Case#: Hudson Proband II:5, 66yo, female, UK

DiseaseAssertion: OA plus

FamilyInfo: Pedigree (Fig 1) shows 6 segregations

CasePresentingHPOs: HP:0007663, HP:0001288, HP:0001730, HP:0000746, HP:0002367, HP:0000648, HP:0000544, HP:0001488, HP:0001349, HP:0002066, HP:0001315, HP:0003236, HP:0033568, HP:0001272, HP:0002120

CaseHPOFreeText: slowly progressive deterioration in her visual acuity, a progressive gait disturbance of 20 years duration, and a 5-year history of deteriorating hearing, acute paranoid delusions, low mood, just able to perceive light, bilateral optic atrophy, plantar responses flexor, elevated serum creatine kinase (417 U/l, normal <190 U/l) with a normal fasting blood glucose and lactate, mild cortical disturbance, prominent small-vessel ischaemic lesions in the cerebral white matter bilaterally. Muscle biopsy of the index case (II:5) revealed features that were diagnostic of mitochondrial myopathy

CaseNotHPOs: HP:0001627, HP:0031983

CaseNotHPOFreeText:

PreviouslyPublished: n/a

PreviousTesting: The entire mitochondrial genome-coding region was amplified and found (m.8839G>A) in the MTATP6 gene. No sequence variants were identified in the coding region or flanking exon–intron boundaries for POLG1, PEO1, POLG2 and SLC25A4.

GenotypingMethod: The 30 coding exons and intron–exon junctions of the OPA1 gene were sequenced using a set of 30 primer pairs

Variant: c.1800C>G (p.Ser600Arg)

ClinVar: 30461

CAID: CA10575554

SupplementalData:

annotating here since this is a PDF

Case#: Yamagishi Case 2, female, 10m at dx

DiseaseAssertion: Hurler

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: mental delay. height=70cm

CaseNotHPOs: HP:0002240

CaseNotHPOFreeText: cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5/704ins homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: n/a

annotating here since this is a PDF

Case#: Yamagishi Case 3, female, 3y4m at dx

DiseaseAssertion: Hurler/Scheie

FamilyInfo: Case 4 is this patient's sibling. Same genotype and similar phenotype

CasePresentingHPOs: HP:0001433

CaseHPOFreeText: height=90cm (-1.2SD)

CaseNotHPOs:

CaseNotHPOFreeText: mental delay. cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5; R89Q

ClinVar: 11921; 11922

CAID: CA256123; CA256124

SupplementalData: n/a

annotating here since this is a PDF

Case#: Yamagishi Case 1, female, 3y1m at dx

DiseaseAssertion: Hurler

FamilyInfo: consanguinity

CasePresentingHPOs: HP:0002240

CaseHPOFreeText: mental delay. height=89cm (-1.5SD)

CaseNotHPOs:

CaseNotHPOFreeText: cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5/704ins homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: n/a

Case#: KMP 1, female, 39 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVEF 60%; NYHA I.; ECG; echocardiography

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO; no ICD

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093 https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

CAID: n/a

gnomAD: absent

Case#: KMP 16, female, 60 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVOTO yes; LVEF 39-40%; NYHA I.; ICD yes; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093 https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

CAID: n/a

gnomAD: absent

Case#: N5214, F, 62 y.o., Italian

CasePresentingHPOs: HP:0007354, HP:0002015, HP:0001260, HP:0002380, HP:0003690, HP:0003202

CaseNotHPOs: HP:0100543

CaseGenotypingMethod: Sanger sequencing

Variant: NM_006000.3(TUBA4A):c.1045A>T p.Thr349Ser

CAID: CA350723588

CaseAddInfo: While most cases were found to be negative during pre-screening for known mutations, some cases were positive for mutations in SOD1 (n=4), C9orf72 (n=12), TARDBP (n=4), & FUS/TLS (n=1) genes. Whether this case tested positive for any of these is not specified.

Case#: P937, F, Italian

CasePresentingHPOs: HP:0007354

CaseGenotypingMethod: Sanger sequencing

Variant: c.19C>A p.Val7Ile

CaseAddInfo: This allele is not found in the reference NM_006000.2 or NM_006000.3 (CAID can not be created or retrieved because there is a G in this location instead of the C reported here).

CaseAddInfo: While most cases were found to be negative during pre-screening for known mutations, some cases were positive for mutations in SOD1 (n=4), C9orf72 (n=12), TARDBP (n=4), & FUS/TLS (n=1) genes. Whether this case tested positive for any of these is not specified.

Case#: B1103, M, 57 y.o., Italian

CasePresentingHPOs: HP:0007354, HP:0003202, HP:0007340

CaseNotHPOs: HP:0100543

CaseGenotypingMethod: Sanger sequencing

Variant: NM_006000.3(TUBA4A):c.226+4A>G IVS2+4A>G

CAID: CA2018007638

CaseAddInfo: While most cases were found to be negative during pre-screening for known mutations, some cases were positive for mutations in SOD1 (n=4), C9orf72 (n=12), TARDBP (n=4), & FUS/TLS (n=1) genes. Whether this case tested positive for any of these is not specified.

Case#: Consequence 4 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2156G>A (p.Arg719Gln)

ClinVar: 14107 https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/

CAID: n/a

gnomAD: absent

Case#: Consequence 6 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2146G>A (p.Gly716Arg)

ClinVar: 14105 https://www.ncbi.nlm.nih.gov/clinvar/variation/14105/

CAID: n/a

gnomAD: absent

Case#: Consequence 3 Table 1 in Data Supplement (4 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly)

ClinVar: 14125 https://www.ncbi.nlm.nih.gov/clinvar/variation/14125/

CAID: n/a

gnomAD: 0.000008792 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23893321-T-C

Case#: Consequence 12 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.208A>T (p.Thr70Ser)

ClinVar: 42877 https://www.ncbi.nlm.nih.gov/clinvar/variation/42877/

CAID: n/a

gnomAD: 0.00001761 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23902430-T-A

Case#: Consequence 24 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.1357C>T (p.Arg453Cys)

ClinVar: 14089 https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/

CAID: n/a

gnomAD: absent

Case#: Consequence 1 Table 1 in Data Supplement (1 case)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.1988G>A (p.Arg663His)

ClinVar: 42875 https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/

CAID: n/a

gnomAD: 0.00003097 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23896042-C-T

Case#: Consequence 17 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2681A>G (p.Glu894Gly)

ClinVar: 42922 https://www.ncbi.nlm.nih.gov/clinvar/variation/42922/

CAID: n/a

gnomAD: absent

Case#: Consequence 21 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2945T>C (p.Met982Thr)

ClinVar: 42941 https://www.ncbi.nlm.nih.gov/clinvar/variation/42941/

CAID: n/a

gnomAD: 0.001416 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23892910-A-G

Case#: Consequence 18 Table 1 in Data Supplement (4 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.1750G>C (p.Gly584Arg)

ClinVar: 14090 https://www.ncbi.nlm.nih.gov/clinvar/variation/14090/

CAID: n/a

gnomAD: 0.000008790 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23896932-C-G

Patients 2, 4, and 5 are all homozygous for this variant. Previously published in PMID: 22718273

Case: Fritzen Individual 2, male, German, AOR= 3 yo

CasePresentingHPOs: HP:0001511, HP:0001518, HP:0000252, HP:0000047, HP:0001643, HP:0001655, HP:0008947, HP:0001263, HP:0001344, HP:0001256, HP:0000486, HP:0000483, HP:000432, HP:0001357, HP:0000348, HP:0009890, HP:0000490, HP:0000455, HP:0000430, HP:0000343, HP:0010804, HP:0002714, HP:0012471, HP:0000047, HP:0001814, HP:0000752

CasePresentingText: intrauterine growth retardation noted at 22 weeks gestation. PFO/PDA closed spontaneously. Started walking at 18 months, at 3 years old no speech. EEG was not able to be evaluated.

