HP:0000218, HP:0000689, HP:0002857, HP:0001166, HP:0001634, HP:0001263, HP:0000750, HP:0002240, HP:0002353

(Severe intellectual disability, Osteoporosis, Thoracic kyphosis, Sternal anomaly, Long face, Thin face, High palate, Malocclusion, Genu valgum, Arachnodactyly, Lens dislocation, Mitral valve prolapse, Delayed milestones, Speech delay, Enlarged liver, EEG abnormality)

HPOsFreeText Patient had severe intellectual disability. Her spine was normal, but long bones were osteoporotic. Upon exam at 5yo, she had mild kyphosis of upper thoracic spine, mild sternal depression, marked genu valgum, and arachnodactyly. Patient was also myopic with bilateral lens dislocation. She had prominent recurrent malar flush, long and thin face, high-arched palate, malocclusion and mitral valve prolapse.

(PMID: 20329304): Patient was born at term after normal pregnancy weighing 3.4kg. Normal neonatal course, but with delayed milestones. Speech at 5yo was monosyllabic , but verbal comprehension was good. No convulsions at this time. She had a palpable liver, 2cm below margin, but had normal consistence. She had an abnormal EEG with non-specific diffuse changes and excess slow-wave activity. Patient's IQ was 36.

CaseNotHPOs HP:0001250, HP:0002086, HP:0000707

(Seizures, Respiratory abnormality, Neurologic abnormality)

NotHPOsFreeText n/a

CasePreviousTesting Plasma homocysteine was 70μM pretreatment. Pyroxidine treatment reduced those levels to trace amounts. In patient fibroblasts, no CBS protein was detect on Western blot and CBS assay detected no activity. (PMID: 20329304): "Full hemogram, routine urine analysis, liver function tests, serum ion and iron-binding capacity, plasma magnesium, serum calcium, inorganic phosphate, fasting blood sugars, blood urea nitrogen, and bone marrow examination were all normal". Heavy homocysteine spot shown on chromatogram of urinary amino acids.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod Created a bacteria expression system in E.coli by substituting one of three fragments of (PCR amplified)patient cDNA into WT CBS sequence already subcloned in expression plasmids. Bacteria were screened based on which ones did not have CBS activity. Those that did not have activity were thought to have LOF variants in CBS. Plasmids containing the inactivating fragments, ones cut with NcoI/XmaI, were sequenced.

Variant 1. NM_000071.2:c.233C>G (p.Pro78Arg);2. NM_000071.2:c.306G>C (p.Lys102Asn) - 1&2 in cis

ClinVar 1. 188988;2. 188989

gnomAD 1. MAF=0.0001631(Other), no homozygotes, 2. MAF=0.0001630(Other), no homozygotes

CaseAddInfo n/a

CasePMIDs 20329304

Case1875(M.C.) Female, 22yo died, Irish

CasePresentingHPOs HP:0001263, HP:0001249, HP:0001250, HP:0002650, HP:0002625, HP:0005625, HP:0002857, HP:0000545, HP:0000276, HP:0000275, HP:0000218, HP:0000678, HP:0002878, HP:0001695, HP:0002240

(Developmental delay, Intellectual disability, Seizures, Scoliosis, Deep vein thrombosis, Osteoporosis of vertebrae, Genu valgum, Myopia, Long face, Narrow face, High palate, Crowded teeth, Respiratory failure, Cardiac arrest, Enlarged liver)

HPOsFreeText Diagnosed with homocystinuria after exam for developmental delay at 13mo. Patient had severe intellectual disability and seizures. At 14yo she had surgery for scoliosis, postsurgery she had a popliteal vein thrombosis. In addition to osteoporosis of the spine, she had genu valgum and myopia. The patient also had a long and narrow face, high-arched palate and crowded teeth. Respiratory failure and cardiac arrest at 22yo likely due to overuse of antiasthmatic medication.

