Case#: Subject number 33, female, 16 years (diagnosis), 20 years (baseline visit)

DiseaseAssertion: Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0003236 (Elevated circulating creatine kinase concentration)

CaseHPOFreeText:

CaseNotHPOs: HP:0002098 (respiratory distress), HP:0002870 (obstructive sleep apnea), HP:0001324 (Muscle Weakness)

CaseNotHPOFreeText: no mechanical ventilation at Baseline Visit, no mechanical ventilation at last visit

CasePreviousTesting: "reduced enzymatic activity on fibroblasts, blood leukocytes or skeletal muscle and/or the presence of two known mutations in the GAA gene"

PreviouslyPublished: N/A

Patient3: Female, 4.5yo, Family B (fig. 2)

CasePresentingHPOs: HP:0001733 (pancreatitis)

HPOsFreeText: acute neonatal IVA, treated with IVA special formula and vegetarian diet, stopped formula at 2yo and remained on vegetarian diet. Urinary organic acid analysis showed elevated lactic acid, 3-hydroxy-isovaleric acid, and isovalerylglycine, C5-carnitine = 10.8 µmol/l, fluctuating levels of serum ammonia which were eventually normalized with oral sodium benzoate treatment, admitted to hospital 2 times for gastroenteritis with metabolic acidosis and then for recurrent vomiting due to acute pancreatitis. sat unsupported at 6mo, walked and spoke first word at 12mo. As last physical, height = 105cm, weight = 18kg, and had unremarkable neurologic, chest, cardiovascular, and abdominal exams

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: diagnosed at birth via NBS, consanguineous family

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: c.ins386T (p.Tyr129fs) no ClinVar or CAID

Variant2: NM_002225.3(IVD):c.732C>T (p.Asp244=)

ClinVar: 94057, https://www.ncbi.nlm.nih.gov/clinvar/variation/94057/

gnomAD: n/a

Variant3: NC_000015.9:g.40699940T>C (NM_002225.4(IVD):c.234+14C=)

CAID: CA147572, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NC_000015.9%3Ag.40699940T%3EC

ClinVar: 94053, https://www.ncbi.nlm.nih.gov/clinvar/variation/94053/

gnomAD: 0.6830, https://gnomad.broadinstitute.org/variant/15-40699940-T-C

Patient8: Male, 6yo, Family C (fig. 2)

CasePresentingHPOs: HP:0000486, HP:0000651 (squint, diplopia)

HPOsFreeText: acute neonatal IVA, treated with IVA special formula and oral L-carnitine, elevated isovalerylglycine, C5-carnitine = 6.8 µmol/l, normal development for age, weight = 128cm, weight = 28kg, normal chest, cardiovascular, and abdominal exams

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: diagnosed at 3do via NBS, consanguineous family, family history and multiple sibling deaths

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.3:c.1207T>A

CAID: CA391724509, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391724509

gnomAD: n/a

Variant2: NC_000015.9:g.40699940T>C (NM_002225.4(IVD):c.234+14C=)

CAID: CA147572, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NC_000015.9%3Ag.40699940T%3EC

ClinVar: 94053, https://www.ncbi.nlm.nih.gov/clinvar/variation/94053/

gnomAD: 0.6830, https://gnomad.broadinstitute.org/variant/15-40699940-T-C

Patient4: Male, 2.5yo

CasePresentingHPOs: HP:0002033, HP:0001254, HP:0001987, HP:0001873, HP:0002013 (poor sucking, lethargy, hyperammonaemia, thrombocytopenia, vomiting)

HPOsFreeText: acute neonatal IVA, treated with IVA special formula along with sodium benzoate and glycine (benzoate and glycine discontinued after 1yr), elevated isovalerylglycine, C5-carnitine = 17.4 µmol/l, birth weight = 3kg, able to sit at 6mo, walked at 13mo, began to babble at 17mo, did not have bladder/bowel control until 2.5yo, current weight = 14kg, current height = 86.5cm

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: symptom onset at 5do, diagnosis at 30do via clinical presentation, consanguineous family

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.4(IVD):c.863C>T (p.Ala288Val) listed in paper as c.872C>T (p.Ala291Val)

ClinVar: 281076, https://www.ncbi.nlm.nih.gov/clinvar/variation/281076/

gnomAD: n/a

Variant2: NC_000015.9:g.40699940T>C (NM_002225.4(IVD):c.234+14C=)

CAID: CA147572, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NC_000015.9%3Ag.40699940T%3EC

ClinVar: 94053, https://www.ncbi.nlm.nih.gov/clinvar/variation/94053/

gnomAD: 0.6830, https://gnomad.broadinstitute.org/variant/15-40699940-T-C

Patient1: Male, 4yo, Twin A, Family A (fig. 2)

CasePresentingHPOs:

HPOsFreeText: acute neonatal IVA, treated with IVA special formula, elevated isovalerylglycine in urine organic acids, C5-carnitine = 6.15 µmol/l, at 2yo stopped formula and switched to vegetarian diet with L-carnitine supplements, admitted every 3-4mo due to metabolic crisis, at 4yo began formula again along with vegetarian diet and L-carnitine supplements, sat alone at 6mo, walked alone at 1yo, spoke first word at 1yo, unremarkable systemic examination at 4yo

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: diagnosed at 3 days old via NBS (positive family history and 3 sibling deaths), consanguineous family

CasePMIDs: PMID: 24516753

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.4(IVD):c.1184G>A (p.Arg395Gln) listed in paper as c.1193G>A (p.R398Q)

ClinVar: 529434, https://www.ncbi.nlm.nih.gov/clinvar/variation/529434/

gnomAD: n/a

Variant2: NC_000015.9:g.40699940T>C (NM_002225.4(IVD):c.234+14C=)

CAID: CA147572, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NC_000015.9%3Ag.40699940T%3EC

ClinVar: 94053, https://www.ncbi.nlm.nih.gov/clinvar/variation/94053/

gnomAD: 0.6830, https://gnomad.broadinstitute.org/variant/15-40699940-T-C

CaseGM01565: Female, 16 years report, Caucasian, Europe

CasePresentingHPOs: HP:0003153 (Cystathioninuria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband is a homozygote for this variant.

CasePreviousTesting: N/A

CaseGenotypingMethod: Primers were developed and the CTH exons 1-12 and exon-intron boundaries were PCR amplified and sequenced. All sequence variations were verified by restriction enzyme analysis and/or repeat sequencing.

Variant: NM_001902.5:c.200C>T (p.Thr67Ile)

ClinVar: 2939 https://www.ncbi.nlm.nih.gov/clinvar/variation/2939/

gnomAD: Ashkenazi Jewish 9.934e-3, Overall 6.308e-3 https://gnomad.broadinstitute.org/variant/1-70881670-C-T

CaseGM01454: Male, 7 years report, Asian, China

CasePresentingHPOs: HP:0003153 (Cystathioninuria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband is a homozygote for this variant.

CasePreviousTesting: N/A

CaseGenotypingMethod: Primers were developed and the CTH exons 1-12 and exon-intron boundaries were PCR amplified and sequenced. All sequence variations were verified by restriction enzyme analysis and/or repeat sequencing.

Variant: CTH, 2-BP DEL, 940CT AKA: NM_001902.5:c.784_785del (p.Leu262Thrfs*21)

ClinVar: 2937 https://www.ncbi.nlm.nih.gov/clinvar/variation/2937/

gnomAD: East Asian 1.088e-4, Overall 7.960e-6 https://gnomad.broadinstitute.org/variant/1-70897822-ACT-A

CaseDII-2: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 970 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

CaseAII-4: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 2085 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband for Family A

Variant1: NM_000277.3(PAH):c.165del (p.Phe55fs)

ClinVar: 611 https://www.ncbi.nlm.nih.gov/clinvar/variation/611/

gnomAD: 0.00002639, https://gnomad.broadinstitute.org/variant/12-103306571-CA-C?dataset=gnomad_r3

Variant2: NM_000277.3(PAH):c.143T>C (p.Leu48Ser)

ClinVar: 608 https://www.ncbi.nlm.nih.gov/clinvar/variation/608/

gnomAD: 0.001025, https://gnomad.broadinstitute.org/variant/12-102912816-A-G?dataset=gnomad_r3

CaseBI-1: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 375 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.688G>A (p.Val230Ile)

ClinVar: 102784 https://www.ncbi.nlm.nih.gov/clinvar/variation/102784/

gnomAD: 0.0009025, https://gnomad.broadinstitute.org/variant/12-102855154-C-T?dataset=gnomad_r3

CaseEI-1: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 430 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

Variant1: NM_000277.3(PAH):c.1066-11G>A

ClinVar: 607 https://www.ncbi.nlm.nih.gov/clinvar/variation/607/

gnomAD: 0.0004116, https://gnomad.broadinstitute.org/variant/12-103237568-C-T

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

CaseAI-1: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 330 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

Variant1: NM_000277.3(PAH):c.143T>C (p.Leu48Ser)

ClinVar: 608 https://www.ncbi.nlm.nih.gov/clinvar/variation/608/

gnomAD: 0.001025, https://gnomad.broadinstitute.org/variant/12-102912816-A-G?dataset=gnomad_r3

Variant2: NM_000277.3(PAH):c.898G>T (p.Ala300Ser)

ClinVar: 92751 https://www.ncbi.nlm.nih.gov/clinvar/variation/92751/

gnomAD: 0.006318, https://gnomad.broadinstitute.org/variant/12-102851701-C-A?dataset=gnomad_r3

CaseDI-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.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.898G>T (p.Ala300Ser)

ClinVar: 92751 https://www.ncbi.nlm.nih.gov/clinvar/variation/92751/

gnomAD: 0.006318, https://gnomad.broadinstitute.org/variant/12-102851701-C-A?dataset=gnomad_r3

CaseAII-5: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 440 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

Variant1: NM_000277.3(PAH):c.165del (p.Phe55fs)

ClinVar: 611 https://www.ncbi.nlm.nih.gov/clinvar/variation/611/

gnomAD: 0.00002639, https://gnomad.broadinstitute.org/variant/12-103306571-CA-C?dataset=gnomad_r3

Variant2: NM_000277.3(PAH):c.898G>T (p.Ala300Ser)

ClinVar: 92751 https://www.ncbi.nlm.nih.gov/clinvar/variation/92751/

gnomAD: 0.006318, https://gnomad.broadinstitute.org/variant/12-102851701-C-A?dataset=gnomad_r3

CaseAII-3: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 370 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

Variant1: NM_000277.3(PAH):c.165del (p.Phe55fs)

ClinVar: 611 https://www.ncbi.nlm.nih.gov/clinvar/variation/611/

gnomAD: 0.00002639, https://gnomad.broadinstitute.org/variant/12-103306571-CA-C?dataset=gnomad_r3

Variant2: NM_000277.3(PAH):c.898G>T (p.Ala300Ser)

ClinVar: 92751 https://www.ncbi.nlm.nih.gov/clinvar/variation/92751/

gnomAD: 0.006318, https://gnomad.broadinstitute.org/variant/12-102851701-C-A?dataset=gnomad_r3

Case2929: Male, 4 months diagnosis, Czech

CasePresentingHPOs: HP:0001270, HP:0011344, HP:0003153, HP:0003698, HP:0002300, HP:0004484, HP:0008454 (Motor delay, Severe psychomotor retardation, Cystathioninuria, Difficulty standing, Mutism, Craniofacial asymmetry, Lumbar kyphosis)

HPOsFreeText: Unknown total homocysteine (N/A μM/l; reference 5.1–13.9), Elevated cystathionine (5.4 μM/l; reference 0.04–0.34), Unknown total cysteine (N/A μmol/l; reference 203–369), Response to B6 treatment unknown

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CasePMIDs: 615480

CaseAddInfo: Patient is homozygous for this mutation, Proband is born of father-daughter incest and is therefore consanguineous

CasePreviousTesting: Cystathionine (Cysta), total cysteine (tCys), and total homocysteine (tHcy) panels

CaseGenotypingMethod: PCR amplification of CTH coding regions and exon-intron boundaries was performed. These fragments were sequenced and aligned with a reference to find mutations. Those found were confirmed by restriction digest of 100 controls.

Variant: NM_001902.5:c.589C>T (p.Arg197Cys)

CAID: CA906222 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_001902.5%3Ac.589C%3ET

gnomAD: South Asian 1.312e-4, Overall 6.378e-5 https://gnomad.broadinstitute.org/variant/1-70895477-C-T

Case2930: Female, 3 weeks diagnosis, United States

CasePresentingHPOs: HP:0003153 (Cystathioninuria)

HPOsFreeText: Elevated total homocysteine (18.2 μM/l; reference 5.1–13.9), Elevated cystathionine (11.8 μM/l; reference 0.04–0.34), Normal total cysteine (246 μmol/l; reference 203–369)

CaseNotHPOs: HP:0001270, HP:0001263, HP:0100543, HP:0030972 (Motor delay, Global developmental delay, Cognitive impairment, Abnormal systemic blood pressure)

NotHPOsFreeText: Unresponsive to B6 treatment

CaseAddInfo: Patient is compound heterozygous for these mutations, Parental testing has confirmed these variants are in trans

CasePreviousTesting: Cystathionine (Cysta), total cysteine (tCys), and total homocysteine (tHcy) panels

CaseGenotypingMethod: PCR amplification of CTH coding regions and exon-intron boundaries was performed. These fragments were sequenced and aligned with a reference to find mutations. Those found were confirmed by restriction digest of 100 controls.