CaseNOTHPOs: HP:0000365, HP:0001250

CasePreviousTesting: Chromosome analysis, microdeletion 22q11.2 testing, chromosomal microarray analysis, fragile X testing (FMR1) and methylation sensitive MLPA for chromosome 11 and 7 loci (Silver-Russell syndrome) testing were unremarkable and normal.

CaseGenotypingMethod: WES

Sanger sequencing was used to confirm the mutation and to exclude the presence of the mutant in the parents.

The WES identified a heterozygous mutation in ARID1A, a gene that is associated with Coffin-Siris syndrome. The mutation was a 6 bp duplication in (NM_006015.4:c.489_494dupCGCCGC, p.[(A164_A165dup)]. It was maternally inherited, and the mother was not noted to have behavioral abnormalities. In addition, the WES revealed 18 different mutations in 12 genes (Supplemental Table 1). Most of these were ruled out due to high frequencies in the control population in homozygoues state, or the genes were associated with disease entities that had disparate phenotypes than the those presenting in the proband.

Variant: chr2:g.48035302_48035303del; NM_001190274.1:c.2738_2739delAT (p.Y913X)

CA ID: CA658820925

de novo

gnomAD: not present

AddCaseInfo:

VariantEvidence: No variant evidence to confer alteration of FBXO11 function or pathogenicity. Furthermore, the presence of a VUS in ARID1A that is responsible for Coffin-Siris syndrome, which has many overlapping phenotype, cannot be ruled out as contributory, even in the absence of an strongly overt phenotype in the mother. Subtle behvioral phenotypes could be present, and she was not fully evaluated to rule out and behavioral abnormalities. Albeit, this mutation has arisen in another unrelated individual, de novo, in Martinez et al., 2017 (PMID: 27620904 ), as well as one patient, de novo in the DECIPHER DDD study (case 325596).Therefore, I am downgrading the score but minimally.

Case# Subject 3-1, male, 11yo, Pakistani

CasePresentingHPOs HP:0000750, HP:0011342, HP:0000286, HP:0000431, HP:0000490, HP:0000717, HP:0007302, HP:0000218, HP:0001500, HP:0001837, HP:0002650, HP:0001249, HP:0001252, HP:0000717 (Speech delay, Mild global developmental delay, Epicanthus, Broad nasal bridge, Deep set eyes, Bipolar disorder, High palate, Broad fingers, Broad toes, Scoliosis, Intellectual Disability, Hypotonia, Autism)

HPOFreeText: mild speech/motor/cognitive delay, mild prominence of lateral ventricles, mild scoliosis, mild-moderate hypotonia

CaseNotHPOs HP:0002376, HP:0001250 (Developmental regression, Seizures)

NotHPOFreeText: Ventillator dependence

CasePreviousTesting Variants previously reported with a minor allele frequency > 1% were excluded. WES for additional compound-heterozygous, X-linked, or heterozygous de novo variants was negative.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES on all families, confirmed heterozygous/compound heterozygous with Sanger. Sanger on individuals with an affected family member. Parents confirmed heterozygous for childrens' variants

Variant NM_001163435.2:c.1652T>C(p.Leu551Pro), homozygous

ClinVar n/a

CAID CA357822100

gnomAD n/a

VariantEvidence n/a

CaseAddInfo consanguinity

CasePMIDs n/a

Case# Subject 1-1, male, 5yo died, Saudi

CasePresentingHPOs HP:0001558, HP:0000750, HP:0011344, HP:0002283, HP:0006829, HP:0001250, HP:0000340, HP:0000414, HP:0010804, HP:0000582, HP:0000496, HP:0002099, HP:0000964, HP:0001249 (Decreased fetal movement, Speech delay, Severe global developmental delay, Diffuse brain atrophy, Severe hypotonia, Seizures, Sloping forehead, Bulbous nose, Tented upper lip, Upslanted palpebral fissure, Abnormality of eye movement, Asthma, Eczema, Intellectual disability)

HPOFreeText: Oligohydramnios, Abnormal white matter signal intensity, Delayed reflexes

CaseNotHPOs HP:0002376 (Developmental regression)

NotHPOFreeText: Ventilator dependence

CasePreviousTesting Variants previously reported with a minor allele frequency > 1% were excluded. WES for additional compound-heterozygous, X-linked, or heterozygous de novo variants was negative. Included in previous study based on a neurogenetic diagnosis, positive family history, consanguineous parents, and no candidate genes identified by autozygosity mapping.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES on all families, confirmed heterozygous/compound heterozygous with Sanger. Sanger on individuals with an affected family member. Parents confirmed heterozygous for childrens' variants

Variant NM_033115.4(TBCK):c.1708+1G>A, homozygous

ClinVar 183338

gnomAD 0.00006693(European(Non-Finnish)), 0.00003244(total)

VariantEvidence (Fig 2A) Western blot: TBCK expression reduced in patient fibroblasts by 78%.

CaseAddInfo Consanguinity

CasePMIDs 25558065

Case2: Female, Austria, 18 yrs report

CasePresentingHPOs: HP:0010628, HP:0002643, HP:0002015, HP:0040288, HP:0001260, HP:0003690, HP:0003798, HP:0001511, HP:0001561, HP:0005216, HP:0002540, HP:0002650 (Facial weakness, Neonatal respiratory distress, Swallowing difficulties, Nasogastric tube feeding, Dysarthric speech, Limb weakness, Nemaline bodies, Intrauterine growth restriction, Polyhydramnios, Chewing difficulties, Non-ambulatory, Scoliosis)

HPOsFreeText: 3/3/5 Apgar score

CaseNotHPOs: HP:0002015 (Swallowing difficulties)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: Whole exome sequencing of the proband revealed these homozygous LMOD3 mutations.

Variant1: NM_198271.4:c.1648C>T (p.Leu550Phe)

ClinVar: 374498 https://www.ncbi.nlm.nih.gov/clinvar/variation/374498/

gnomAD: Not in gnomAD

Variant2: NM_198271.4:c.1004A>G (p.Gln335Arg)

ClinVar: 374499 https://www.ncbi.nlm.nih.gov/clinvar/variation/374499/

gnomAD: Not in gnomAD

Case3: Male, Germany, 20 yrs report

CasePresentingHPOs: HP:0010628, HP:0002015, HP:0040288, HP:0001260, HP:0003690, HP:0003798, HP:0002650 (Facial weakness, Swallowing difficulties, Nasogastric tube feeding, Dysarthric speech, Limb weakness, Nemaline bodies, Scoliosis)

HPOsFreeText: 7/8/9 Apgar score

CaseNotHPOs: HP:0002015, HP:0002540, , HP:0002098 (Swallowing difficulties, Non-ambulatory, Respiratory distress)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: Next generation sequnecing-based panel analysis detected the below variants in LMOD3.