(PMID:20329304): She was delivered normally at term, weighed 3kg, made uncomplicated neonatal progress, no history of convulsions,reached early milestones at expected times but did not sit up until 13mo. On report she was well fed and well developed, but with persistent shadow in right upper load on roentgenogram, enlarged liver of normal consistence, spleen was not palpable, negative neurological exam, mental age was 9mo. Aortogram was negative for vascular abnormalities in upper left chest. Skull and long bones were normal but osteoporosis of the spine was detected by roentgenogram.

CaseNotHPOs HP:0001083

(Lens dislocation)

NotHPOsFreeText no malar flush, lens displacement, or skeletal deformity on exam at 13mo.

CasePreviousTesting Plasma homocysteine was 45μM pretreatment. Pyroxidine treatment reduced those levels to trace amounts. In patient fibroblasts, no CBS protein was detect on Western blot and CBS assay detected no activity. (PMID: 20329304): "Full hemogram, routine urine analysis, liver function tests, serum ion and iron-binding capacity, plasma magnesium, serum calcium, inorganic phosphate, fasting blood sugars, blood urea nitrogen, and bone marrow examination were all normal". Strong positive on cyanide nitroprusside, heavy homocysteine spot on chromatogram of urinary amino acids.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod Created a bacteria expression system in E.coli by substituting one of three fragments of (PCR amplified)patient cDNA into WT CBS sequence already subcloned in expression plasmids. Bacteria were screened based on which ones did not have CBS activity. Those that did not have activity were thought to have LOF variants in CBS. Plasmids containing the inactivating fragments, one cut with NcoI/XmaI and another cut with Bpu1102/BstX, were sequenced.

Variant 1. NM_000071.2:c.715G>A (p.Glu239Lys),

1. NM_000071.2:c.233C>G (p.Pro78Arg);3. NM_000071.2:c.306G>C (p.Lys102Asn) - 2&3 in cis, compound heterozygous

ClinVar 1. n/a, 2. 188988;3. 188989

CAID 1. CA410600501

gnomAD 1. not in gnomAD, 2. MAF=0.0001631(Other), no homozygotes, 3. MAF=0.0001630(Other), no homozygotes

CaseAddInfo n/a

CasePMIDs 20329304

FamilyLabel Family 1

Family1PresentingHPOs HP:0000924, HP:0000939

(Skeletal anomalies, Osteoporosis)

HPOsFreeText Patients diagnosed with homocystinuria after finding abnormally high homocysteine on urine sample exam.

FamilyNotHPOs n/a

NotHPOsFreeText n/a

CountryOrigin Ireland

Ethnicity n/a

Race n/a

Family1PreviousTesting Tested pretreatment plasma homocysteine in each patient. Pyroxidine treatment dramatically reduced plasma homocysteine in all patients. In patient fibroblasts, no CBS protein was detect on Western blot and CBS assay detected no activity. (PMID: 20329304): "Full hemogram, routine urine analysis, liver function tests, serum ion and iron-binding capacity, plasma magnesium, serum calcium, inorganic phosphate, fasting blood sugars, blood urea nitrogen, and bone marrow examination were all normal". Heavy homocysteine spot was detected on chromatogram of urinary amino acids.

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod Created a bacteria expression system in E.coli by substituting one of three fragments of (PCR amplified)patient cDNA into WT CBS sequence already subcloned in expression plasmids. Bacteria were screened based on which ones did not have CBS activity. Those that did not have activity were thought to have LOF variants in CBS. Plasmids containing the inactivating fragments were sequenced.