Variant1: NM_001902.5:c.932C>T (p.Thr311Ile)

CAID: CA340839077 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_001902.5%3Ac.932C%3ET

gnomAD: Not in gnomAD

Variant Too Long

Variant2: NP_001893.2:p.Gly57_Gln196del

ClinVar:

gnomAD:

CaseF4P: 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 disrupts the WT donor site and is predicted to alter splicing

CasePreviousTesting: Blood phenylalanine before treatment was 1150 μmol/l, Blood tyrosine before treatment was 30 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(PAH):c.60+5G>A

ClinVar: 120281 https://www.ncbi.nlm.nih.gov/clinvar/variation/120281/

gnomAD: Not in gnomAD

CaseF5S: 21 yrs report, India

CasePresentingHPOs: N/A

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variant has been shown to abolish canonical splice donor site and lead to a null protein

CasePreviousTesting: Blood phenylalanine before treatment was 1698 μmol/l, Blood tyrosine before treatment was 37 μmol/l

CaseGenotypingMethod: N/A

Variant: NM_000277.3(PAH):c.842+1G>A

ClinVar: 599 https://www.ncbi.nlm.nih.gov/clinvar/variation/599/

gnomAD: 0.00007752, http://gnomad.broadinstitute.org/variant/12-103246592-C-T

CaseF5P: 18 yrs report, India

CasePresentingHPOs: N/A

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband for Family 5, Variant has been shown to abolish canonical splice donor site and lead to a null protein

CasePreviousTesting: Blood phenylalanine before treatment was 1260 μmol/l, Blood tyrosine before treatment was 36 μmol/l

CaseGenotypingMethod: N/A

Variant: NM_000277.3(PAH):c.842+1G>A

ClinVar: 599 https://www.ncbi.nlm.nih.gov/clinvar/variation/599/

gnomAD: 0.00007752, http://gnomad.broadinstitute.org/variant/12-103246592-C-T

CaseF1S: 5 yrs report, India

CasePresentingHPOs: N/A

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variant is demonstrated to activate a cryptic splice site and abolish the canon splice site leading to a premature termination and nonsense-mediated decay

CasePreviousTesting: Blood phenylalanine before treatment was 1431 μmol/l, Blood tyrosine before treatment was 35 μmol/l

CaseGenotypingMethod: N/A

Variant: NM_000277.3(PAH):c.169-2A>G

ClinVar: 555212 https://www.ncbi.nlm.nih.gov/clinvar/variation/555212/

gnomAD: 0.00003267, http://gnomad.broadinstitute.org/variant/12-103288698-T-C

CaseF2P: 2 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 and is predicted to be null

CasePreviousTesting: Blood phenylalanine before treatment was 1619 μmol/l, Blood tyrosine before treatment was 60 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.1177_1178insT (p.Asn393Ilefs*2)

CAID: CA16020958 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA16020958

gnomAD: Not in gnomAD

CaseCA2: Male, 17 months death

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

HPOsFreeText: N/A

CaseNotHPOs: HP:0003107 (Abnormal circulating cholesterol concentration)

NotHPOsFreeText: N/A

CaseAddInfo: Family history of high urinary 3-MGC

CasePreviousTesting: N/A

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

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

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

gnomAD: Not in gnomAD

CaseCA4: Male, 6 months death

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

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

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

CasePreviousTesting: N/A

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

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

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

gnomAD: Not in gnomAD

CaseWA: Female, 5 yrs onset, French-Canadian

CasePresentingHPOs: HP:0002013, HP:0001944, HP:0001289, HP:0002367, HP:0001942, HP:0031962, HP:0001987, HP:0003236, HP:0001946, HP:0002919, HP:0000651, HP:0012120 (Vomiting, Dehydration, Confusion, Visual hallucinations, Metabolic acidosis, Elevated serum anion gap, Hyperammonemia, Elevated serum creatine kinase, Ketosis, Ketonuria, Diplopia, Methylmalonic aciduria)

HPOsFreeText: Low incorporation of 14C-propionate (4.1 nmol propionate/mg protein/18 h; control mean 10.8, SD 3.7) with no response to hydroxycobalamin

CaseNotHPOs: HP:0002151 (Increased serum lactate)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous with unremarkable family history, Treatment with carnitine and restricted protein intake normalized symptoms, Sequencing of the mother revealed Variant 2 without Variant 1 confirming compound heterozygosity

CasePreviousTesting: Metabolic acidosis values w/ elevated anion gap (pH = 6.96, bicarbonate 3.5 mmol/L and pCO2 15.9 mm Hg, anion gap 25.5 mmol/L); Mild hyperammonemia (107 μmol/L; ref. < 50); Elevated creatine kinase (from 498 IU/L initially up to 3062 IU/L, ref. < 150); Organic acid profiles were analyzed via gas chromatography–mass spectrometry with Table 1 showing relevant organic acid values; Proband was negative for propionyl-coA carboxylase deficency (811 pmol/min/mg protein with control mean 1123, PCCA and PCCB variants were negative) and ruled out MUT/cobalamin issues as well; Fusion experiments showed negative results for mut, cblA, and cblB complementation but no increase in activity when fused with MCEE confirming the pathway blockage

CaseGenotypingMethod: Extracted DNA from blood was amplified and three coding exons/splice site junctions of MCEE were Sanger sequenced. A deletion/duplicaiton analysis yeilded normal results. To search for an intronic sequence variant, total RNA was extracted and reverse-transcribed to confirm a 92-bp insertion between Exons 2 and 3. Resulting sequencing of this genomic area revealed a deep intronic variant that created a new consensus donor splice site that leads to a premature stop codon.

Variant1: NM_032601.4(MCEE):c.139C>T (p.Arg47Ter)

ClinVar: 2343, http://www.ncbi.nlm.nih.gov/clinvar/variation/2343

gnomAD: 0.0004884, https://gnomad.broadinstitute.org/variant/2-71351575-G-A

Variant2: NM_032601.3:c.379-644A>G

CAID: CA892631472, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA892631472

gnomAD: Not in gnomAD

CaseOS-104_II-1: Male, Birth onset, Turkey

CasePresentingHPOs: HP:0001992, HP:0001324, HP:0002317 (Organic aciduria, Muscular hypotonia, Unsteady gait)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001263, HP:0001252 (Global developmental delay, Muscle weakness)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous, Two younger brothers are unaffected, The variant results in a frameshift that extends the WT protein to 408 AAs and affects the C-terminal peptidase domain

CasePreviousTesting: GS-MS analysis identified urinary organic acids dominated by N-aceylated AAs, supported by NMR spectroscopy of urine samples with serum samples being negative; Metabolite pattern of brother was unremarkable; Values of excreted AAs are in Table 1; Ultrasound, electromyography, and NMR tomography of the musculature from the lower extremities showed unremarkable results; Routine histological, histochemical, enzyme histochemical, and immunohistochemical studies did not reveal any significant myopathological abnormalities

CaseGenotypingMethod: Genomic DNA was extracted from blood samples or after EBV transformation of peripheral blood lymphocytes. Exons and exon-intron boundaries were amplified and bidirectionally sequenced.

Variant: NM_000666.3(ACY1):c.1102_1103AC[3] (p.Pro369fs)

ClinVar: 18109, https://www.ncbi.nlm.nih.gov/clinvar/variation/18109/

gnomAD: Not in gnomAD

CaseOS-120_II-1: Female, Birth onset, German/Italian

CasePresentingHPOs: HP:0001992, HP:0011343 (Organic aciduria, Moderate global developmental delay)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Younger brother is unaffected; Proband is confirmed compound heterozygous as mother is heterozygous for R353C but father is unavailable

CasePreviousTesting: GS-MS analysis identified urinary organic acids dominated by N-aceylated AAs, supported by NMR spectroscopy of urine samples with serum samples being negative; Values of excreted AAs are in Table 1; Neuropediatric evaluation performed

CaseGenotypingMethod: Genomic DNA was extracted from blood samples or after EBV transformation of peripheral blood lymphocytes. Exons and exon-intron boundaries were amplified and bidirectionally sequenced.

Variant1: NM_000666.3(ACY1):c.699A>C (p.Glu233Asp)

ClinVar: 18111, https://www.ncbi.nlm.nih.gov/clinvar/variation/18111/

gnomAD: 0.0001846, https://gnomad.broadinstitute.org/variant/3-52021204-A-C

Variant2: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110, https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T

Case2: Male, 1y 7m, Chinese

HPOsFreeText: (at 11 days) 1.69 C4 umol/L, 0.19 C4/C2, 2.38 C4/C3

NotHPOsFreeText: normal urine isobutyrylglycine

Case2 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2:c.286G>A (p.Gly96Ser)

ClinVar: n/a

CAID: CA6372895

gnomAD: 0.001453 (East Asian)

CaseAddInfo:

Case7: Male, 6m, Chinese

CasePresentingHPOs: HP:0002248, HP:0001290, HP:0008872, HP:0002572 (haematemesis, hypotonia, feeding difficulties in infancy, recurrent vomiting)

HPOsFreeText: (at 19 days) 1.01 C4 umol/L, 0.38 C4/C2, 1.61 C4/C3

NotHPOsFreeText: normal urine isobutyrylglycine

Case7 (Level 2):

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2:c.444G>T (p.Pro148=)

ClinVar: n/a

CAID: CA6372946

gnomAD: 0.0002772 (Other)

Variant2: NM_014384.2:c.1176G>T (p.Arg392Ser)

ClinVar: n/a

CAID: CA6373249

gnomAD: 0.0001088 (East Asian)

CaseAddInfo: trans heterozygous, inherited one allele from each parent

Case 14 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group __

Variant1: NM_015506.2(MMACHC):c.658_660delAAG (p.Lys220del)

ClinVar: 95707

CAID: CA223197

gnomAD: 0.0003071 (East Asian)

Variant2: NM_015506.2(MMACHC):c.567dupT (p.Ile190Tyrfs*13)

ClinVar: 556708

CAID: CA522810899

gnomAD: [0.0001024] (https://gnomad.broadinstitute.org/variant/1-45974604-G-GT) (East Asian)

CaseAddInfo: proband genotype, unknown cis or trans, no phenotypic info, sibling (fetus) carrier for p.K220del maternal variant

Case 2 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group

Variant1: NM_015506.2(MMACHC):c.217C > T

ClinVar: 203825

CAID: CA312728

gnomAD: 0.00005560 (East Asian)

Variant2: NM_015506.2(MMACHC):c.658_660delAAG

ClinVar: 95707

CAID: CA223197

gnomAD: 0.0003071 (East Asian)

CaseAddInfo: proband genotype, unknown cis or trans, not any phenotypic info given, sibling (fetus) carrier of p.R73X maternal variant

Case 15 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group

__

Variant1: NM_015506.2(MMACHC):c.394C > T (p.Arg132Ter)

ClinVar: 1423

CAID: CA251787

gnomAD: 0.0007190 (South Asian)

Variant2: NM_015506.2(MMACHC):c.615C > A (p.Tyr205Ter)

ClinVar: 558292

CAID: CA340133688

gnomAD: 0.0006427 (East Asian)

CaseAddInfo: proband genotype, unknown cis or trans, no phenotypic info, sibling (fetus) carries both variants

Case 13 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group __

Variant1: NM_015506.2(MMACHC):c.609G > A (p.Trp203Ter)

ClinVar: 30800

CAID: CA259906

gnomAD: 0.0005562 (East Asian)

CaseAddInfo: proband genotype, homozygous, no phenotypic info, sibling (fetus) carrier for p.W203X variant

Case 16 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group

Variant1: NM_015506.2(MMACHC):c.217C > T (p.Arg73Ter)

ClinVar: 203825

CAID: CA312728

gnomAD: 0.00005560 (East Asian)

CaseAddInfo: proband genotype, homozygous, no phenotypic info, sibling (fetus) is a carrier of variant

Case 5 (Level 2)

**CasePreviousTesting: ** same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group

Variant1: NM_015506.2(MMACHC):c.626dupT (p.Thr210Aspfs*35)

ClinVar: not in ClinVar

CAID: Not in ClinGen

gnomAD: not in gnomAD

Variant2: NM_015506.2(MMACHC):c.609G > A (p.Trp203Ter)