Variant1: NM_198271.4:c.1648C>T (p.Leu550Phe)

ClinVar: 374498 https://www.ncbi.nlm.nih.gov/clinvar/variation/374498/

gnomAD: Not in gnomAD

Variant2: NM_198271.4:c.1004A>G (p.Gln335Arg)

ClinVar: 374499 https://www.ncbi.nlm.nih.gov/clinvar/variation/374499/

gnomAD: Not in gnomAD

Case#: 3, female, 12 days (onset), 4 y (current- this differs than what is in table 1), Chinese

CasePresentingHPOs: HP: 0008344, HP: 0012088, HP:0011968, HP: 0002013, HP:0011344, HP: 0002543, HP: 0012751 (elevated A keto acids in urine, abnormal urinary odor, feeding difficulties, vomiting, severe global developmental delay, abnormal globus pallidus, abnormal basal ganglia)

HPOsFreeText: Bilateral damage to capsula interna and externa, Blood ammonia: 205 uM, Hemoglobin: 118 g/L, Leucin: 891.90 uM, Valine: 502.50 uM, Isoleucine: 165.99 uM, Alloisoleucine: 90.12 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 2 different variants, unsure of cis or trans

CasePreviousTesting: n/a

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_000709.3(BCKDHA):c.178G>T (p.Glu60Ter), NM_000709.3(BCKDHA):c.1214_1219dupCCAACC (p.Asn406Leu407insProGln)

ClinVar: n/a

CAID: CA406004676 , CA658820662

gnomAD: neither in gnomAD

Case#: 6, male, 18 m (onset), 2 y 6 m (current), Chinese

CasePresentingHPOs: HP: 0008344, HP; 0012088, HP: 0011342, HP: 0001332, HP:0002543, HP: 0012751, HP:0012747 (elevated A keto acids in urine, abnormal urinary odor, mild global developmental delay, dystonia, abnormal globus pallidus, abnormal basal ganglia, abnormal brainstem MRI signal intensity)

HPOsFreeText: damage to cerebellar dentate nucleus, damage to corpora quadrigemina, damage to frontal lobe, damage to insular cortex, Isoleucine: 167.13 uM, Alloisoleucine: 44.88 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: unsure cis or trans

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_183050.3:c.767A>G (p.Tyr256Cys), NM_183050.3:c.768C>G (p.Tyr256Ter)

ClinVar: neither found

CAID: CA364659935, CA142287564

gnomAD: 0.000008820 (European, non-Finnish), not found

Case#: 8, male, 13 days (onset), 1 y 6 m (current), Chinese

CasePresentingHPOs: HP: 0008344, HP:0012088, HP:0011968, HP:0001254, HP:0002415, HP: 0006989 (elevated A keto acids in urine, abnormal urinary odor, feeding difficulties, lethargy, leukodystrophy, dysplastic corpus callosum)

FreeTextHPOs: blood ammonia: 96 uM, hemoglobin: 98 g/L, leucin: 1047.24 uM, isoleucine: 261.09 uM, alloisoleucine: 127.05 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: homozygous mutation

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_001918.3:c.1A>G (p.Met1Val)

ClinVar: not found

CAID: CA969877

gnomAD: not found

Case#: 1, male, 3 days (onset), 2 y 8 mo (current), Chinese

CasePresentingHPOs: HP:0008344 HP: 0012088, HP: 0001250, HP: 0011968, HP: 0001941, HP: 0001943, HP: 0001987, HP: 0001903, HP:0012751, HP:0002543, HP: 0001276, HP:0011343 (elevated A keto acids in urine, abnormal urinary odor, seizures, feeding difficulties, acidosis, hypoglycemia, hyperammonemia, anemia, abnormal basal ganglia MRI signal intensity, abnormal globus pallidus signals, hypertonia, moderate global developmental delay)

HPOsFreeText: Blood ammonia: 75 uM, Valine: 532.83 uM, Isoleucine: 384.90 uM, Alloisoleucine: 213.09 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: variants also found in parents

Case (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000709.3(BCKDHA): IVS6+1delG (can't search this format of an intronic mutations, how do I change it?)

ClinVar: not sure how to search for BCKDHA IVS6 + 1delG

CAID:

gnomAD:

Variant2: NM_000709.3(BCKDHA):c.740A>G (p.His247Arg)

ClinVar: not found

CAID: CA406012849

gnomAD: not in gnomAD

There are two variants listed for every patient except, one. The text said that all the mutations found were also found in the parents so does that mean they would be in trans?

(didn't see this template at first, so still need to apply it to the other entries)

CaseVI-4: Male, 3.5 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0002540, HP:0002970 (Hypophosphatemic rickets, Inability to walk, Genu varum)

HPOsFreeText: -3.76 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Variant is asserted de novo and confirmed by parental testing, Proband is hemizygous for this mutation

CasePreviousTesting: Calcium levels (9.8 mg/dL), Decreased serum phosphate levels (2.8 mg/dL; reference 3.8-6.5), Elevated serum ALP (925 IU/L; reference 90-325), 25OHD3 levels (35 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (62.2 ng/L), TPR levels (69.7), Decreased TmP/GFR levels (1.95; reference 2.9-6.1)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5:c.1217G>T (p.Cys406Phe)

CAID: CA412573391 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000444.5%3Ac.1217G%3ET

gnomAD: Not in gnomAD

Case# P7, 2yo report

CasePresentingHPOs HP:0005528, HP:0001873

CasePreviousTesting genes related to MDS/inherited bone marrow failure syndromes was performed in patients, negative for this patient

CaseMethod1 NGS

CaseMethod2 Sanger

CaseGenotypingMethod NGS then variant confirmed with Sanger

Variant NM_152703.4(SAMD9L):c.2640C>A (p.His880Gln)

ClinVar 242372

CaseAddInfo transient monosomy 7 with somatic mutation of new variant NM_152703.3:c.3951_3955del (p.Ser1317ArgfsTer21) - CA658820702

Case# P5, 7yo report

CasePresentingHPOs HP:0005528, HP:0001873

CasePreviousTesting genes related to MDS/inherited bone marrow failure syndromes was performed in patients, negative for this patient

CaseMethod1 NGS

CaseMethod2 Sanger

CaseGenotypingMethod NGS then variant confirmed with Sanger

Variant NM_152703.4(SAMD9L):c.2956C>T (p.Arg986Cys)

ClinVar 446530

VariantEvidence (Figure 5) 293FT cells transfected with p.Arg986Cys showed more limited cell proliferation than WT SAMD9L in 28202457

CaseAddInfo "The HLA-identical brother of P5 was thoroughly evaluated as a potential bone marrow donor. He was clinically healthy and had a normal complete blood count, but he did not qualify as a donor because of hypocellular bone marrow with mild dysplastic features. He was also a carrier of the p.R986C mutation."