ProbandLabel 1875

Variant 1. NM_000071.2:c.715G>A (p.Glu239Lys),

1. NM_000071.2:c.233C>G (p.Pro78Arg);3. NM_000071.2:c.306G>C (p.Lys102Asn) - 2&3 in cis, compound heterozygous

ClinVar 1. n/a, 2. 188988;3. 188989

CAID 1. CA410600501

gnomAD 1. not in gnomAD, 2. MAF=0.0001631(Other), no homozygotes, 3. MAF=0.0001630(Other), no homozygotes

FamilyAddInfo Father unavailable for study. Mother was clinically/biochemically healthy with an unexplained macrocytosis. Mother had absent CBS activity, but no homocystinuria symptoms and was heterozygous for the Glu239Lys variant. The variant was found in inactive bacteria carrying the BB segment. Presence of the variant was reinforced by amplifying, subcloning, then sequencing her genomic DNA of the region corresponding to BB.

FamilyPMIDs 20329304

Case1873(W.C.) Male, 37yo report, Irish

CasePresentingHPOs HP:0002625, HP:0000766, HP:0002942, HP:0006682, HP:0005625, HP:0002353

(Deep vein thrombosis, Sternal anomaly, Thoracic kyphosis, Ventricular extrasystoles, Osteoporosis of vertebrae, EEG abnormality)

HPOsFreeText Patient had single episode of deep vein thrombosis of left leg at 30yo. No further clinical sequelae related to homocystinuria.

(PMID: 20329304): Patient was born normally at 36wks gestation weighing 2.9kg. By 9 and half years old he was well developed and nourished, mentally normal at IQ 93. He did have pronounced malar flush, some grey hair of normal texture, slightly depressed sternum, mild kyphosis of upper thoracic spine. Exam of major systems was normal save for occasional ventricular extrasystole. Roengenogram showed marked osteoporosis of spine, but normal long bones. EEG showed non-specific diffuse abnormality.

CaseNotHPOs HP:0001083

(Lens dislocation)

NotHPOsFreeText lenses were found to not be displaced upon exam at 9 and a half years old.

CasePreviousTesting Plasma homocysteine was 450μM pretreatment. Pyroxidine treatment reduced those levels to trace amounts. In patient fibroblasts, no CBS protein was detect on Western blot and CBS assay detected no activity. (PMID: 20329304): "Full hemogram, routine urine analysis, liver function tests, serum ion and iron-binding capacity, plasma magnesium, serum calcium, inorganic phosphate, fasting blood sugars, blood urea nitrogen, and bone marrow examination were all normal". Heavy homocysteine spot shown on chromatogram of urinary amino acids.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod Created a bacteria expression system in E.coli by substituting one of three fragments of (PCR amplified)patient cDNA into WT CBS sequence already subcloned in expression plasmids. Bacteria were screened based on which ones did not have CBS activity. Those that did not have activity were thought to have LOF variants in CBS. Plasmids containing the inactivating fragments, one cut with NcoI/XmaI and another cut with Bpu1102/BstX, were sequenced.

Variant 1. NM_000071.2:c.715G>A (p.Glu239Lys),

1. NM_000071.2:c.233C>G (p.Pro78Arg);3. NM_000071.2:c.306G>C (p.Lys102Asn) - 2&3 in cis, compound heterozygous

ClinVar 1. n/a, 2. 188988;3. 188989

CAID 1. CA410600501

gnomAD 1. not in gnomAD, 2. MAF=0.0001631(Other), no homozygotes, 3. MAF=0.0001630(Other), no homozygotes

CaseAddInfo Mother had edema of both legs with no other features of pre-eclampsia during the last six weeks of pregnancy.