ClinVar: 30800

CAID: CA259906

gnomAD: 0.0005562 (East Asian)

CaseAddInfo: proband genotype, unknown cis or trans, no phenotypic info, sibling (fetus) carrier for c.626dupT maternal variant

Case 6 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group

Variant1: NM_015506.2(MMACHC):c.658_660delAAG (p.Lys220del)

ClinVar: 95707

CAID: CA223197

gnomAD: 0.0003071 (East Asian)

Variant2: NM_015506.2(MMACHC):c.609G > A (p.Trp203Ter)

ClinVar: 30800

CAID: CA259906

gnomAD: 0.0005562 (East Asian)

CaseAddInfo: proband genotype, unknown cis or trans, no phenotypic info, sibling (fetus) carrier for both variants

CaseKO: Male, 22 yrs report, Serbia

CasePresentingHPOs: HP:0002076, HP:0002017, HP:0000505, HP:0002357, HP:0003474, HP:0004302, HP:0001269, HP:0012229, HP:0011288, HP:0002321, HP:0000622 (Migraine, Nausea and vomiting, Visual impairment, Dysphasia, Sensory impairment, Functional motor deficit, Hemiparesis, CSF pleocytosis, EEG with parietal sharp slow waves, Vertigo, Blurred vision)

HPOsFreeText: Mechanosensitivity

CaseNotHPOs: HP:0011182, HP:0001251, HP:0001250 (Interictal epileptiform activity, Ataxia, Seizure)

NotHPOsFreeText: N/A

CaseAddInfo: No evidence of headache attacks with focal neurological deficits in any other family member, but the patient’s father was found to suffer from migraine without aura

CasePreviousTesting: Responsive to treatment with ibuprofen; Mild head trauma is a trigger; Neuroimaging during attacks was normal; Screen for variants in CACNA1A, ATP1A2, SCN1A, and PRRT2 was negative

CaseGenotypingMethod: All exons and exon-intron boundaries of the SLC1A3 gene were seuqenced and a variant was found that segregates with the phenotype.

Variant: NM_004172.5:c.1159A>C (p.Thr387Pro)

CAID: CA359482299, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA359482299

gnomAD: Not in gnomAD

CaseJE: Male, 10 yrs report,

CasePresentingHPOs: HP:0002131, HP:0004374, HP:0001319, HP:0001270, HP:0001350, HP:0002076, HP:0010547, HP:0001272, HP:0002381, HP:0002181, HP:0011182, HP:0045084, HP:0001289, HP:0002078, HP:0007034, HP:0007772, HP:0011289 (Episodic ataxia, Hemiplegia/hemiparesis, Neonatal hypotonia, Motor delay, Slurred speech, Migraine, Muscle flaccidity, Cerebellar atrophy, Aphasia, Cerebral edema, Interictal epileptiform activity, Limb myoclonus, Confusion, Truncal ataxia, Generalized hyperreflexia, Impaired smooth pursuit, EEG with temporal sharp slow waves)

HPOsFreeText: Left visual field neglect, Episodic left hemifield distortion

CaseNotHPOs: HP:0000639, HP:0000570, HP:0007670, HP:0000267 (Nystagmus, Impaired saccades, Abnormal vestibulo-ocular reflex, Cranial asymmetry)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed heterozygous de novo via parental testing and confirmed paternity; No family member has any neurological signs or symptoms

CasePreviousTesting: Previously screened for CACNA1A and ATP1A2 with negative results; Episodic migraine attacks led to progressive right-sided headache and left-sided symptoms such as weakness and visual field neglect; Comprehensive metabolic workup revealed no abnormality in the CSF, serum, and urine; MRI showed a diffuse right-sided cortical hyperintensity most prominent in fluid-attenuated inversion recovery (FLAIR); EEG showed subclinical seizure activity in the left frontal temporal cortex and diffuse slowing on the right

CaseGenotypingMethod: DNA was extracted from blood samples. All exons and flanking intronic regions of SLC1A3 were PCR-amplified and directly sequenced. These were confirmed via resequencing.

Variant: NM_004172.5(SLC1A3):c.869C>G (p.Pro290Arg)

ClinVar: 9441, https://www.ncbi.nlm.nih.gov/clinvar/variation/9441/

gnomAD: Not in gnomAD

Case1: Amish

HPOsFreeText: GA1 confirmed

Case (Level 2)

CasePreviousTesting: GA1 confirmed

CaseMethod1: PCR

CaseMethod2: MaeII restriction digest

CaseGenotypingMethod: same as Amish group

Variant: NM_000159.3(GCDH):c.1262C>T (p.Ala421Val)

ClinVar: 2082

gnomAD: 0.0002867 (European non-Finnish)

CaseAddInfo: homozygous, founder allele in Amish of Lancaster County from immigrant from Switzerland to US in early 18th century. 4 non-Amish patients were found heterozygous for this allele with central European ancestry.

CaseBH: Male, Somalia, 8 yrs report

CasePresentingHPOs: HP:0003026, HP:0001511, HP:0000973, HP:0008936, HP:0000023, HP:0008780, HP:0000519, HP:0000639, HP:0011493, HP:0001263, HP:0001999, HP:0000337, HP:0000325, HP:0000494, HP:0000160, HP:0000977, HP:0001181, HP:0002119, HP:0005116 (Short long bone, Intrauterine growth retardation, Cutis laxa, Truncal hypotonia, Inguinal hernia, Congenital bilateral hip dislocation, Developmental cataract, Nystagmus, Central opacification of the cornea, Global developmental delay, Abnormal facial shape, Broad forehead, Triangular face, Downslanted palpebral fissures, Narrow mouth, Soft skin, Adducted thumb, Ventriculomegaly, Arterial tortuosity)

HPOsFreeText: At age 8 years, his height was 96 cm (Z=−5.8) and weight was 11.6 kg (Z=−7.26); Head circumference was 45.4 cm, (Z=−5.0) which is the 50th centile for a 10-month-old boy; Walked with support

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous fourth cousins, Had an older sister and younger brother who were developmentally appropriate and well grown

CasePreviousTesting: N/A

CaseGenotypingMethod: PYCR1 and ALDH18A1 were Sanger sequenced in the proband which revealed a single variant. Chromosomal SNP microarray showed no regions of homozygosity or any other deletions or duplications. Whole Exome Sequencing of genomic DNA from the proband was performed for confirmation again only revealing the single heterozygous missense variant in ALDH18A1. Copy-number analysis was performed and identified no significant variation. Sequencing of the parents revealed a de novo inheritance pattern.

Variant: NM_002860.3:c.377G>A (p.Arg126His)

CAID: CA377706756 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA377706756

gnomAD: Not in gnomAD

Case1: Male, 3 months diagnosis/death, Egypt, African

CasePresentingHPOs: HP:0001999, HP:0011968, HP:0001531, HP:0001270, HP:0001252, HP:0003468, HP:0001636, HP:0001274 (Dysmorphic facial features, Poor feeding, Failure to thrive in infancy, Motor delay, Muscle hypotonia, Abnormal vertebrae, Tetraology of Fallot, Agenesis of corpus callosum)

HPOsFreeText: Agenesis of the cingulate gyrus

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: Parents are consanguinous, Proband is homozygous for this mutation, Died a few days after hospital admission in infancy

CasePreviousTesting: Increased levels of S-2-carboxypropyl-cysteamine and S-2-carboxypropyl-cysteine, Fibroblast and liver homogenates of patient 1 showed normal hydratase activities towards methacrylyl-CoA (as well as crotonyl-CoA and tiglyl-CoA),

CasePMIDs: 7122152

CaseGenotypingMethod: After confirming low HICBH activity in fibroblasts of the patients, the gene was analyzed at the genomic level and the mRNA level in both patients using sequence analysis.

Variant: NM_014362.3:c.220-9T>G

ClinVar: 1144 https://www.ncbi.nlm.nih.gov/clinvar/variation/1144/

gnomAD: Not in gnomAD

Case2: Male, Caucasian, 9 months onset

CasePresentingHPOs: HP:0011968, HP:0001270, HP:0001251, HP:0002376, HP:0002121, HP:0000737, HP:0002317, HP:0002599, HP:0002078, HP:0012389, HP:0001310, HP:0001337, HP:0001254, HP:0001942, HP:0002329, HP:0001308, HP:0002599, HP:0001332, HP:0002181, HP:0002134 (Poor feeding, Delayed motor milestones, Ataxia, Developmental regression, Absence seizures, Irritability, Unsteady gait, Head titubation, Truncal ataxia, Appendicular hypotonia, Dysmetria, Tremor, Lethargy, Metabolic acidosis, Drowsiness, Tongue fasciculation, Head titubation, Dystonia, Cerebral edema, Abnormality of the basal ganglia)

HPOsFreeText: Head bobbing at 4 months, Rolled over at 5 mo but lost the ability at 10 mo, Reaching out and grasping objects at 4 mo but lost the ability at 13 mo, Eye rolling episodes at 9 months, Lost ability to finger feed at 10 months, Inability to sit unsupported, At 14 months blood pH was 7.29 with a base deficit of 15.8 mmol/L, Sluggish papillary responses, Pooling of secretions in the mouth, No improvement on treatment with thiamine or a combination of vitamin C, vitamin E, and ubiquinone, Signal abnormalities in the globus pallidus and the midbrain

CaseNotHPOs: HP:0000639, HP:0002151, HP:0001987, HP:0003116, HP:0012443 (Nystagmus, Increased serum lactate, Hyperammonemia, Abnormal echocardiogram, Abnormality of brain morphology)

NotHPOsFreeText: N/A

CaseAddInfo: Parents were nonconsanguinous, Proband is compound heterozygous for these mutations with parental testing

CasePreviousTesting: Pyruvate dehydrogenase and pyruvate carboxylase in cultured human skin fibroblasts, Activities of respiratory chain complexes in a muscle biopsy, Marked reduction of complex I (patient 0.089, controls 0.104–0.268) and a borderline reduction of complex IV (patient 0.013, controls 0.014–0.034), Organic acid analysis during ketotic episodes showed excessive excretion of 3-hydroxybutyrate and acetoacetate and moderate excretion of lactate, 2-hydroxyisovalerate, 2-oxoisocaproate, dicarboxylic acids (C6, C8, C10), and methylmalonate, with normal levels of methylcitrate as opposed to normal levels when well, Urine amino acid analysis, Elevated levels of hydroxy-C4-carnitine (patient 0.45-1.73 μM, controls <0.4 μM) even when not ketotic

CaseGenotypingMethod: After confirming low HICBH activity in fibroblasts of the patients, the gene was analyzed at the genomic level and the mRNA level in both patients using sequence analysis.

Variant1: NM_014362.4:c.365A>G (p.Tyr122Cys)

ClinVar: 1145 https://www.ncbi.nlm.nih.gov/clinvar/variation/1145/

gnomAD: Latino 4.338e-4, Overall 6.373e-5 https://gnomad.broadinstitute.org/variant/2-191155151-T-C

Variant2: NM_014362.3:c.79-3C>G

ClinVar: 1146 https://www.ncbi.nlm.nih.gov/clinvar/variation/1146/

gnomAD: Not in gnomAD

CaseCHN2.1: Canada, 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:c.532C>T (p.Arg178Ter)

CAID: CA3182753, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182753

gnomAD: 0.0004414, https://gnomad.broadinstitute.org/variant/5-1212468-C-T

Variant2: NM_001003841.3:c.1213G>A (p.Glu405Lys)

CAID: CA3183103, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3183103

gnomAD: 0.0001203, https://gnomad.broadinstitute.org/variant/5-1219057-G-A

CaseCHN1.1: Canada, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease, Has a sibling with the same variant and amino acid profile

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:c.982C>T (p.Arg328Cys)

CAID: CA3182972, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182972

gnomAD: 0.0002479, https://gnomad.broadinstitute.org/variant/5-1216767-C-T

CaseAHN16.1: 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:c.277G>A (p.Gly93Arg)

CAID: CA3182636 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182636

gnomAD: 0.0001195, https://gnomad.broadinstitute.org/variant/5-1208935-G-A

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

Case9: Male, Turkey, 24 yrs report,

CasePresentingHPOs: HP:0002251, HP:0001321, HP:0001161, HP:0025356, HP:0002474, HP:0000708, HP:0001488, HP:0002317, HP:0000646, HP:0000486 (Aganglionic megacolon, Cerebellar hypoplasia, Hand polydactyly, Psychomotor retardation, Expressive language delay, Behavioral abnormality, Bilateral ptosis, Unsteady gait, Strabismus)

HPOsFreeText: Dysgnathia

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous, Parents are consanguineous, cDNA amplification of the exons 8 and 9 in this patient revealed an insertion of 64 base pairs due to the use of a cryptic donor site leading to a premature stop codon and a likely null allele; Proband has two healthy sisters

CasePreviousTesting: Patient fibroblasts were analyzed for mutations in SLC25A21 and activities of KATII with no abnormalities; A metabolic work-up revealed alpha-ketoadipic aciduria and alpha-aminoadipic aciduria; A non-verbal intelligence test yielded a slightly decreased value; A single metabolic decompensation in adulthood was ascribed to Helicobacter pylori and its eradication improved the patient’s well-being.