Case1: Male, 3 months onset, Australia

CasePresentingHPOs: HP:0002878, HP:0002460, HP:0001270, HP:0003701, HP:0000467, HP:0001488, HP:0002938, HP:0003691, HP:0003391, HP:0003803, HP:0003755 (Respiratory failure, Distal muscle weakness, Motor delay, Proximal muscle weakness, Neck muscle weakness, Bilateral ptosis, Lumbar hyperlordosis, Scapular winging, Gowers sign, Type 1 muscle fiber predominance, Type 1 fibers relatively smaller than type 2 fibers)

HPOsFreeText: BiPAP from 3.5 yrs, Type 2B fibers absent

CaseNotHPOs: HP:0003798, HP:0030177, HP:0031237 (Nemaline bodies, Abnormal nerve conduction study, Internally nucleated skeletal muscle fibers)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is de novo with parental testing confirmed

CasePreviousTesting: Patients were diagnosed with CFTD via clinical notes and muscle biopsies at pathology centers throughout Australia and several international centers.

CaseGenotypingMethod: Two methods were used for genotyping. In 16 patients, the 10 exons spliced onto the muscle-specific isoform of TPM3 were bidirectionally sequenced from genomic DNA. For the other 7 patients, complementary DNA was generated from patient muscle and isoform-specific primers were used to sequence the transcript. Paternity was confirmed in isolated patients using microsatellite markers.

Variant: NM_152263.4(TPM3):c.733A>G (p.Arg245Gly)

ClinVar: 42117 https://www.ncbi.nlm.nih.gov/clinvar/variation/42117/

gnomAD: Not in gnomAD

Case2: Male, Birth onset, Australia

CasePresentingHPOs: HP:0008947, HP:0002460, HP:0001270, HP:0003701, HP:0000467, HP:0001488, HP:0002938, HP:0010628, HP:0003391, HP:0002942, HP:0003803, HP:0003755 (Infantile muscular hypotonia, Distal muscle weakness, Motor delay, Proximal muscle weakness, Neck muscle weakness, Bilateral ptosis, Lumbar hyperlordosis, Facial palsy, Gowers sign, Thoracic kyphosis, Type 1 muscle fiber predominance, Type 1 fibers relatively smaller than type 2 fibers)

HPOsFreeText: Type 2B fibers absent

CaseNotHPOs: HP:0003798, HP:0030177, HP:0030877, HP:0031237 (Nemaline bodies, Abnormal nerve conduction study, Obstructive deficit on pulmonary function testing, Internally nucleated skeletal muscle fibers)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is de novo with parental testing confirmation

CasePreviousTesting: Patients were diagnosed with CFTD via clinical notes and muscle biopsies at pathology centers throughout Australia and several international centers.

CaseGenotypingMethod: Two methods were used for genotyping. In 16 patients, the 10 exons spliced onto the muscle-specific isoform of TPM3 were bidirectionally sequenced from genomic DNA. For the other 7 patients, complementary DNA was generated from patient muscle and isoform-specific primers were used to sequence the transcript. Paternity was confirmed in isolated patients using microsatellite markers.

Variant: NM_152263.4(TPM3):c.505A>G (p.Lys169Glu)

ClinVar: 42115 https://www.ncbi.nlm.nih.gov/clinvar/variation/42115/

gnomAD: Not in gnomAD

Case9 Male, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001829, HP:0010066, HP:0000157, HP:0002101, HP:0002324, HP:0010664, HP:0030449

(Oral cleft, Micrognathia, Hand polydactyly, Duplicated hallux, Tongue abnormality, Defective lung lobation, Hydranencephaly, Fused thalami, Therapeutic abortion)

HPOsFreeText Crown-heel body length 22cm, body weight 245g, brain weight 6g, abnormal larynx/trachea, occipitoschisis/keyhole, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus, duplicated central canal in lumbar spinal cord, posterior columns seem disorganized. The ventral horn shows normal-appearing motor neurons with an SMI-311 neurofilament immunostain.

CaseNotHPOs HP:0001161

(Hand polydactyly)

NotHPOsFreeText Uterus duplex, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 19+5wk gestational age

CasePMIDs n/a

Case14 Female, Finland

CasePresentingHPOs HP:0000347, HP:0001829, HP:0010066, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260

(Micrognathia, Foot polydactyly, Duplicated hallux, Defective lung lobulation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly)

HPOsFreeText Crown-heel body length 35.5cm, body weight 1162g, brain weight 153g, abnormal larynx/trachea, uterus duplex, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia in the Sylvian fissures , neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus, large hypothalamic hamartoma that covers the brainstem (Fig4:) consisting of slightly nodular areas of small, round, probably partly immature, neuronal, and possibly some oligodendroglial cells, capillaries, astroglial cells, and occasional larger pyramidal neuronal cells on hematoxylin and eosin stain.

CaseNotHPOs HP:0000202, HP:0001627, HP:0000157, HP:0007165

(Oral cleft, Congenital heart defect, Tongue abnormality, Periventricular neuronal heterotopia)

NotHPOsFreeText hydranencephaly/anencephaly, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo death at 20 minutes old, 33+5wk gestational age

CasePMIDs n/a

Case8 Male, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001829, HP:0010066, HP:0001627, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0030449

(Oral cleft, Micrognathia, Foot polydactyly, Duplicated hallux, Congenital heart defect, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly, Therapeutic abortion)

HPOsFreeText Crown-heel body length 20cm, Body weight 323g, abnormal larynx/trachea, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0001161, HP:0000157, HP:0007165

(Hand polydactyly, Tongue abnormality, Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, hydranencephaly/anencephaly, leptomeningeal heterotopia, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 19+0wk gestational age

CasePMIDs n/a

Case3 Female, Finland

CasePresentingHPOs HP:0000347, HP:0010066, HP:0001829, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007165, HP:0030449

(Micrognathia, Duplicated hallux, Foot polydactyly, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Periventricular neuronal heterotopia, Therapeutic abortion)

HPOsFreeText crown-heel body length 17cm, body weight 103g, abnormal larynx/trachea, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, hydrocephalus/open-book, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000202, HP:0001627, HP:0000157, HP:0007260

(Oral cleft, Congenital heart defect, Tongue abnormality, Type II lissencephaly)

NotHPOsFreeText Uterus duplex, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 15+6wk gestational age

CasePMIDs n/a

Case18 Male, Finland

CasePresentingHPOs HP:0003826, HP:0000347, HP:0001627, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260

(Stillbirth, Micrognathia, Congenital heart defect, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly)

HPOsFreeText Crown-heel bodylength 45cm, body weight 2050g, brain weight 265g, abnormal larynx/trachea, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000202, HP:0001161, HP:0001829, HP:0007165

(Oral cleft, Hand polydactyly, Foot polydactyly, Periventricular heterotopia)

NotHPOsFreeText Uterus duplex, neuroepithelial rosettes, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo stillbirth, 36+6wk gestational age

CasePMIDs n/a

Case5 Male, Finland

CasePresentingHPOs HP:0000347, HP:0001161, HP:0001829, HP:0000157, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0030449