CasePMIDs 20329304

Case# HCU-102-3, 8yo report, Iran, Sistani

CasePresentingHPOs HP:0001083, HP:0003235, HP:0000924

(Ectopia lentis, Increased methionine in blood, Skeletal abnormality)

HPOsFreeText skeletal abnormality/elongated long bone, increased urinary cysteine, elevated plasma methionine

CaseNotHPOs HP:0001249, HP:0002970, HP:0001010, HP:0000501

(Intellectual disability, Genu varum, Hypopigmentation, Glaucoma)

NotHPOsFreeText n/a

CasePreviousTesting plasma methionine 108μm/l(normal range 6-40μm/l)

CaseMethod1 Sanger

CaseMethod2 n/a

CaseGenotypingMethod Sanger sequenced exon 3 of the CBS gene

Variant NM_000071.2(CBS):c.346G>A (p.Gly116Arg), homozygous

ClinVar 188787

gnomAD MAF=0.00002892(Latino), no homozygotes

CaseAddInfo from the province of Sistan and Baluchestan. no known consanguinity although the patient is homozygous for a founder variant

CasePMIDs n/a

FamilyLabel HCU-103

Family#PresentingHPOs HP:0001249

(Intellectual disability)

HPOsFreeText elevated plasma homocysteine, elevated urinary cysteine

FamilyNotHPOs HP:0001083, HP:0002970, HP:0001010, HP:0000501, HP:0000924

(Ectopia lentis, Genu varum, Hypopigmentation, Glaucoma, Skeletal abnormalities)

NotHPOsFreeText skeletal abnormality/elongated long bones

CountryOrigin Iran

Ethnicity Sistani

Race n/a

Family#PreviousTesting tested for homocysteine in plasma and for cysteine in urine

FamilyMethod1 Sanger

FamilyMethod2 n/a

FamilyGenotypingMethod Sanger sequenced exon 3 of the CBS gene

ProbandLabel HCU-103-4

Variant NM_000071.2(CBS):c.346G>A (p.Gly116Arg), homozygous

ClinVar 188787

gnomAD MAF=0.00002892(Latino), no homozygotes

FamilyAddInfo from the province of Sistan and Baluchestan. no known consanguinity although the affected individuals are homozygous for a founder variant

FamilyPMIDs n/a

Case# HCU-101-3, 10yo report, Iran, Sistani

CasePresentingHPOs HP:0001249, HP:0001083, HP:0002970, HP:0001634, HP:0003235, HP:0000924

(Intellectual disability, Ectopia lentis, Genu varum, Mitral valve prolapse, Increased methionine in blood, Skeletal abnormality)

HPOsFreeText skeletal abnormality/elongated long bones, elevated, elevated plasma homocysteine, elevated urinary cysteine, elevated plasma methionine

CaseNotHPOs HP:0001010, HP:0000501

(Hypopigmentation, Glaucoma)

NotHPOsFreeText n/a

CasePreviousTesting Plasma homocysteine 330μm/l(upper normal limit 15μm/l), plasma methionine 142μm/l(normal range 6-40μm/l)

CaseMethod1 Sanger

CaseMethod2 n/a

CaseGenotypingMethod Sanger sequenced exon 3 of the CBS gene

Variant NM_000071.2(CBS):c.346G>A (p.Gly116Arg), homozygous

ClinVar 188787

gnomAD MAF=0.00002892(Latino), no homozygotes

CaseAddInfo from the province of Sistan and Baluchestan. no known consanguinity although the patient is homozygous for a founder variant

CasePMIDs n/a

FamilyLabel HCU-220

Family#PresentingHPOs HP:0001249, HP:0001083, HP:0002970, HP:0001010, HP:0000924, HP:0001263

(Intellectual disability, Ectopia lentis, Genu varum, Hypopigmentation, Skeletal abnormality, cognitive delay)

HPOsFreeText CBS deficiency diagnosis, skeletal abnormality/elongated long bones, cognitive delay was apparent as early as 2yo

FamilyNotHPOs HP:0000501

(Glaucoma)

CountryOrigin Iran

Ethnicity Sistani

Race n/a

Family#PreviousTesting no other CBS variants were observed after Sanger sequencing

FamilyMethod1 Linkage analysis or Homozygosity mapping (genome-wide)

FamilyMethod2 Sanger

FamilyGenotypingMethod Genome-wide SNP genotyping and whole genome linkage analysis using MERLIN to analyze DNA of the parents and 7 siblings. Homoygosity mapping of the homozygous regions common to the three affected individuals and absent in unaffected individuals then narrowed the homozygous region to a locus including 296 protein coding genes. CBS, being one of those genes, was considered since intellectual disability accompanies homocysteinuria. The 15 coding exons and flanking intronic sequences of the CBS gene were PCR amplified then Sanger sequenced.