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced.

Variant: NM_018706.6:c.1671+1G>A

CAID: CA5407905 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA5407905

gnomAD: 0.0001399, https://gnomad.broadinstitute.org/variant/10-12139996-G-A

Case8: Female

CasePresentingHPOs: HP:0001270, HP:0001252, HP:0011342, HP:0007479 (Motor delay, Muscular hypotonia, Mild motor developmental delay, Congenital nonbullous ichthyosiform erythroderma)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Consanguineity is suspected, Proband is homozygous

CasePreviousTesting: Patient fibroblasts were analyzed for mutations in SLC25A21 and activities of KATII with no abnormalities; Urine AAA and KAA were elevated. Oxidation of radiolabeled AAA in fibroblasts was deficient.

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced.

CasePMIDs: 1112064, 1112065

Variant: NM_018706.7(DHTKD1):c.2134C>T (p.Arg712Ter)

ClinVar: 572241 https://www.ncbi.nlm.nih.gov/clinvar/variation/572241/

gnomAD: 0.00003267, https://gnomad.broadinstitute.org/variant/10-12149994-C-T

CaseSA3P: Female, 16 months onset, European

CasePresentingHPOs: HP:0001988, HP:0000825, HP:0001987 (Recurrent hypoglycemia, Hyperinsulinemic hypoglycemia, Hyperammonemia)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband is confirmed de novo via parental teting and confirmed paternity

CasePreviousTesting: Protein/leucine restriction was effective at reducing symptoms

CaseGenotypingMethod: Genomic DNA was prepared from all patients via peripheral blood leukocytes. The GLUD1 gene exons 1-13 and the flanking intronic regions were PCR-amplified and directly sequenced. All variants were confirmed via restriction enzyme analysis. Additionally, paternity testing was performed by HLA typing and by southern blot analysis of DNA fragments as well as PCR analysis of STRs.

Variant: NM_005271.5(GLUD1):c.965G>A (p.Arg322His)

ClinVar: 16129, https://www.ncbi.nlm.nih.gov/clinvar/variation/16129/

gnomAD: Not in gnomAD

CaseSA5P: Female, 3 months onset, European

CasePresentingHPOs: HP:0001988, HP:0000825, HP:0001249, HP:0001250 (Recurrent hypoglycemia, Hyperinsulinemic hypoglycemia, Intellectual disability, Seizure)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001987 (Hyperammonemia)

NotHPOsFreeText: N/A

CaseAddInfo: Has father with confirmed variant and similar phenotypes

CasePreviousTesting: Leucine load test showed leucine sensitivity; Protein/leucine restriction and dioxazide was effective at reducing symptoms

CaseGenotypingMethod: Genomic DNA was prepared from all patients via peripheral blood leukocytes. The GLUD1 gene exons 1-13 and the flanking intronic regions were PCR-amplified and directly sequenced. All variants were confirmed via restriction enzyme analysis. Additionally, paternity testing was performed by HLA typing and by southern blot analysis of DNA fragments as well as PCR analysis of STRs.

Variant: NM_005271.5(GLUD1):c.965G>A (p.Arg322His)

ClinVar: 16129, https://www.ncbi.nlm.nih.gov/clinvar/variation/16129/

gnomAD: Not in gnomAD

CaseSA2P: Female, 3 months onset, European

CasePresentingHPOs: HP:0001988, HP:0000825, HP:0001987 (Recurrent hypoglycemia, Hyperinsulinemic hypoglycemia, Hyperammonemia)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband is confirmed de novo via parental teting and confirmed paternity

CasePreviousTesting: Leucine load test showed leucine sensitivity in some patients; Protein/leucine restriction was effective at reducing symptoms

CaseGenotypingMethod: Genomic DNA was prepared from all patients via peripheral blood leukocytes. The GLUD1 gene exons 1-13 and the flanking intronic regions were PCR-amplified and directly sequenced. All variants were confirmed via restriction enzyme analysis. Additionally, paternity testing was performed by HLA typing and by southern blot analysis of DNA fragments as well as PCR analysis of STRs.

Variant: NM_005271.5(GLUD1):c.965G>A (p.Arg322His)

ClinVar: 16129, https://www.ncbi.nlm.nih.gov/clinvar/variation/16129/

gnomAD: Not in gnomAD

Patient16: Group 3

CasePresentingHPOs: same as group 3

CasePreviousTesting: same as group 3

CaseGenotypingMethod: same as group 3

Variant1: NM_001159508.1:c.149G>C (p.Arg50Thr) listed in paper as (p.Arg21Pro)

CAID: CA391743853, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391743853

gnomAD: n/a

Variant2: NM_002225.4:c.851G>A

CAID: CA7480763, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA7480763

**In ClinVar as: NM_002225.3(IVD):c.860G>A (p.Arg287Gln), https://www.ncbi.nlm.nih.gov/clinvar/variation/555453/ **

gnomAD: 0.00001770, http://gnomad.broadinstitute.org/variant/15-40707154-G-A

Patient18: Group 3

CasePresentingHPOs: same as group 3

CasePreviousTesting: same as group 3

CaseGenotypingMethod: same as group 3

Variant1: NM_002225.3:c.1136T>C (p.p.Ile349Thr) **listed in paper as (p.Phe350Ser)

CAID: CA391723904, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391723904

gnomAD: n/a

Variant2: IVS3+5G>T no ClinVar or CAID

Patient8: Group 2

CasePresentingHPOs: same as group 2

CasePreviousTesting: same as group 2

CaseGenotypingMethod: same as group 2

Variant1: NM_002225.3(IVD):c.941C>T (p.Ala314Val) listed in paper as c.932C>T (p.Ala282Val)

ClinVar: 100060, https://www.ncbi.nlm.nih.gov/clinvar/variation/100060/

gnomAD: 0.0006507, http://gnomad.broadinstitute.org/variant/15-40707653-C-T

Variant2: NM_002225.3:c.262G>T

CAID: CA391745812, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391745812

gnomAD: n/a

Patient4: Female, 3yo sibling to patient 5

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 4.0 μmol l−1, IVA incorp (%) = 80, IVG in urine mmol permol creatinine = 242, Ammonium (μmol l−1) = 31, pH = 7.37, Protein intake (g kg−1 per day) = 1.5, treated with carnitine supplements, PDI/IQ in follow-up = 92

CaseNotHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259

(poor feeding, vomiting, dehydration, lethargy, coma)

NotHPOsFreeText: sweaty feet odor

CaseAddInfo: Diagnosed with NBS, diagnosed at 26 days old

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.4(IVD):c.1205T>C (p.Ile402Thr)

ClinVar: 529433, https://www.ncbi.nlm.nih.gov/clinvar/variation/529433/

gnomAD: n/a

Variant2: NM_001159508.1:c.500T>C

CAID: CA391717541, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391717541

gnomAD: n/a

Patient7: Male, 2yo

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 1.6 μmol l−1, IVG in urine mmol permol creatinine = 272, IVA incorp (%) = 72, Ammonium (μmol l−1) = 51, pH = 7.39, Protein intake (g kg−1 per day) = 1.5, PDI/IQ in follow-up = 93

CaseNotHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259

(poor feeding, vomiting, dehydration, lethargy, coma)

NotHPOsFreeText: sweaty feet odor

CaseAddInfo: Diagnosed with NBS at 28 days, homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_002225.3:c.706G>A

CAID: CA268780419, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA268780419

gnomAD: 0.00003187, http://gnomad.broadinstitute.org/variant/15-40705199-G-A

Patient14: Male, 24yo

CasePresentingHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259, HP:0001987, HP:0001941

(poor feeding, vomiting, dehydration, lethargy, coma, hyperammonemia, acidosis)

HPOsFreeText: intermittent isovaleric acidemia, C5 (DBS) = 4.3 μmol l−1, IVA incorp (%) = 12, IVG in urine mmol permol creatinine = 16594, Ammonium (μmol l−1) = 126, pH = 7.17, Protein intake (g kg−1 per day) = 0.7, treated with carnitine and glycine supplements, PDI/IQ in follow-up = 88

CaseNotHPOs:

NotHPOsFreeText: sweaty feet odor

CaseAddInfo: diagnosed via clinical findings at 1yo, hospitalized outside of detection period

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: c.1-?_c.295+? (Delexons 1–3) no ClinVar or CAID

Variant2: NM_002225.4(IVD):c.1184G>A (p.Arg395Gln) listed in paper as (p.Arg395His)

CAID: CA268781747, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA268781747

ClinVar: 529434, https://www.ncbi.nlm.nih.gov/clinvar/variation/529434/

gnomAD: 0.00001415, http://gnomad.broadinstitute.org/variant/15-40710365-G-A

Patient11: Female, 19yo, sibling to patient 10

CasePresentingHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259

(poor feeding, vomiting, dehydration, lethargy, coma)

HPOsFreeText: intermittent isovaleric acidemia, IVA incorp (%) = 13, IVG in urine mmol permol creatinine = 3488, Ammonium (μmol l−1) = 47 pH = 7.33, Protein intake (g kg−1 per day) = 1.0, treated with carnitine and glycine supplements, PDI/IQ in follow-up = 85, sweaty feet odor

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: Diagnosed via clinical findings at 2yo

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.3(IVD):c.884T>C (p.Leu295Pro)

ClinVar: 555464, https://www.ncbi.nlm.nih.gov/clinvar/variation/555464/

gnomAD: n/a

Variant2: NM_002225.3:c.1211A>G

CAID: CA391724518, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391724518

gnomAD: n/a

Patient13 Male, 9yo

CasePresentingHPOs: HP:0011968, HP:0001254, HP:0001259, HP:0001987

(poor feeding, lethargy, coma, hyperammonemia)

HPOsFreeText: acute isovaleric acidemia, C5 (DBS) = 16.3 μmol l−1, IVA incorp (%) = 5.5, IVG in urine mmol permol creatinine = 3352, Ammonium (μmol l−1) = 606, pH = 7.26, Protein intake (g kg−1 per day) = 0.8, treated with carnitine and glycine supplements, PDI/IQ in follow-up = 87, sweaty feet odor

CaseNotHPOs: HP:0002013, HP:0001944 (vomiting, dehydration)

NotHPOsFreeText:

CaseAddInfo: diagnosed via clinical findings at 20 days old, homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_002225.3:c.158G>C listed in clinvar as NM_002225.4(IVD):c.149G>C (p.Arg50Pro)

CAID: CA274129, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA274129

ClinVar: 188922, https://www.ncbi.nlm.nih.gov/clinvar/variation/188922/

gnomAD: 0.00001591, http://gnomad.broadinstitute.org/variant/15-40699841-G-C

Case10: Male, Ecuador

CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283, HP:0001561, HP:0001558, HP:0000602, HP:0001622, HP:0001371, HP:0001623, HP:0002804 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness, Polyhydramnios, Decreased fetal movements, Ophthalmoplegia, Preterm delivery, Contractures, Breech presentation, Arthrogryposis)

HPOsFreeText: Bilateral femoral fractures

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Severe congenital myopathy, Deceased in 6 weeks

CasePreviousTesting: N/A

CaseGenotypingMethod: After LMOD3 was identified as a potential causal gene, bidirectional Sanger sequencing was performed on DNA in genetically unresolved patients using PCR amplification covering 3 exons.

Variant1: NM_198271.4:c.976G>C (p.Gly326Arg)

CAID: CA353473660 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_198271.4%3Ac.976G%3EC

gnomAD: Not in gnomAD

Variant2: NM_198271.4:c.1372C>T (p.Gln458*)

CAID: CA353470920 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_198271.4%3Ac.1372C%3ET

gnomAD: Not in gnomAD

Case6: Female, Japan, Asian

CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283, HP:0003798, HP:0001561, HP:0001558, HP:0001789, HP:0000252, HP:0001622, HP:0001371 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness, Nemaline bodies, Polyhydramnios, Decreased fetal movement, Hydrops fetalis, Microcephaly, Preterm delivery, Contractures)

HPOsFreeText: Atrophic myofibers

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Severe congenital myopathy, Alive at 10 months

CasePreviousTesting: N/A

CaseGenotypingMethod: After LMOD3 was identified as a potential causal gene, bidirectional Sanger sequencing was performed on DNA in genetically unresolved patients using PCR amplification covering 3 exons.