(Micrognathia, Hand polydactyly, Foot polydactyly, Tongue abnormality, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly, Therapeutic aboriton)

HPOsFreeText Crown-heel body length 22cm, body weight 315g, Toe polydactly with multiple extra toes, Abnormal larynx/trachea, Hydrocephalus/open-book, Occipitotemporal hypoplasia, Infratentorial hypoplasia, occipitotemporal hypoplasia, leptomeningeal heterotopia, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000202, HP:0001627, HP:0002444, HP:0007165

(Oral cleft, Congenital heart defect, Hypothalamic hamartoma, Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, hypothalamic hamartoma/bulging, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 18+1wk gestational age

CasePMIDs n/a

Case13 Female, 6day old death, Finland

CasePresentingHPOs HP:0000347, HP:0000157, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0007165

(Micrognathia, Tongue abnormality, Defective lung lobulation, Hydrocephalus, Olfactory lobe aplasia, Callosal aplasia, Fused thalami, Polymicrogyria, Type II lissencephaly, Periventricular neuronal heterotopia)

HPOsFreeText Crown-heel body length 42cm, Body weight 2326g, brain weight 206g, abnormality larynx/trachea, uterus duplex, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus, small unilateral remnant of the olfactory tract, (Fig2:)small proximal stumps of callosal fibers with a small longitudinal Probst bundle element, lateral periventricular nodular heterotopia, smooth cortical surface without normal gyration; missing midline commissures , large leptomeningeal heterotopia between the ba and brain tissue surface immunopositive for microtubule-associated protein 2 (MAP-2), hypoplastic temporal lobe displays a miniature dentate fascia, dysplastic hippocampus, heterotopic (Fig5:) glioneuronal wart-like eruption, irregular and disrupted bundles of radial glial structures, calretinin (CR)-positive and reelin positive neurons in dysplastic cortex, (Fig6:) minute dysplastic inferior olive only in some neuronal groups, totally narrowed pyramid medially below in the right lower corner of the medulla oblongata, all layers are narrowed in the atrophic cerebellar cortex of HLS, short and small frontal bundle of Probst

CaseNotHPOs HP:0000202, HP:0001829, HP:0001627

(Oral cleft, Foot polydactyly, Congenital heart defect)

NotHPOsFreeText true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo 33+5wk gestational age

CasePMIDs n/a

Case# Fam2:II-4, M, 7yo onset, Finnish

CasePresentingHPOs HP:0001310, HP:0001260, HP:0001251, HP:0000639, HP:0009072, HP:0008969, HP:0003487

CaseMethod1 WES

Variant NM_152703.4(SAMD9L):c.2672T>C (p.Ile891Thr)

ClinVar 446529

CaseAddInfo previously in 28202457

Case# UW-AP:III-3, 60yo reported

CasePresentingHPOs HP:0001251, HP:0001310, HP:0001260, HP:0000639, HP:0007256

Variant NM_152703.4(SAMD9L):c.2640C>A (p.His880Gln)

ClinVar 242372

CaseAddInfo only genotyping methods described are for extended Family 1 or in a previous study. Is this UW family also from another study?

Case# Subject 3, F, 5mo onset, Hispanic

CasePresentingHPOs HP:0002910, HP:0001942, HP:0003201, HP:0001664, HP:0002878, HP:0001663, HP:0001249, HP:0001250, HP:0008619, HP:0100295, HP:0001260, HP:0004756, HP:0001259, HP:0012734, HP:0002151, HP:0003236, HP:0002307, HP:0000252, HP:0004322, HP:0004325, HP:0002058, HP:0002136

HPOcont: Elevated Transaminases, Metabolic acidosis, Rhabdomyolysis, Torsade de pointes, Respiratory Failure, Ventricular fibrillation, Intellectual Disability, Seizures, Bilateral sensorineural hearing impairment, Muscle fiber atrophy, Dysarthria, Ventricular tachycardia, Coma, Ketotic hypoglycemia, Elevated Lactate, Elevated CPK, Drooling, Microcephaly, Short Stature, Low body weight, Myopathic facies, Broad-based gait

HPOFreeText: (5 months) coma, metabolic acidosis and rhabdomyolysis. (24 years) torsade de pointes, respiratory and multiorgan failure, ventricular fibrillation, epilepsy, bilateral sensorineural hearing loss, intellectual disability and atrophic muscle fibers. She was ambulatory, some speech, drooling, myopathic facies, and wide-based gait. "Height and weight below the 5th percentile for age (weight 42.9 kg, height 147 cm), head circumference below 5th percentile for age (51.4 cm)."

CaseNotHPOs HP:0002540, HP:0001987

NotHPOcont: Non-ambulatory, Hyperammonemia

CasePreviousTesting CPK elevated to 8,000 U/I on first episode, then 22,000 U/I during most severe episode.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES and cSNP results confirmed with Sanger

Variant (1) NM_152906.6:c.460G>A (p.Gly154Arg)

ClinVar (1) 208823

CAID (1) CA358646

gnomAD (1) 0.001549(Other), 0.0001208(Overall)

VariantEvidence (Figure 3) using "EBV-transformed B-lymphoblastoid cell lines (BLCLs) from another individual, subject 4 with homozygous c.460G>A (p.Gly154Arg) mutation, and evaluated the Golgi by intracellular staining with WGA, as well as cis Golgi marker, anti-GM130 antibody." WGA stain resolved lower area of golgi bodies in p.Gly154Arg cells than WT. Measured immunoglobulin heavy chain binding protein levels in WT and and patient fibroblasts, BiP levels in patient cells lower than WT after ER induced stress by Brefeldin A.

CaseAddInfo nonconsanguineous, parents confirmed heterozygotes

CasePMIDs n/a

Case: Family D/Prendiville Patient 4, male, 12yo, American, Causasian

CasePresentingHPOs: HP:0100651, HP:0000953, HP:0000998, HP:0005912, HP:0001993

CasePresentingHPOsFreeText: Hyperpigmentation onset at 10yo; located on proximal anterior thighs initially, but spread to chest, lower back, abdomen, thighs, and posterior lower legs. Decreased IgM.

CaseNOTHPOs: HP:0002716, HP:0001433, HP:0003493, HP:0001999, HP:0004322, HP:0001738

CaseNOTHPOSFreeText: inflammatory symptoms

CasePreviousTesting: ADAMTS14, C10orf27, CDH23, EIF4EBP2, LRRC2, KIAA1274, NODAL, NPFFR1, PCBD1, PPA1, PRF1, SLC29A3, SGPL1, UNC5B were sequenced since they were positional candidate genes

CaseGenotypingMethod: homozygosity mapping (50K SNP array), candidate gene sequencing

Variant: M116R homozygous

ClinVarID: or CAID: CA114353

gnomAD: This missense variant, p.M116R, is present in gnomAD v4.0.0 with a MAF=0.0001517 (179/1180030 alleles) in the European NF population and 0 homozygotes. Downscoring for homozygosity since parents are consanguineous.

AddCaseInfo: consanguineous parents

PreviouslyPublished: 17461801

VariantEvidence: Functional studies in Xenopus oocytes expressing M116R displayed a near-total loss of transport activity compared to WT SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated mistrafficking of the mutant protein to the ER or Gogli apparatus (Kang et al. 2010; PMID: 20595384).