ProbandLabel HCU-220-5

Variant NM_000071.2(CBS):c.346G>A (p.Gly116Arg), homozygous

ClinVar 188787

gnomAD MAF=0.00002892(Latino), no homozygotes

FamilyAddInfo family from a remote village in the province of Sistan and Baluchestan. consanguinity-first cousin parents, several heterozygous family members (both parents and 2 siblings) had cardiac disorders such as mitral regurgitation or mitral valve prolapse, but were generally negative for the phenotypes of the affected individuals. Heterozygous sibling HCU-220-3 is the only individual who presented in this study with glaucoma and mitral valve prolapse.

FamilyPMIDs n/a

Case5 Female, 6yo diagnosis, Korean

CasePresentingHPOs HP:0001083, HP:0003235

(Ectopia lentis, Increased blood methionine)

HPOsFreeText pretreatment homocysteine was normal, increased post-treatment total homocysteine, patient treated with low-methionine diet, vitamin B6, folate, vitamin B12, and betaine after diagnosis

CaseNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText Marfan syndrome, vascular occlusion

CasePreviousTesting pretreatment/posttreatment methionine: 697/648 μM(nv 7-47), pretreatment homocysteine: 3 μM(nv 0-5), posttreatment total homocysteine 121 μM(nv 5-15)

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified all 16 coding exons of CBS gene, then direct sequenced

Variant 1. NM_001178008.1:c.464C>T(p.Ala155Val), 2. NM_000071.2(CBS):c.1039G>A (p.Gly347Ser), compound heterozygous

ClinVar 1. n/a, 2. 188801

CAID 1. CA410601498

gnomAD 1. not in gnomAD, 2. MAF=0.00006497(European(non-Finnish)), no homozygotes

CaseAddInfo A155V inherited from father, G347S from mother

CasePMIDs n/a

Case1 Female, 1mo diagnosis, Korean

CasePresentingHPOs HP:0003235

(Increased blood methionine)

HPOsFreeText increased pre-treatment blood homocysteine and post-treatment total homocysteine, patient treated with low-methionine diet, vitamin B6, folate, vitamin B12, and betaine after diagnosis

CaseNotHPOs HP:0001083, HP:0001249

(Ectopia lentis, Intellectual disability)

NotHPOsFreeText Marfan syndrome, vascular occlusion

CasePreviousTesting pretreatment/posttreatment methionine: 1,239/123 μM(nv 7-47), pretreatment/posttreatment homocysteine: 28/0 μM(nv 0-5), posttreatment total homocysteine 144 μM(nv 5-15). Diagnosis upon neonatal screen

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified all 16 coding exons of CBS gene, then direct sequenced

Variant 1. NM_001320298.1:c.461T>A(p.Leu154Gln), 2. NM_000071.2(CBS):c.770C>T (p.Thr257Met), compound heterozygous

ClinVar 1. n/a, 2. 188927

CAID 1. CA410601512

gnomAD 1. not in gnomAD, 2. MAF=0.0001396(Other), no homozygotes

CaseAddInfo L154Q variant from father, T257M from mother. Additional R18C variant inherited from father, but protein from this SNP retains normal expression, 30-70% of enzyme activity and was found to have a 1/100 frequency in the study's control population

CasePMIDs n/a

Case4 Female, 7yo diagnosis, Korean

CasePresentingHPOs HP:0001083, HP:0001249, HP:0003235

(Ectopia lentis, Intellectual disability, Increased blood methionine)