Variant: NM_198271.4:c.349C>T (p.Gln117*)

CAID: CA353477271 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_198271.4%3Ac.349C%3ET

gnomAD: Not in gnomAD

Case3: Female, Portugal

CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283, HP:0002804, HP:0001558, HP:0001561, HP:0001371 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness, Decreased fetal movement, Polyhydramnios, Contracture)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Severe congenital myopathy, Deceased in neonatal period

CasePreviousTesting: N/A

CaseGenotypingMethod: After LMOD3 was identified as a potential causal gene, bidirectional Sanger sequencing was performed on DNA in genetically unresolved patients using PCR amplification covering 3 exons.

Variant: NM_198271.4:c.154del (p.Met52*)

CAID: CA909810717 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_198271.4%3Ac.154delA

gnomAD: Not in gnomAD

Case12a: Male, Afghanistan

CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283, HP:0002804, HP:0001558, HP:0001622, HP:0001623, HP:0003798 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness, Arthrogryposis, Decreased fetal movement, Preterm delivery, Breech presentation, Nemaline bodies)

HPOsFreeText: Atrophic myofibers

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Severe congenital myopathy, Deceased in 2 months, Has 2 siblings with same genotype/phenotype

CasePreviousTesting: N/A

CaseGenotypingMethod: After LMOD3 was identified as a potential causal gene, bidirectional Sanger sequencing was performed on DNA in genetically unresolved patients using PCR amplification covering 3 exons.

Variant: NM_198271.4:c.1099_1100delAA (p.Asn367Glnfs*11)

ClinVar: 162218 https://www.ncbi.nlm.nih.gov/clinvar/variation/162218/

gnomAD: South Asian 4.575e-4, Overall 5.625e-5 https://gnomad.broadinstitute.org/variant/3-69168405-GTT-G

Case14a: Female, Australia

CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283, HP:0001561, HP:0001622, HP:0002804, HP:0003798, HP:0001558, HP:0000602 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness, Polyhydramnios, Nemaline bodies, Decreased fetal movements, Ophthalmoplegia)

HPOsFreeText: Atrophic myofibers, Percutaneous endoscopic gastrostomy performed, Nocturnal noninvasive ventilation

CaseNotHPOs: HP:0001627, HP:0002540 (Cardiac abnormality, Inability to walk)

NotHPOsFreeText: N/A

CaseAddInfo: Typical congenital nemaline myopathy, Alive at 10 yrs, Parents are not consanguineous

CasePreviousTesting: N/A

CaseGenotypingMethod: Linkage analysis combined with homozygosity mapping was used to identify candidate chromosomal loci. Whole exome sequencing in this family revealed likely pathogenic mutations in LMOD3 which agreed with the aforementioned analysis and was consistent with autosomal recessive inheritance.

Variant1: NM_198271.4:c.1103_1105del (p.Asn368del)

ClinVar: 162216 https://www.ncbi.nlm.nih.gov/clinvar/variation/162216/

gnomAD: Not in gnomAD

Variant2: NM_198271.4:c.1201C>T (p.Arg401Ter)

ClinVar: 162217 https://www.ncbi.nlm.nih.gov/clinvar/variation/162217/

gnomAD: African 4.137e-5, Overall 7.135e-6 https://gnomad.broadinstitute.org/variant/3-69168305-G-A

Case5: Female, Japan, Asian

CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283, HP:0003798, HP:0001561, HP:0001558, HP:0100309 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness, Nemaline bodies, Polyhydramnios, Decreased fetal movements, Subdural hemorrhage)

HPOsFreeText: Atrophic myofibers

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Severe congenital myopathy, Alive at 2 months

CasePreviousTesting: N/A

CaseGenotypingMethod: After LMOD3 was identified as a potential causal gene, bidirectional Sanger sequencing was performed on DNA in genetically unresolved patients using PCR amplification covering 3 exons.

Variant1: NM_198271.4:c.300_304delGACTC (p.Thr101Argfs*4)

CAID: CA913203453 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203453

gnomAD: Not in gnomAD

Variant1: NM_198271.4:c.601_602delGA (p.Asp201Glnfs*9)

CAID: CA913203454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203454

gnomAD: Not in gnomAD

CaseAN: Male, 78 yrs report, Germany, White

CasePresentingHPOs: HP:0003774, HP:0001638, HP:0000822, HP:0002099, HP:0012125, HP:0001297, HP:0002134, HP:0002549, HP:0000738, HP:0000739, HP:0000746, HP:0002322, HP:0002172, HP:0012120 (Stage 5 chronic kidney disease, Cardiomyopathy, Hypertension, Asthma, Prostate cancer, Stroke, Abnormality of the basal ganglia, Deficit in phonologic short-term memory, Hallucinations, Anxiety, Delusions, Resting tremor, Postural instability, Methylmalonic aciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Mother had dementia, Proband is diagnosed with Parkinson's disease, Sanger sequencing confirmed compound heterozygous as unaffected sons are heterozygous for one variant each

CasePreviousTesting: Montreal Cognitive Assessment (MoCA) score of 17/30 in 2013; Mild MMA-uria, together with increased plasma levels of propionyl-carnitine, was demonstrated in 2016 via metabolic investigation (values in Table 1)

CaseGenotypingMethod: Whole genome sequencing data was analyzed using a pipeline restricted to 681 genes known to cause IEM. Heterozygous mutations in MCEE were identified.

Variant1: NM_032601.4(MCEE):c.139C>T (p.Arg47Ter)

ClinVar: 2343, http://www.ncbi.nlm.nih.gov/clinvar/variation/2343

gnomAD: 0.0004884, https://gnomad.broadinstitute.org/variant/2-71351575-G-A

Variant2: NM_032601.3:c.419del (p.Lys140Argfs*6)

CAID: CA1702578, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA1702578

gnomAD: 0.00007076, https://gnomad.broadinstitute.org/variant/2-71337211-CT-C

Case1: Male, 15 months onset, Iran

CasePresentingHPOs: HP:0006579, HP:0001324, HP:0001336, HP:0000639, HP:0002134, HP:0002282, HP:0002453, HP:0002540, HP:0002463, HP:0006801, HP:0001252, HP:0011443, HP:0001251, HP:0001310, HP:0000565, HP:0001510 (Neonatal jaundice, Muscle weakness, Myoclonus, Nystagmus, Abnormality of the basal ganglia, Heterotopia, Abnormality of the globus pallidus, Inability to walk, Language impairment, Hyperactive deep tendon reflexes, Muscular hypotonia, Abnormality of coordination, Ataxia, Dysmetria, Esotropia, Growth delay)

HPOsFreeText:

CaseNotHPOs: HP:0012443, HP:0012447 (Abnormality of brain morphology, Abnormal myelination)

NotHPOsFreeText:

CaseAddInfo: No parental consanguinity,

CasePreviousTesting: Plasma amino acids and plasma acylcarnitine profile were normal. The organic acid in the urine showed an elevated 3‐hydroxyisovaleric acid (110 mmol/mol creatinine, normal <44 mmol/mol creatinine). Serum biotinidase activity was normal. Blood lactate and ammonia were normal in repeated measurements.

CaseGenotypingMethod: Patient had the IVD exons and exon-intron boundaries analyzed using PCR/Sanger sequencing to follow up on suspected IVA, with no variants found. Whole Exome Sequencing was performed to determine the correct genetic cause of the disorder by evaluating all known exons and their flanking regions. This found two heterozygous missense mutations in HIBCH consistent with the diagnosis. Trio PCR/Sanger sequencing confirmed parental heterozygosity and the variants in the patient.

Variant1: NM_014362.3:c.641C>T (p.Thr214Ile)

CAID: CA349890265 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_014362.3%3Ac.641C%3ET

gnomAD: Not in gnomAD

Variant2: NM_014362.3:c.913A>G (p.Thr305Ala)

CAID: CA62635843 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_014362.3%3Ac.913A%3EG

gnomAD: European (Non-Finnish) 1.767e-5, Overall 7.978e-6 https://gnomad.broadinstitute.org/variant/2-191077780-T-C

CaseST-8: Female, 1 day onset, Germany

CasePresentingHPOs: HP:0006579, HP:0001643, HP:0001410, HP:0001319, HP:0006236, HP:0001786 (Prolonged neonatal jaundice, Patent ductus arteriosus, Decreased liver function, Neonatal hypotonia, Slender metacarpals, Narrow foot)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001250 (Seizure)

NotHPOsFreeText: N/A

CaseAddInfo: Family is non-consanguineous, Proband is compound heterozygous for these variants

CasePreviousTesting: See Group

CaseGenotypingMethod: See Group

Variant1: NM_001123.3:c.893C>A (p.Ala298Asp)

CAID: CA377399006, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA377399006

gnomAD: Not in gnomAD

Variant2: NM_001123.3:c.925C>T (p.Gln309Ter)

CAID: CA377398330, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA377398330

gnomAD: Not in gnomAD

CaseST-6: Male, 1 day onset, Morocco

CasePresentingHPOs: HP:0006579, HP:0001249, HP:0001270, HP:0001324, HP:0004322, HP:0000256, HP:0000316, HP:0006236, HP:0001786, HP:0008070, HP:0000708, HP:0002355, HP:0003202, HP:0002071 (Prolonged neonatal jaundice, Intellectual disability, Motor delay, Muscle weakness, Short stature, Macrocephaly, Hypertelorism, Slender metacarpals, Narrow foot, Sparse hair, Behavioral abnormality, Difficulty walking, Skeletal muscle atrophy, Abnormality of extrapyramidal motor function)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001250 (Seizure)

NotHPOsFreeText: N/A

CaseAddInfo: Family is consanguineous, Proband is homozygous for the variant

CasePreviousTesting: See Group

CaseGenotypingMethod: See Group

Variant: NM_001123.3:c.685_687delinsCC (p.Thr229ProfsTer16)

CAID: CA1139768931, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA1139768931

gnomAD: Not in gnomAD

Case4: Female, 2 wks at initation of follow up, European ancestry

HPOsFreeText: NBS C4-acylcarnitine 2.0 umol/L, Plasma C4-acylcarnitine 1.52 umol/L

CaseAddInfo: no data for urine excretion, unremarkable clinical condition

Case4 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2:c.443C>T (p.Pro148Leu)

ClinVar: n/a

CAID: CA6372945

gnomAD: not in gnomAD

Variant2: NM_014384.2(ACAD8):c.455T>C (p.Met152Thr)

ClinVar: 5355

CAID: CA117433

gnomAD: 0.0001395 (European Non-Finnish)

CaseAddInfo: compound heterozygote, indicated alleles 1 and 2 but not specified maternal and paternal, potential splice site variant of ACAD8 at exon3 (+3A>G)

Case3a: Male, 5d at initiation of follow up, East Indian Ancestry, sibling of Case 3b (family 1)

HPOsFreeText: NBS C4-acylcarnitine 2.4 umol/L, Plasma C4-acylcarnitine 1.14 umol/L, in vitro probe isoC4-acylcarnitine 0.133 umol/ g protein,

NotHPOsFreeText: normal urine isobutyrylglycine ug/mg creatinine

CaseAddInfo: unremarkable clinical condition

Case3a (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2(ACAD8):c.867C>A (p.His289Gln)

ClinVar: 5358

CAID: CA117441

gnomAD: not in gnomAD

CaseAddInfo: homozygous mutations

Case9: Male, 2 mo at initiation of follow up, Hispanic ancestry

HPOsFreeText: NBS C4-acylcarnitine 1.8 umol/L, Plasma C4-acylcarnitine 3.28, umol/L, in vitro probe isoC4-acylcarnitine 0.074 umol/g protein, urine C4-acylcarnitine 7.86 mmol/mol creatinine, Urine C4/C3 ratio 63

NotHPOsFreeText: normal urine isobutyrylglycine

CaseAddInfo: unremarkable clinical condition

Case9 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2(ACAD8):c.233T>C (p.Met78Thr)

ClinVar: 430160

CAID: CA6372883

gnomAD: n/a

CaseAddInfo: homozygous variants, no potential splice site alterations, no data for ACADS (SCAD-deficient) gene variants

Case2: Female, 3 m at initiation of follow up, European ancestry

HPOsFreeText: NBS C4-acylcarnitine 2.5 umol/L, plasma C4-acylcarnitine 10.00 umol/L, isoC4-acylcarnitine 0.120 umol/g protein, in vitro prob C4-acylcarnitine 0.220 umol/ g protein

CaseAddInfo: no data for urine excretion, unremarkable clinical condition

Case2 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2(ACAD8):c.289G>A (p.Gly97Arg)

ClinVar: 281037

CAID: CA6372897

gnomAD: 0.0002175 (East Asian)

Variant2: NM_014384.2(ACAD8):c.455T>C (p.Met152Thr)

ClinVar: 5355

CAID: CA117433

gnomAD: 0.0001395 (European Non-Finnish)

CaseAddInfo: compound heterozygous, potential splice-site alteration on ACAD8 at Exon 3 (+3A>G), homozygous for two common ACADS (SCAD-deficient) gene variants (625G>A/625G>A) which has 22% frequency in general population and correlates with increased accumulation of butyrylcarnitine

CaseLE12: Female, 23 yrs report

CasePresentingHPOs: HP:0002725 (Systemic lupus erythematosus)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variant 1 homozygous, with variant 2 in-cis with one copy confirmed via parental testing

CasePreviousTesting: Specific plasma MMA levels, urine MMA levels, urine MA levels, and MMA/MA ratio available in Table 2

CaseGenotypingMethod: See Group

Variant1: NM_001243279.3:c.1553C>A (p.Ala518Asp)

CAID: CA8238286, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA8238286

gnomAD: 0.00006153, https://gnomad.broadinstitute.org/variant/16-89212397-C-A

Variant2: NM_001243279.3:c.473C>T (p.Pro158Leu)

CAID: CA8237662, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA8237662

gnomAD: 0.0002823, https://gnomad.broadinstitute.org/variant/16-89167562-C-T

CaseOS-138_II-1: Female, 4 yrs report, Asian

CasePresentingHPOs: HP:0001992, HP:0002373, HP:0001263 (Organic aciduria, Febrile seizure (within the age range of 3 months to 6 years), Global developmental delay)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous, Proband is homozygous for this variant

CasePreviousTesting: Routine urine screening for organic acidurias by gas chromatography–mass spectrometry showed markedly increased urinary excretion of several N-acetylated amino acids

CaseGenotypingMethod: PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries was performed on genomic DNA.