Case: Family A/Prendiville Patient 1, male, 14yo at report, East Indian

CasePresentingHPOs: HP:0004322, HP:0000343, HP:0030084, HP:0001993, HP:5000011, HP:0003261, HP:0000953, HP:0000998, HP:0000520, HP:0001433, HP:0012094, HP:0430023, HP:0003565, HP:0001935, HP:0012343, HP:0040303, HP:0100651, HP:0004322, HP:0001999, HP:0100534, HP:0000670, HP:0000767, HP:0031664, HP:0002716, HP:0001763, HP:0001698

CasePresentingHPOsFreeText: hyperpigmentation onset at 15yo; located on chin, axillae, back, abdomen. inner thigh, inguinal folds, genitalia. Pancreatomegaly. Orbital thickening and EOM infiltrate on MR/CT. Opacification of the maxillary sinuses. Posterior pericardial thickening. Thickened right atrial wall.

CaseNOTHPOs: HP:0001738

CaseNOTHPOSFreeText: inflammatory symptoms

CasePreviousTesting: ADAMTS14, C10orf27, CDH23, EIF4EBP2, LRRC2, KIAA1274, NODAL, NPFFR1, PCBD1, PPA1, PRF1, SLC29A3, SGPL1, UNC5B were sequenced since they were positional candidate genes

CaseGenotypingMethod: homozygosity mapping (50K SNP array), candidate gene sequencing

Variant: E444X homozygous

ClinVarID: or CAID: CA114350

gnomAD: This nonsense variant p.E444X, located in exon 6/6, is present in gnomAD v4.0.0 with a MAF=0.0002525 (23/91078 alleles) in the South Asian population and 1 homozygote. Downscoring this variant since NMD is not expected to occur and there is 1 homozygote in gnomAD.

AddCaseInfo: consanguinity not reported

PreviouslyPublished: 17461801

VariantEvidence: Functional studies in Xenopus oocytes expressing E444X displayed a partial reduction in nucleoside transport activity and impaired protein stability.

Case# B1-4, Male, UK

CasePresentingHPOs HP:0001279

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link

Case# A2, Male, UK

CasePresentingHPOs HP:0002119

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link

Case# B4, Male, UK

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.424G>A (p.Glu142Lys)

ClinVar 46147

gnomAD 0.001121 link

Case# Subject 10, female, 14yo, non-Hispanic

CasePresentingHPOs HP:0010535, HP:0002098, HP:0031064, HP:0000729, HP:0000750, HP:0001249, (Sleep apnea, Difficulty breathing, Impaired continence, Autism spectrum disorder, Speech delay, Intellectual disability)

HPOFreeText: Phenotypes described postnatally.

CaseNotHPOs HP:0001250, HP:0001252, HP:0000708, HP:0001285, HP:0007018, HP:0011968, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0410030, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002020, HP:0002247, HP:0001734, HP:0002021, HP:0000076, HP:0000107, HP:0001159, HP:0001385, HP:0002650, HP:0002938, HP:0001511, HP:0011328, HP:0002007, HP:0000325, HP:0000534, HP:0000601, HP:0000316, HP:0000582, HP:0000494, HP:0045025, HP:0000286, HP:0000490, HP:0000598, HP:0004467, HP:0000414, HP:0000463, HP:0000319, HP:0012471, HP:0000160, HP:0000221, HP:0000164, HP:0000187, HP:0000218, HP:0000347, HP:0002557, HP:0003186, HP:0200055, HP:0004209, HP:0011297, HP:0001792, HP:0010490, HP:0000349, HP:0004532, HP:0000957 (Seizures, Hypotonia, Behavioral problems, Spastic quadriparesis, ADHD, Poor feeding, Coloboma, Optic atrophy, Microphthalmia, Peter's anomaly, Iris anomalies, Blepharophimosis, Sensorineural hearing loss, Choanal atresia, Cleft lip, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Gastroesophageal reflux, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidney, Syndactyly, Hip dysplasia, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Fontanel abnormality, Frontal bossing, Triangular face, Abnormal eyebrows, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Down-slanting palpebral fissures, Small palpebral fissures, Epicanthal folds, Deeply set eyes, Abnormal ears, Preauricular pits, Bulbous nose, Anteverted nares, Flat philtrum, Full lips, Small mouth, Furrowed tongue, Abnormal teeth, Broad alveolar ridges, High-arched palate, Micrognathia, Small nipples, Inverted nipples, Small hands, 5th finger clinodactyly, Digital Anomalies, Nail hypoplasia, Abnormal palmar creases, Widow's peak, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting Screen for variants involved with Autism, de novo RERE variant was only result

CaseMethod1 Exome sequencing

CaseMethod2 sanger

CaseGenotypingMethod exome sequencing confirmed with sanger in patient and parents by Krumm et al.

Variant NM_012102.3:c.2278C>T(p.Gln760Ter), de novo

ClinVar n/a

CAID CA338172916

gnomAD n/a

VariantEvidence n/a

CaseAddInfo both parents tested

CasePMIDs 25961944

Case# FamilyC:IV-13, 33 AoO, Female, USA

CasePresentingHPOs HP:0002064, HP:0001258, HP:0002355

CaseMethod1 WES

CaseMethod2 Sanger

Variant NM_005186.3(CAPN1):c.407delC (p.Pro136Argfs), NM_001198868.1(CAPN1):c.1605+5G>A

ClinVar 225767, 225768

gnomAD none, 0.0003171

CaseAddInfo nonconsanguineous family

Family#PresentingHPOs HP:0001258, HP:0002460, HP:0007067, HP:0002395

CountryOrigin Morocco

Race White

Family#Method1 WES

Family#Method2 Sanger

Affected 4

Unaffected 3

Segregations 4

eLOD 1.93

AddSegregationInfo consanguineous

ProbandLabel FamilyB:IV-1 age of onset 35, Male

Variant NM_001198868.1(CAPN1):c.1579C>T (p.Gln527Ter)

ClinVar 225766

FamilyAddInfo Fig 1

Case#: Speigel Patient I-1, onset at birth, death at 10mo

DiseaseAssertion: Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy

FamilyInfo: Parents are healthy first-degree cousins with no visual or neurological complaints. Both parents were heterozygous for this OPA1 variant. Their optic discs did not look pale on dilated fundus examination and optical coherence tomography (OCT) imaging did not show any subclinical thinning of the retinal nerve fibre layer. The parents have two clinically unaffected sons who were 14 and 11 years old when last reviewed in clinic. The older son is heterozygous for the c.1601T>G OPA1 variant, whereas the other son only carries the wild-type OPA1 allele.