HPOsFreeText Marfan syndrome, vascular occlusion, increased pre-treatment blood homocysteine and post-treatment total homocysteine, patient treated with low-methionine diet, vitamin B6, folate, vitamin B12, and betaine after diagnosis

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting pretreatment/posttreatment methionine: 24/575 μM(nv 7-47), pretreatment/posttreatment: 34/0 μM(nv 0-5), posttreatment total homocysteine 194 μM(nv 5-15)

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified all 16 coding exons of CBS gene, then direct sequenced

Variant 1. NM_000071.2(CBS):c.1006C>T (p.Arg336Cys), 2. NM_000071.2(CBS):c.1058C>T (p.Thr353Met), compound heterozygous

ClinVar 1. 92423, 2. 131

gnomAD 1. MAF=0.00004417(European(non-Finnish)), no homozygotes, 2. MAF=0.0002916(African), no homozygotes

CaseAddInfo R336C variant was paternally inherited, T353M variant was maternally inherited

CasePMIDs n/a

FamilyLabel Family 1

Family1PresentingHPOs HP:0003235

(Increased blood methionine)

HPOsFreeText increased pre-treatment blood homocysteine and post-treatment total homocysteine, affected individuals were treated with low-methionine diet, vitamin B6, folate, vitamin B12, and betaine after diagnosis

FamilyNotHPOs n/a

NotHPOsFreeText Marfan syndrome, vascular occlusion

CountryOrigin Korea

Ethnicity n/a

Race n/a

Family1PreviousTesting tested plasma homocysteine and methionine in both siblings, both metabolites were elevated

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod PCR amplified all 16 coding exons of CBS gene, then direct sequenced. Deletion variant sequenced after cloning into pGEM T easy vector.

ProbandLabel Case 2

Variant 1. NM_001178008.1:c.700_702del(p.Asp234del), NM_000071.2(CBS):c.770C>T (p.Thr257Met), compound heterozygous

ClinVar 1. n/a, 2. 188927

CAID 1. register link

gnomAD 1. not in gnomAD, 2. MAF=0.0001396(Other), no homozygotes

FamilyAddInfo D234del inherited from father, T257M inherited from mother

FamilyPMIDs n/a

FamilyLabel Family 1

Family1PresentingHPOs HP:0001083, HP:0000545, HP:0000501, HP:0001249, HP:0001260, HP:0001251, HP:0007256, HP:0000577, HP:0002317, HP:0007663, HP:0030854)

(Ectopia lentis, Myopia, Glaucoma, Intellectual disability, Dysarthria, Ataxia, Pyramidal signs, Exotropia, Gait instability, Poor visual acuity, Staphyloma)

HPOsFreeText skeletal deformities, malar flush, increased serum homocysteine and methionine, corneal staphyloma, biocular lens dislocation

FamilyNotHPOs n/a

CountryOrigin China

Ethnicity n/a

Race n/a

Family1PreviousTesting Screened for variants MTHFR by PCR amplifying its coding sequence. No variants were detected in MTHFR. Also measured metabolite levels of homocysteine and methionine in plasma, both were elevated in affected individuals

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod Coding sequences of both MTHFR and CBS were PCR amplified and Sanger sequenced detecting no variants in MTHFR. Sequence primers for CBS were designed from flanking sequences of each exon.

ProbandLabel III:3

Variant 1. NM_001178008.1:c.407T>C(p.Leu136Pro), 2. NM_001178008.1:c.473C>T(p.Ala158Val), compound heterozygous

ClinVar n/a

CAID 1. CA321097579, 2. CA410601473

gnomAD 1. MAF=0.000008809(European(non-Finnish)), no homozygotes, 2. MAF=0.00004164(South Asian), no homozygotes

FamilyAddInfo parents, grandparents and other relatives were asymptomatic for homocystinuria. A158V variant inherited from father(II:3), L136P from mother(II:4). Han Chinese

FamilyPMIDs n/a