Variant: NM_000666.3(ACY1):c.589C>T (p.Arg197Trp)

ClinVar: 18113, https://www.ncbi.nlm.nih.gov/clinvar/variation/18113/

gnomAD: 0.00001764, https://gnomad.broadinstitute.org/variant/3-52021009-C-T

CaseOS-146_II-1: Male, 5 yrs report, Romani

CasePresentingHPOs: HP:0001992, HP:0000954, HP:0000431, HP:0000316, HP:0040194, HP:0004322, HP:0001250, HP:0010819, HP:0032792, HP:0002121, HP:0000752, HP:0002342 (Organic aciduria, Single transverse palmar crease, Wide nasal bridge, Hypertelorism, Increased head circumference, Short stature, Seizure, Atonic seizure, Tonic seizure, Generalized non-motor (absence) seizure, Hyperactivity, Moderate Intellectual disability)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are healthy consanguineous cousins, Two cousins and a niece of the mother have epilepsy, Proband is homozygous for this variant

CasePreviousTesting: Routine urine screening for organic acidurias by gas chromatography–mass spectrometry showed markedly increased urinary excretion of several N-acetylated amino acids; Cerebral MRI was normal at the ages of 17 months and 2.5 years

CaseGenotypingMethod: PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries was performed on genomic DNA.

Variant: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110 https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T

CaseSE5: Male, Australia

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseGenotypingMethod: Five loci were investigated for evidence of linkage to Hartnup due to their established role in amino acid transport including SLC3A2, SLC7A8, SLC1A5, SLC6A18, and SLC6A19. These 5 regions were studied with microsattelite markers and produced linkage only between D5S392 and D5S417, the region with SLC6A18 and 19. SLC6A18 did not increase neutral amino acid uptake in X. laevis oocytes so SLC6A19 was investigated and directly sequenced in the families each of which displayed a causal variant.

CasePreviousTesting: SLC1A5 had no causative variants detected.

CaseAddInfo: Asymptomatic except for hyperaminoaciduria

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?dataset=gnomad_r2_1

Variant2: 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

CaseC1: Female, Arab, Israel

CasePresentingHPOs: HP:0010896, HP:0010897, HP:0001638 (Hypersarcosinemia, Hypersarcosinuria, Cardiomyopathy)

HPOsFreeText: Elevated blood Sarcosine (345 μmol/l; reference 0-9), Elevated urine Sarcosine (481 μmol/mmol; reference 0-36)

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous and first cousins, sister has the same genotype

CasePreviousTesting: N/A

CaseGenotypingMethod: DNA was extracted from the probands and immediate family. The whole coding region and the exon-intron boundaries of the SARDH gene was then amplified and sequenced.

Variant: NM_007101.3:c.211G>T (p.Val71Phe)

ClinVar: 39448 https://www.ncbi.nlm.nih.gov/clinvar/variation/39448/

gnomAD: Not in gnomAD

CaseF2: Female, 6 yrs report, Italy

CasePresentingHPOs: HP:0004923 (Hyperphenylalaninemia)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents do not appear to be tested, DNA sequence analysis "shows the sense sequence expected of compound heterozygotes with two comigrating bands seen"

CasePreviousTesting: Pre-treatment phenylalanine levels determined soon after birth were above 20 mg / 100 ml, Proband has been under treatment since birth and currently tolerates less than 20 mg Phe/kg bodyweight per day

CaseGenotypingMethod: DNA as isolated from leukocytes and haplotype analysis performed. Enzymatic digestion of PCR-amplified DNA fragments was performed and DGGE analysis of all 13 exons and flanking introns were carried out. The resulting samples containing abberant bands were sequenced and cleaved by MaeI and MaeIII for analysis.

Variant1: NM_000277.3(PAH):c.620A>G (p.Asn207Ser)

ClinVar: 102765 https://www.ncbi.nlm.nih.gov/clinvar/variation/102765/

gnomAD: Not in gnomAD

Variant2: NM_000277.3(PAH):c.842C>T (p.Pro281Leu)

ClinVar: 589 https://www.ncbi.nlm.nih.gov/clinvar/variation/589/

gnomAD: 0.0002016, https://gnomad.broadinstitute.org/variant/12-103246593-G-A

CaseF1: Male, 6 yrs report, Italy

CasePresentingHPOs: HP:0004923 (Hyperphenylalaninemia)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents were confirmed heterozygous, Splicing variant is predicted to lead to a null protein

CasePreviousTesting: Pre-treatment phenylalanine levels determined soon after birth were above 20 mg / 100 ml, Proband has been under treatment since birth and currently tolerates less than 20 mg Phe/kg bodyweight per day

CaseGenotypingMethod: DNA as isolated from leukocytes and haplotype analysis performed. Enzymatic digestion of PCR-amplified DNA fragments was performed and DGGE analysis of all 13 exons and flanking introns were carried out. The resulting samples containing abberant bands were sequenced and cleaved by MaeI and MaeIII for analysis.

Variant1: NM_000277.2(PAH):c.611A>G (p.Tyr204Cys)

ClinVar: 590 https://www.ncbi.nlm.nih.gov/clinvar/variation/590

gnomAD: 0.0001632, https://gnomad.broadinstitute.org/variant/12-103249009-T-C

Variant2: NM_000277.2(PAH):c.442-2A>C

ClinVar: 120276 https://www.ncbi.nlm.nih.gov/clinvar/variation/120276

gnomAD: Not in gnomAD

CaseKLE: Male, Japan, Asian

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText:

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePreviousTesting: Identified via neonatal mass screening

CaseGenotypingMethod: Both SLC6A18 and SLC6A19 were investigated for possible pathogenicity, with SLC6A19's pattern of expression supporting it as a primary candidate. Intronic primers were used to bidirectionally sequence each exon and flanking intronic regions, locating two compound heterozygous mutations that perfectly segregate with the phenotype.

Variant1: NM_001003841.3:c.340del (L114fs*114)

CAID: CA916079859 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA916079859

gnomAD: Not in gnomAD

Variant2: NM_001003841.3:c.682_683delinsTA (p.Thr228Ter)

CAID: CA916079860 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA916079860

gnomAD: Not in gnomAD

CaseES: Female, 1 yr onset

CasePresentingHPOs: HP:0002312, HP:0002131, HP:0002719, HP:0002078, HP:0002066, HP:0100560, HP:0002345, HP:0008376, HP:0000666, HP:0001348, HP:0002342, HP:0410217, HP:0012237 (Clumsiness, Episodic ataxia, Recurrent infections, Truncal ataxia, Gait ataxia, Upper limb asymmetry, Action tremor, Dysarthic speech, Horizontal nystagmus, Brisk reflexes, Moderate intellectual disability, Reduced blood 5-methyltetrahydrofolate level, Urocanic aciduria)

HPOsFreeText: Urocanis acid levels 158-202 mmol/mol creatinine (reference <10)

CaseNotHPOs: HP:0000496, HP:0001324, HP:0002160, HP:0001903 (Abnormal ocular movements, Muscle weakness, Hyperhomocystinemia, Anemia)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are healthy and nonconsanguineous, Steady improvement after mid-life, Proband is confirmed compound heterozygous by parental confirmation (father heterozygous for Variant 2)

CasePreviousTesting: Cranial MRI and neurophysiological studies, including electroencephalography, electroretinography, visual and brainstem evoked potentials, electromyography, nerve conduction velocities, fundus oculi and cardiological examinations, gave normal results; Cognitive evaluation rated her IQ at 54; Routine laboratory analyses including serum amino transferases, creatinine, urea and other parameters were normal; Screening for inborn errors of metabolism, including plasma and urine amino acids (no histidine accumulation), blood lactate, sialotransferrin isoelectricfocusing, creatine deficiency syndromes, purine and pyrimidine defects, and organic acidurias, gave normal results; Hypothyroidism and coeliac disease were also excluded; Biochemical and/or genetic screening for early onset forms of inherited ataxia gave normal results; Deficiencies in 5-methyltetrahydrofolate, neopterin and biopterin deficiencies were seen, together with an evident reduction in homovanillic acid (HVA) and the HVA:5-hydroxyindolacetic acid ratio; Other parameters determined in cerebrospinal fluid (CSF), such as glucose, proteins, cells and amino acids were normal.

CaseGenotypingMethod: Genomic DNA was obtained from peripheral white blood cells from the proband and her father. Mutation analysis of UROC1 was performed via direct sequencing and PCR amplification of the 20 exons and flanking exon-intronic sequences. In-silico analysis and modeling was performed on the variants.

Variant1: NM_144639.3(UROC1):c.209T>C (p.Leu70Pro)

ClinVar: 408 https://www.ncbi.nlm.nih.gov/clinvar/variation/408/

gnomAD: 0.00005647, https://gnomad.broadinstitute.org/variant/3-126229555-A-G

Variant2: NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys)

ClinVar: 407, https://www.ncbi.nlm.nih.gov/clinvar/variation/407/

gnomAD: 0.00008012, https://gnomad.broadinstitute.org/variant/3-126216984-G-A

CaseFI2: Male, Turkey, Birth onset

CasePresentingHPOs: HP:0009800, HP:0001195, HP:0000773, HP:0003026, HP:0001650, HP:0003561, HP:0001518, HP:0000252, HP:0004887, HP:0001274, HP:0001250, HP:0000411, HP:0007957, HP:0007495, HP:0000963, HP:0000973, HP:0100678, HP:0010648, HP:0001382, HP:0009815, HP:0001181, HP:0010557, HP:0001374, HP:0012330, HP:0030750, HP:0040187 (Maternal diabetes, Single umbilical artery, Short ribs, Short long bone, Aortic valve stenosis, Birth length less than 3rd percentile, Small for gestational age, Microcephaly, Respiratory failure requiring assisted ventilation, Agenesis of corpus callosum, Seizures, Protruding ear, Corneal opacity, Prematurely aged appearance, Thin skin, Cutis laxa, Premature skin wrinkling, Dermal translucency, Joint hypermobility, Aplasia/hypoplasia of the extremities, Adducted thumb, Overlapping fingers, Congenital hip dislocation, Pyelonephritis, Grade III preterm intraventricular hemorrhage, Neonatal sepsis)

HPOsFreeText: Intrauterine growth restriction birth length: 38 cm (< 3rd percentile), birth weight 1370 g (< 3rd percentile) and microcephaly (OFC at birth was 29.5 cm (3rd–10th percentile)). APGAR scores were 5, 9, and 9 after 1, 5, and 10 min, respectively; Typical facial gestalt

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are first-degree cousins that had three healthy daughters and three early abortions

CasePreviousTesting: N/A

CaseGenotypingMethod: Familial DNA was extracted from peripheral blood samples. Direct sequencing of PYCR1 and exons 2-18 of ALDH18A1 was performed in the affected individual with a homozygous single-basepair deletion found predicted to lead to a frameshift and premature stop codon.