CasePresentingHPOs: HP:0001622, HP:0001531, HP:0008936, HP:0001276, HP:0002179, HP:0001612, HP:0000617, HP:0031964, HP:0012758, HP:0001639, HP:0002104

CaseHPOFreeText: elevated lactate levels, but a normal cerebrospinal fluid (CSF) lactate concentration. progressive, non-obstructive, generalised hypertrophic cardiomyopathy,

CaseNotHPOs: HP:0001635

CaseNotHPOFreeText: abnormal brain MRI

GenotypingMethod: genome-wide autozygosity mapping and next-generation exome sequencing

PreviouslyPublished: n/a

Variant: OPA1 NM_015560.2 c.1601T>G p.Leu534Arg

ClinVar:

CAID: CA357235

SupplementalData: n/a

Case#: Wilson_Australian kindred_Person II:2

Demographics: Male, 44y at diagnosis, Australia

CasePresentingHPOs: HP:0000750, HP:0001249, HP:0007351, HP:0002362, HP:0002067, HP:0100660, HP:0002396, HP:0000256

Age at onset <2y, while age at tremor onset was 38y. Birth and early milestones were normal. Early learning difficulties were reported and the proband was able to read and write. Parkinsonism classification was akinetic-rigid. Proband showed L-Dopa response, hypokinetic dysarthria, and normal cerebellar function. Other normal features included normal eye examination, MRI, Fragile X testing, karyotype, Copper testing, blood count and chemistry, urine metabolic testing and hearing.

CaseNotHPOs:

CasePreviousTesting: Linkage analysis using homozygous recessive model identified no linkage to autosomes, but to two regions: Xp22.2 and Xq27.3–qter

CaseMethod1: Copy number variation analysis

CaseMethod2: PCR

CaseGenotypingMethod: A ~45-kb deletion within the Xq haplotype was identified that encompassed the complete RAB39B gene and the last 3 coding exons of CLIC2.

Variant: NC_000023.11:g.(155246216_?)_(?_155288781)del

ClinVar: 157665

CAID:

gnomAD:

VariantEvidence: The proband was hemizygous for the ~45-kb deletion encompassing the complete RAB39B and partial CLIC2 genes. Expression of both transcripts was absent from fibroblast cells of affected individuals. The proband is not scored any points as the variant involves deletion of part of an additional gene, CLIC2. Although the authors ruled out seizures and cardiac anomalies (phenotypes associated with CLIC2 missense variant) in patients from the family, it is not conclusive that CLIC2 deletion does not have any impact on the proband's phenotype.

CaseAddInfo: The proband's siblings were also similarly affected. Elder brother of the proband died at 48y from positional asphyxia, and postmortem neuropathological studies on proband's brain showed pallor of the substantia nigra and locus coeruleus. H&E staining of substantia nigra revealed PD features, including loss of pigmented neurons and Lewy bodies in surviving neurons. Abundance of cortical Lewy bodies, were noted. Tau-immunoreactive NFTs were also observed in a small proportion of the surviving pigmented SN neurons

CasePMIDs:

Individual

Case#: NGI

Caseprevioustesting: SSCP Scan

Casemethod1: PCR, Sanger

Variant: NM_000268.3:c.1219C>T (nonsense)

CAID: CA021304

Caseaddinfo:

gnomad: no data

CasePt3 male, 4yo death, Italian

CasePresentingHPOs HP:0001987 (Hyperammonemia)

HPOsFreeText Severe hyperammonemia at 48h of life

CaseNotHPOs n/a

CasePreviousTesting Metabolic testing: ammonia(348[normal< 75 μg/dl])

CaseMethod1 PCR

CaseMethod2 n/a

CaseGenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Variant 1. NM_001875.4:c.1022T>C(p.Leu341Ser), 2. NM_001875.4:c.3784C>T(p.Arg1262Ter ) compound heterozygous

ClinVar n/a

CAID 1. CA350430554, 2. CA350438463

gnomAD 1. n/a, 2. 0.00004485(European (Finnish)), 0.000004062(Total)

VariantEvidence n/a

CaseAddInfo similarly affected brother died without diagnosis

CasePMIDs n/a

Case# Fam2Pat1, F, Turkish, 15yo onset

CasePresentingHPOs HP:0002061, HP:0002066, HP:0002070, HP:0001260, HP:0001310, HP:0000563, HP:0006986

CasePreviousTesting Neurologic examination revealed severe spasticity in the lower and mild spasticity in the upper extremities, hyperactive deep tendon reflexes, bilateral extensor plantar responses, and patellar clonus. The Hoffmann sign was positive. She had bilateral mild dysmetria and dysdiadochokinesia. Nerve conduction studies, EMG, sensory evoked potential tests, and MRI did not reveal any pathology

CaseMethod1 Whole Exome

Variant NM_001198869.1:c.1176G>A

CAID CA6093326

VariantEvidence premature stop codon

gnomAD 1.554e-05(European (Non-Finnish)), 8.513e-06(Overall)-Exac

FamilyName: Family 2

FamilyPresentingHPOs: HP:0000685

FamilyNotHPOs:

CountryOrigin: Pakistan

Ethnicity: Pakistani

Race: Asian

FamilyPreviousTesting: n/a

FamilyMethod1: WES

FamilyMethod2:

FamilyGenotypingMethod: Whole exome sequencing identified 26 regions of homozygosity for Family 1, specifically from WES of the proband IV:3 (Supplemental Table 4).

Affected: 1

Unaffected: 2

Segregations: 0

Consanguineous: yes

PublishedLOD: n/a The minimum requirement for segregation inclusion is not met according to the ClinGen SOP version 6.

eLOD: n/a

AddSegregationInfo: Three other siblings were not tested for the variant, and appeared to not have the phenotype, including a set of twins (whether dizygotic or monozygotic was not noted).

ProbandLabel: Family 2-IV:2, female

Variant: NM_033068.2(ACP4):c.428C>T (p.Thr143Met)

Assumed Homozygous, only the mother was tested for the ACPT mutation, not the father.

ClinVar: 375700

gnomAD: MAF= 0.0001592 (Other 1/6282) AFt=5.210E-4, no homozygotes.

FamilyAddInfo: WES identified 26 regions of homozygosity for Family 1 (Supplemental Table 4).

Variant deposited into the Leeds AI repository in LOVD, variant #0000000187.

FamilyPMIDs:

CasePresentingHPOs:

CaseNOTHPOS:

CasePreviousTesting: n/a

CaseGenotypingMethod: WES identified 26 regions of homozygosity in which 2 genes, other than ACPT were flagged. These 2 genes/ variants are C18orf25:c.517G>C(p.G172C) (not in gnoMAD) and BTBD7:c.1083G>T(p.K361N) (in gnoMAD, 176 hets and 1 homozyoug AF= 0.007). These variants segregated with disease along with the ACPT variation.

From supplemental tables S2 and S3 (authors used hg19 alignment).

MONDO: MONDO:0005144 for FALS

Case#3: Smith 2014 FALS R215C, F, 78 y.o. onset, Italy

CasePresentingHPOs: HP:0002145, HP:0007354

CaseHPOFreeText: spinal-onset ALS with upper and lower motor neuron signs

CasePreviousTesting: All FALS were screened for known causative mutations/repeat expansions in SOD1, C9orf72, TARDBP, FUS, PFN1, UBQLN2, OPTN, VCP and ANG and removed from cohort if positive for variant.

CaseMethod1: This case identified through case-control study

CaseGenotypingMethod: Exome sequencing, confirmed with Sanger sequencing.