Variant: NM_002860.4(ALDH18A1):c.2131del (p.Leu711fs)

ClinVar: 156546 https://www.ncbi.nlm.nih.gov/clinvar/variation/156546/

gnomAD: Not in gnomAD

Case764: Female, 4 years report, Spain

CasePresentingHPOs: HP:0011344, HP:0003153, HP:0001257, HP:0003698, HP:0002474 (Severe psychomotor retardation, Cystathioninuria, Spasticity, Difficulty standing, Communication delay)

HPOsFreeText: Elevated urine cystathionine (1611 umol/g creatine; reference <46) and Elevated tHcys in urine (54.3 umol/g creatine; reference <20), Elevated plasma tHcys (20.5 umol/l; reference <7.5), Post treatment normal urine cystathionine (42 umol/g creatine)

CaseNotHPOs: HP:0003345 (Glutathione synthetase deficiency)

NotHPOsFreeText: N/A

CaseAddInfo: Patient is homozygous for this variant

CasePreviousTesting: Karyotype, magnetic resonance imaging, specific genetic tests for neurogenetic diseases and screening for inborn errors of metabolism (lactate, pyruvate, ammonium, uric acid, amino acids, organic acids, glycosaminoglycanes, creatine and guanidinoacetate, purines and pyrimidines, and isoelectric focusing pattern of transferrin), as well as folate, pyridoxine and cobalamine deficiencies, neural tumors and genetically determined homocystinurias, were all ruled out.

CaseGenotypingMethod: All twelve exons of the CTH gene and the intronic flanking sequences of the subjects and their parents was PCR amplified and directly sequenced.

Variant: NM_001902.5:c.200C>T (p.Thr67Ile)

ClinVar: 2939 https://www.ncbi.nlm.nih.gov/clinvar/variation/2939/

gnomAD: Ashkenazi Jewish 9.934e-3, Overall 6.308e-3 https://gnomad.broadinstitute.org/variant/1-70881670-C-T

CaseVC: Male, Birth onset

CasePresentingHPOs: HP:0030082, HP:0002013, HP:0200048, HP:0001250, HP:0005949, HP:0001290, HP:0001662, HP:0008610, HP:0002120 (Abnormal drinking behavior, Vomiting, Cyanotic episode, Seizure, Apneic episodes in infancy, Generalized hypotonia, Bradycardia, Infantile sensorineural hearing impairment, Cerebral cortical atrophy)

HPOsFreeText: Birth weight of 2565 g, Length of 48 cm, Head circumference of 33 cm, Elevated excretion of TMS-derivatives of N-acetylated amino acids

CaseNotHPOs: HP:0001263 (Global developmental delay)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous, Proband confirmed homozygous via parental testing

CasePreviousTesting: Cerebral MRI showed abnormal signals in the cortico-subcortical zones of the fronto-parietal and temporo-occipital areas consistent with cortical laminar necrosis; Most presenting phenotypes were ameliorated after 6 weeks of age; N-acetylated amino acid excretion shown in Table 1

CaseGenotypingMethod: RT-PCR confirmed expression of aminoacylase I mRNA was significantly lowered in the proband than in controls. Southern blot and nested PCR confirmed the weak band observed was aminoacylase I mRNA and the relative expression levels. Following this, PCR amplification of all 14 coding exons and flanking introns of ACY1 was performed and sequenced.

Variant: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110 https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T

CaseBE2P3: Male, 9 days onset

CasePresentingHPOs: HP:0001399, HP:0006579, HP:0001396, HP:0004914, HP:0002240, HP:0001290, HP:0007772, HP:0000347, HP:0000218, HP:0000954, HP:0012448, HP:0001684, HP:0003265, HP:0002490, HP:0002151, HP:0003235, HP:0001897, HP:0001272, HP:0002119, HP:0001263, HP:0000733, HP:0001414, HP:0002612 (Hepatic failure, Prolonged neonatal jaundice, Cholestasis, Recurrent infantile hypoglycemia, Hepatomegaly, Generalized hypotonia, Impaired smooth pursuit, Micrognathia, High palate, Single transverse palmar crease, Delayed myelination, Secundum atrial septal defect, Neonatal hyperbilirubinemia, Increased CSF lactate, Increased serum lactate, Hypermethioninemia, Normocytic anemia, Cerebellar atrophy, Ventriculomegaly, Global developmental delay, Stereotypy, Microvesicular hepatic steatosis, Congenital hepatic fibrosis)

HPOsFreeText: Increased bile salts, Biliary stones in gallbladder, Severe intrahepatic extramedullary haematopoiesis

CaseNotHPOs: HP:0001744, HP:0000842, HP:0008163 (Splenomegaly, Hyperinsulinemia, Decreased circulating cortisol level)

NotHPOsFreeText: Abnormally coloured stools

CaseAddInfo: Parents are first cousins

CasePreviousTesting: All patients received ursodeoxycholic acid (600 mg.m−2.d−1) and fat-soluble vitamin supplementation; All patients received an enriched diet with medium chain triglycerides and dextrin maltose; Sanger sequencing of POLG, DGUOK, and TRMU in P3 revealed no pathogenic variants; Mitochondrial RC defect was considered but no anomaly was found in isolated lymphocytes and in primary culture of fibroblasts

CaseGenotypingMethod: Sanger sequencing of the ADK gene revealed a homozygous termination variant. Both parents carried this in a heterozygous state and the younger healthy brother did not carry the mutation

Variant: NM_006721.3:c.519G>A (p.Trp173Ter)

CAID: CA377397711, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_006721.3%3Ac.519G%3EA

gnomAD: Not in gnomAD

CaseKDC23: Male, 38 yrs onset, Korea, Asian

CasePresentingHPOs: HP:0002131, HP:0002321, HP:0001260, HP:0000640, HP:0011477, HP:0100543 (Episodic ataxia, Vertigo, Dysarthria, Gaze-evoked nystagmus, Upbeat nystagmus, Cognitive impairment)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband has no family history of disease

CasePreviousTesting: Negtive response to acetazolamide

CaseGenotypingMethod: Next-generation sequencing was perfomed on all probands with 40 candidate genes and five known EA genes.

Variant: NM_004172.5:c.952A>G (p.Thr318Ala)

CAID: CA3235581, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3235581

gnomAD: 0.002656, https://gnomad.broadinstitute.org/variant/5-36679820-A-G NOTE EXTREMELY HIGH gnomAD FREQUENCY

Patient1: Male, 6yo

CasePresentingHPOs:

HPOsFreeText: Blood C5-carnitine (μM) = 18.96, under a protein restricted diet with carnitine and glycine supplementation, normal development

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 10days old and asymptomatic at diagnosis

CasePMIDs:

CasePreviousTesting: Blood amino acids and acylcarnitine analyzed with ESI-MS/MS, urine organic acid analysis with GC/MS

GroupMethod1: PCR (primers in table 2)

GroupMethod2: Direct sequencing

CaseGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes, IVD exons amplified via PCR, then products were purified and underwent direct sequencing for variant analysis

Variant1: NM_002225.3:c.386A>G (p.Tyr99Cys) listed in paper as (p.His100Arg)

CAID: CA391716511, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391716511

gnomAD: n/a

Variant2: NM_002225.4(IVD):c.1199A>G (p.Tyr400Cys) listed in paper as (p.Tyr371Cys)

ClinVar: 371390, https://www.ncbi.nlm.nih.gov/clinvar/variation/371390/

gnomAD: n/a

Patient5-1: Female, 2.5yo, sibling to patient 5-2

CasePresentingHPOs:

HPOsFreeText: under a protein restricted diet with carnitine and glycine supplementation, normal development

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 2mo diagnosis

CasePMIDs:

CasePreviousTesting: Blood amino acids and acylcarnitine analyzed with ESI-MS/MS, urine organic acid analysis with GC/MS

GroupMethod1: PCR (primers in table 2)

GroupMethod2: Direct sequencing

CaseGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes, IVD exons amplified via PCR, then products were purified and underwent direct sequencing for variant analysis

Variant1: NM_002225.4:c.347C>T (p.Ser89Phe) listed in paper as (p.Ser87Phe)

CAID: CA391716394, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391716394

gnomAD: n/a

Variant2: NM_002225.4(IVD):c.1199A>G (p.Tyr400Cys) listed in paper as (p.Tyr371Cys)

ClinVar: 371390, https://www.ncbi.nlm.nih.gov/clinvar/variation/371390/

gnomAD: n/a

CaseTS: Male, Poland

CasePresentingHPOs: HP:0000256, HP:0001263, HP:0000729, HP:0001992 (Macrocephaly, Global developmental delay, Autistic behavior, Organic aciduria)

HPOsFreeText: Apgar score of 9

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous though grandfathers were from neighboring villages, Older brother is healthy, Proband is confirmed homozygous via parental testing

CasePreviousTesting: Biochemical tests included urinary organic acid analysis, amino acid analysis, transaminases, transferrin isoforms, phosphoribosylaminoimidazole-succinocarboxamide (SAICAr), and D-arabinitol; Urinary organic acids analysis by GC-MS was performed repeatedly and revealed N-acetylated derivatives of methionine, glutamic acid, alanine, and glycine in large amounts, as well as leucine, valine, and isoleucine in smaller amounts with brother and parent analysis being unremarkable

CaseGenotypingMethod: PCR amplification and bidirectional sequencing of all exons and exon-intron boundaries was performed on genomic DNA.

Variant: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110 https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T

Case1: Female, Mixed, Birth onset

CasePresentingHPOs: HP:0001508, HP:0000252, HP:0002076, HP:0002018, HP:0002013, HP:0011342, HP:0000750, HP:0001270, HP:0007018 (Failure to thrive, Microcephaly, Migraine, Nausea, Emesis, Mild global developmental delay, Delayed speech and language development, Motor delay, Attention deficit hyperactivity disorder)

HPOsFreeText: Seizure-like episodes, Persistent head tilting, Symptoms impreoved over time

CaseNotHPOs: HP:0001252 (Muscular hypotonia)

NotHPOsFreeText: No brain MRI abnormalities

CaseAddInfo: Parents are non-consanguineous

CasePreviousTesting: Born at full term after a pregnancy complicated by maternal hypertension with no postnatal complications; Elevated levels of plasma 2-aminoadipate (37 μmol/L, nl < 4) with elevated 2-ketoadipate (434 mmol/mol creatinine, nl < 2) and 2-hydroxyadipate (28 mmol/mol creatinine, nl < 2) in urine; Electroencephalogram, magnetic resonance imaging, and magnetic resonance angiogram of the brain were unremarkable

CaseGenotypingMethod: Whole exome sequencing was performed as a trio with both parents. Identified DHTKD1 mutations were evaluated for possible effects and filtered for frequencies and predicted pathogenicity. No other candidate genes were found during the WES analysis for either patient sequenced.

Variant1: NM_018706.6:c.2143C>T (p.Arg715Cys)

ClinVar: 242503 https://www.ncbi.nlm.nih.gov/clinvar/variation/242503/

gnomAD: 0.0002007, https://gnomad.broadinstitute.org/variant/10-12150003-C-T

Variant2: NM_018706.6(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

CaseII-2: Female, Japanese, 4 years death

CasePresentingHPOs: HP:0001290, HP:0001263, HP:0002453, HP:0004372, HP:0001942, HP:0045011, HP:0002339, HP:0002138, HP:0002795, HP:0007695, HP:0008000, HP:0001635, HP:0001942 (Generalized hypotonia, Developmental delay, Abnormality of the globus pallidus, Lowered consciousness, Metabolic acidosis, Decreased urine bicarbonate concentration, Abnormality of the caudate nucleus, Subarachnoid hemorrhage, Abnormal respiration, Abnormal pupillary light reflex, Decreased corneal reflex, Heart failure, Metabolic acidosis)

HPOsFreeText: Her birth weight was 2714 g, She measured 44 cm (− 2.6 SD) in length, Had an occipitofrontal circumference of 32.5 cm (− 0.5 SD), Could hold her head up at 5 months and roll over at 10 months, Febrile illness at 15 months, Required ventilator support, Absence of brain activity, Auditory brainstem response audiometry showed no response

CaseNotHPOs: HP:0009782, HP:0001250, HP:0001332 (Aplasia/Hypoplasia of the biceps, Seizures, Dystonia)

NotHPOsFreeText:

CaseAddInfo: Parents are nonconsanguineous, Older sister of patient II-2 who is also homozygous for the mutation and has the disorder, Parents are confirmed heterozygous for the mutation

CasePreviousTesting: Lactate and pyruvate levels in arterial blood (16.5 mg/dL and 1.48 mg/dL, respectively; normal range: 5–20 mg/dL and 0.3–0.9 mg/dL, respectively) and cerebrospinal liquor (13.5 mg/dL and 1.12 mg/dL, respectively; normal range: 9.1–18.8 mg/dL and 0.26–1.32 mg/dL, respectively) were almost normal, Arterial blood ketone bodies, pH, pCO2, and base excess were (8700 μmol/L; normal range: < 130 μmol/L), 7.051, 6.7 mm Hg, and − 26.9 mEq/L, respectively, CSF lactate at 1.5 (< 2.0 mmol/L reference)

CaseGenotypingMethod: Whole exome analysis was performed on the parents and the proband. Afterwards, genomic DNA was extracted from peripheral blood leukocytes and targeted sequences were amplified and sequenced. All SNVs and Indels were evaluated and filtered to confirm the mutations. Afterwards, after identifying the exon 4 mutation, a DNA segment was amplified via PCR and sequenced to confirm these findings.

Variant: NM_014362.3:c.287C>A (p.Ala96Asp)

CAID: CA349896230 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_014362.3%3Ac.287C%3EA

gnomAD: Not in gnomAD

Case1: Male, 3 months onset, Pakistan,

CasePresentingHPOs: HP:0002376, HP:0008947, HP:0001336, HP:0002197, HP:0002490, HP:0012240, HP:0002572, HP:0000737, HP:0002360, HP:0002453, HP:0002352, HP:0002283, HP:0001332, HP:0002871, HP:0000648, HP:0000365, HP:0000252 (Developmental regression, Infantile hypotonia, Myoclonic jerks, Generalized seizures, Increased CSF lactate, Increased muscle lipid droplets, Episodic vomiting, Irritability, Sleep disturbance, Abnormality of the globus pallidus, Leukoencephalopathy, Global brain atrophy, Dystonia, Central apnea, Optic atrophy, Hearing loss, Microcephaly)

HPOsFreeText: Born at term weighing 3.2 kg, Loss of smile

CaseNotHPOs: HP:0002151, HP:0003200, HP:0003688, HP:0010663, HP:0006846 (Increased serum lactate, Ragged-red fibres, Cytochrome C oxidase-negative muscle fibers, Abnormality of thalamus morphology, Acute encephalopathy)

NotHPOsFreeText: N/A

CaseAddInfo: Parents were distantly related, Died at 3 years, Has a younger brother with the same variant, Has a family history of neurological/neuromuscular disorders, Variant was confirmed by parental testing

CasePreviousTesting: At 8 months Nissen fundoplication was performed because of persistent vomiting, Mildly elevated CSF lactate at 2.2 mmol/l (reference range <2 mmol/l) at 8 months, with a normal venous blood lactate of 1.7 mmol/l (reference range < 1.8 mmol/l), Complex I at 0.068 (Reference; 0.104-0.268 ratio to citrate synthase activity), Complexes II + III at 0.010 (0.040-0.204 ratio to citrate synthase activity), Complex IV (COX) at 0.010 (0.014-0.034 ratio to citrate synthase activity)

CaseGenotypingMethod: Genomic DNA was extracted from skin fibroblasts. Exons and flanking intronic sequences of HIBCH was sequenced after PCR amplification. Sequence data was compared to the reference sequence and filtered for variants.

Variant: NM_014362.3:c.950G>A (p.Gly317Glu)

ClinVar: 187864 https://www.ncbi.nlm.nih.gov/clinvar/variation/187864/

gnomAD: Not in gnomAD

Families 1 and 2

NKX6-2: c.121A>T; p.Lys41∗ (NM_177400.2) absent from gnomAD and has not previously been linked to human phenotypes.

Case: Bolino Proband 2 (Case 25 in PMID:10677858), female, reported at 5yo, symptom onset at 2yo

CasePresentingHPOs: HP:0001270, HP:0030319, HP:0008959, HP:0008994, HP:0009053, HP:0002522, HP:0003474, HP:0000218, HP:0001761, HP:0003447, HP:0012447 (motor delay, facial weakeness, distal upper limb muscle weakness, proximal lower limb muscle weakness, distal lower limb muscle weakness, lower limb areflexia, sensory impairment, high palate, pes cavus, axonal loss, abnormal myelination)

HPOsFreeText: walked at 17mo, tendon reflexes absent in lower limbs but present in upper limbs, sensory action potential absent in all nerves tested , CMAPs had small amplitude and temporal dispersion in upper limbs and were not detectable in lower limbs, EMG of tibialis anterior showed neurogenic features, presence of myelin loops and excessive outfolding, thick and irregular myelin sheaths

NotHPOs: HP:0003383 (onion bulb formation)

CountryOrigin: Saudi Arabia

PreviouslyPublished: 10677858

FamilyInfo: consanguineous family

GenotypingMethod: RT-PCR of RNA from patient lymphoblastoid cell line, available family members analyzed and segregation of variant with disease confirmed in pedigree

Variant 1: NM_003912.1:c.1480_1593del

ClinVar: 637472, https://www.ncbi.nlm.nih.gov/clinvar/variation/637472/

gnomAD: absent

Variant 2: NM_016156.5(MTMR2):c.826G>T (p.Glu276Ter)

ClinVar: 6233, https://www.ncbi.nlm.nih.gov/clinvar/variation/6233/

gnomAD: absent

ScoringNotes: both variants stated to be homozygous on same allele, assume variants in trans

Case: Bolino Proband 1 (proband 1945), male, reported at 4yo, symptom onset at 42mo

CasePresentingHPOs: HP:0001349, HP:0003701, HP:0001284, HP:0001288, HP:0003474, HP:0003693, HP:0003722, HP:0003391, HP:0001761, HP:0003383, HP:0012447 (bilateral facial weakness, proximal muscle weakness, areflexia, abnormal gait, sensory impairment, distal limb muscle atrophy, neck flexor weakness, Gower's sign, pes cavus, onion bulb formation, abnormal myelination)

HPOsFreeText: walked at 14mo, eyes reported to be normal, gait - bilateral steppage, pes equinovarus deformity of both feet, frequent falling, had normal early motor milestones, bilateral pes cavus with retraction of Achille's tendon, intellectually normal. Laboratory testing normal: full blood count, fasting blood glucose, serum electrolytes, creatine kinase, lactic acid, urinary organic acids, serum and urine carnitine, EEG, ECG, and liver echography, segmental demyelination in 92% of fibers, redundant loops of myelin sheath irregularly arrayed near axon, muscle biopsy of rectus femoris showed atrophic and angulated fibers in clusters and large type grouping, lipid accumulation

Median nerve conduction studies: compound motor action potential = 4.6uV, distal motor latency = 7.8msec, sensory action potential = 3.3uV, motor nerve conduction velocity = 17msec, sensory nerve conduction velocity = 18msec

Peroneal nerve conduction studies: compound motor action potential = 0.21uV, distal motor latency = 7.8msec, motor nerve conduction velocity = 14

Sural nerve conduction studies: sensory action potential = no response, sensory nerve conduction velocity = no response

CountryOrigin: Italy

FamilyInfo: consanguineous family, parents reported to be normal at clinical and electrophysiological exams

PreviouslyPublished: PMID:10673338, PMID:8817346, PMID: 8628474, PMID: 8017168

GenotypingMethod: RT-PCR of RNA from patient lymphoblastoid cell line, available family members analyzed and segregation of variant with disease confirmed in pedigree - PMID:8817346 - homozygosity mapping and haplotype sharing through microsatellite and linkage analysis

Variant: NM_016156.5(MTMR2):c.1276C>T (p.Gln426Ter) homozygous

ClinVar: 6231, https://www.ncbi.nlm.nih.gov/clinvar/variation/6231/

gnomAD: 0.000007085, https://gnomad.broadinstitute.org/variant/11-95578227-G-A

Case3: Female, Italy, 7 yrs report

CasePresentingHPOs: HP:0003798, HP:0003325, HP:0001270, HP:0002093, HP:0002650, HP:0002355, HP:0003324, HP:0001283, HP:0003306 (Nemaline bodies, Limb-girdle muscle weakness, Motor delay, Respiratory impairment, Scoliosis, Difficulty walking, Generalized muscle weakness, Bulbar palsy, Spinal rigidity)

HPOsFreeText: Semi-solid diet

CaseNotHPOs: HP:0003560, HP:0003715, HP:0001627, HP:0000602, HP:0001557, HP:0001290 (Muscular dystrophy, Myofibrillar myopathy, Cardiac abnormality, Ophthalmoplegia, Prenatal movement abnormality, Hypotonia)

NotHPOsFreeText: Congenital myasthenic syndromes

CaseAddInfo: Intermediate NM presentation, Parental segregation was confirmed, Variant 2 creates a new splicing donor site and activates an upstream acceptor site which partially expresses intron 125 and causes a premature termination codon

CasePreviousTesting: ACTA1, TPM2 and TPM3 mutations were ruled out via amplification and direct sequencing

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood leukocytes or fibroblasts. 183 exons of NEB, the relative introns, and the full promoter region was captured via litigation-mediated PCR and high-throughput sequencing of resulting fragments. These were then aligned and filtered for inheritance and pathogenicity. Variants were evaluated for amino acid conservation and confirmed by Sanger sequencing.

Variant1: NM_001271208.2:c.24559C>T (p.Arg8187Ter)

ClinVar: 496135 https://www.ncbi.nlm.nih.gov/clinvar/variation/496135/

gnomAD: Not in gnomAD

Variant2: NM_001271208.1:c.19429-381_19429-379delinsA (p.=)

CAID: CA913203565 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203565

gnomAD: Not in gnomAD

Case2: Male, Italy, Birth onset

CasePresentingHPOs: HP:0003798, HP:0002033, HP:0003325, HP:0001558, HP:0001270, HP:0002093, HP:0000194, HP:0006830, HP:0003701, HP:0002650, HP:0003458 (Nemaline bodies, Poor suck, Limb-girdle muscle weakness, Decreased fetal movement, Motor delay, Respiratory impairment, Open mouth, Congenital hypotonia, Proximal muscle weakness, Scoliosis, EMG: myopathic abnormalities)

HPOsFreeText: Wheelchair dependent

CaseNotHPOs: HP:0003560, HP:0003715, HP:0001627, HP:0000602, HP:0001283, HP:0003306 (Muscular dystrophy, Myofibrillar myopathy, Cardiac abnormality, Ophthalmoplegia, Bulbar palsy, Spinal rigidity)

NotHPOsFreeText: Congenital myasthenic syndromes

CaseAddInfo: Intermediate NM presentation, Parental segregation was confirmed

CasePreviousTesting: ACTA1, TPM2 and TPM3 mutations were ruled out via amplification and direct sequencing

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood leukocytes or fibroblasts. 183 exons of NEB, the relative introns, and the full promoter region was captured via litigation-mediated PCR and high-throughput sequencing of resulting fragments. These were then aligned and filtered for inheritance and pathogenicity. Variants were evaluated for amino acid conservation and confirmed by Sanger sequencing.

Variant1: NM_001164507.1:c.17737-2A>T (p.=)

CAID: CA348804839 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_001271208.2%3Ac.17737-2A%3ET

gnomAD: Not in gnomAD

Variant2: NM_001271208.1:c.21423del (p.Lys7141Asnfs*23)

CAID: CA913203564 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203564

gnomAD: Not in gnomAD

Case1: Male, Birth onset

CasePresentingHPOs: HP:0008936, HP:0002058, HP:0200096, HP:0000218, HP:0000774, HP:0005957, HP:0001290, HP:0001284, HP:0002938, HP:0003324, HP:0009046, HP:0008994, HP:0009027, HP:0003722, HP:0002650, HP:0000278, HP:0001724, HP:0002792, HP:0002877, HP:0003557, HP:0100299, HP:0003803 (Muscular hypotonia of the trunk, Myopathic facies, Triangular-shaped open mouth, High-arched palate, Narrow chest, Abnormal breathing, Generalized hypotonia, Areflexia, Exaggerated lumbar lordosis, Generalized muscle weakness, Difficulty running, Proximal muscle weakness in lower limbs, Foot dorsiflexor weakness, Neck flexor weakness, Scoliosis, Retrognathia, Aortic dilatation, Reduced vital capacity, Nocturnal hypoventilation, Increased variation in fiber size, Muscle fiber inclusion bodies, Type 1 muscle fiber predominance)

HPOsFreeText: Crawled at age 10 months and walked independently at age 15 months, Inability to jump, PVC was 37% of predicted, BiPAP commenced at age 20, Cap-like structures

CaseNotHPOs: HP:0003115, HP:0003798 (Abnormal ECG, Nemaline bodies)

NotHPOsFreeText: N/A

CaseAddInfo: No family history of muscle weakness, Variant is de novo and confirmed absent in the parents

CasePreviousTesting: Tested caps appeared pale on all myosin ATPase stains and dark on Gomori Trichrome and NADH stains and were strongly reactive for troponin T, α-actinin-2, myotilin, tropomyosin, actin and desmin by immunoperoxidase, No positive staining for neonatal or embryonic myosin isoforms, Large regions of disorganised thin filament structures containing Z band remnants were present in subsarcolemmal positions

CaseGenotypingMethod: Bidirectional sequencing on TPM2 and TPM3 for all exons and exon-intron boundaries was performed using genomic DNA.

Variant: NM_152263.4(TPM3):c.502C>T (p.Arg168Cys)

ClinVar: 12454 https://www.ncbi.nlm.nih.gov/clinvar/variation/12454/

gnomAD: Not in gnomAD