Variant: NM_006000.3(TUBA4A):c.643C>T (p.Arg215Cys)

ClinVar: 180185

gnomAD: 2-220115778-G-A; total overall AF (non-neuro) = 0.000009609; TUBA4A_pArg215Cys_gnomAD

CaseAddInfo: This variant found in 0/13023 control samples.

From supplemental tables S2 and S3 (authors used hg19 alignment).

MONDO: MONDO:0005144 for FALS

Case#8: Smith 2014 FALS W407X, F, 66 y.o. onset, Italy

CasePresentingHPOs: HP:0007354

CaseHPOFreeText: spinal-onset ALS with upper and lower motor neuron signs

CasePreviousTesting: All FALS were screened for known causative mutations/repeat expansions in SOD1, C9orf72, TARDBP, FUS, PFN1, UBQLN2, OPTN, VCP and ANG and removed from cohort if positive for variant.

CaseMethod1: This case identified through case-control study

CaseGenotypingMethod: Exome sequencing, confirmed with Sanger sequencing.

Variant: NM_006000.3(TUBA4A):c.1220G>A (p.Trp407Ter)

ClinVar: 180184

CaseAddInfo: This variant found in 0/13023 control samples.

Case: Family I Proband III-6, female, 20yo at report

CasePresentingHPOs: HP:0000953, HP:0000998, HP:0030053, HP:0001822, HP:0000365, HP:0001698, HP:0012385, HP:0034373, HP:0002619, HP:0000520, HP:0007380

CasePresentingHPOsFreeText: Dilated lateral scleral vasculature

CaseNOTHPOs: HP:0000823, HP:0001433, HP:0001256

CaseNOTHPOSFreeText:

CasePreviousTesting: Direct sequencing of AIFM2, ADAMTS14, EIF4EBP2, C10ORF54, PPA1, H2AFY2, LRRC20, NODAL, PRF1, TYSND1, SAR1A, PSAP, NPFFR1, and C10ORF27

CaseGenotypingMethod: Microarray, homozygosity mapping, haplotype analysis, direct sequencing of exons of SLC29A3

Variant: G427S homozygous

ClinVarID: or CAID: 563/CA114349

gnomAD: The missense variant G427S is present in gnomAD v4.0.0 with a MAF=0.00005339 (4/74926 alleles) in the African/African American population and 0 homozygotes.

AddCaseInfo: Consanguineous parents, not genotyped. 3 additional affected family members

PreviouslyPublished: n/a

VariantEvidence: Functional studies in Xenopus oocytes demonstrated that G427S results in a total loss of transport activity (Kang et al. 2010; PMID: 20595384).

Case: Family E Proband EII-1, male, Arabic, Israeli, 17yo at report

CasePresentingHPOs: HP:0000953, HP:0030053, HP:0000998, HP:0000054, HP:0000771, HP:0002619, HP:0001433, HP:0000520, HP:0012385, HP:0003565

CasePresentingHPOsFreeText: scrotal masses, dilated scleral vessels, maturation arrest in all tubules with few spermatids in 4% to 5% of the tubules on testicular biopsy

CaseNOTHPOs: HP:0008064, HP:0011025, HP:0000365, HP:0007380

CaseNOTHPOSFreeText:

CasePreviousTesting: direct sequencing of AIFM2, ADAMTS14, EIF4EBP2, C10ORF54, PPA1, H2AFY2, LRRC20, NODAL, PRF1, TYSND1, SAR1A, PSAP, NPFFR1, and C10ORF27

CaseGenotypingMethod: microarray, haplotype analysis, direct sequencing of exons of SLC29A3, restriction digestion

Variant: G437R homozygous

ClinVarID: or CAID: 565/CA114352

gnomAD: The missense variant G437R is present in gnomAD v4.0.0 with a MAF=0.00006666 (4/60002 alleles) in the Admixed American population and 0 homozygotes.

AddCaseInfo: consanguineous, heterozygous, unaffected parents.

PreviouslyPublished: PMID: 18410979

VariantEvidence: Kang et al. (2010; PMID: 20595384) performed functional characterization of the G437R mutation in Xenopus oocytes and observed transport activity that was approximately half that of wildtype SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated accelerated turnover of the G437R mutant compared to wildtype, suggesting decreased stability.

Case#: Li 2018 sALS I42T, Chinese

MonDO:* MONDO:0005145 for sALS

CasePresentingHPOs: HP:0007354

CaseGenotypingMethod: Sanger sequencing. TUBA4A sequencing was performed using Sanger. No further details provided.

Variant: NM_006000.3(TUBA4A):c.125T>C (p.Ile42Thr)

CAID: CA2122537

gnomAD: 2-220116831-A-G; total overall AF (non-neuro) = 0.0001787 --> exceeds VCEP limit of 0.00005 therefore score at 0; TUBA4A_pI42T_gnomAD

Case: TTD241HE

CaseDemographics: Female, diagnosis at 18 months, Moroccan origin

CasePresentingHPOs: HP:0002299, HP:0045055, HP:0001999, HP:0001263, HP:0002342, HP:0000252, HP:0200136, HP:0001508, HP:0008064, HP:0008897, HP:0001276, HP:0004840, HP:0001257, HP:0002497,

cheerful character, mild ichthyosis, length −4.7 SD, weight −2.6 SD, occipitofrontal circumference (OFC) −3.1 SD, recurrent infections, mild cognitive retardation without significant speech at 6 years of age.

CaseNOTHPOs: No progressive deterioration at age 6

CasePreviousTesting: None

CaseGenotypingMethod: Sanger sequencing of the TFIIE subunits

Variant: NM_002095.5(GTF2E2):c.559G>T (p.Asp187Tyr)

ClinVar ID: 225841

Pathogenic, non-LOF variant gnomAD: Not found in gnomAD

AddCaseInfo: The parents of this individual were consanguineous and of Moroccan origin and were found to be heterozygous carriers of the variant. The individual's younger sister (TTD275HE) was also affected and homozygous for this variant. She also presented with brittle hair, dysmorphic features, mild developmental delay, microcephaly, mild difficulty swallowing, no failure to thrive, cheerful character, mild ichthyosis, additional left thumb, no recurrent infections and growth retardation

VariantEvidence: This variant has been identified in two other individuals (other than this proband and her sibling) of Moroccan origin, giving rise to the question of a founder mutation. This proband is not being scored since the variant has already been awarded default points previously.

Case#: 10455, Female, Caucasian, 48 years (onset), 58 years (report)

CaseHPOs: HP:0000643, HP:0012048, HP:0000473 (Blepharospasm, oromandibular dystonia, cervical dystonia/torticollis)

CaseHPOFreeText: Segmental dystonia (BSP, oromandibular, lower face, cervical)

CaseNotHPOs:

CasePreviousTesting: Prior to WES, pathogenic variants in THAP1, GNAL, and Exon 5 of TOR1A were excluded by high resolution melt analysis.

CaseMethod1: WES

CaseMethod2: Confirmation by Sanger sequencing

Variant: NM_020821.2:c.9605C>G (p.Ala3202Gly)

ClinVar: NA

CAID: CA7594605

gnomAD 0.000009584 (European non-Finnish); no homozygotes

VariantEvidence: None

Case#: III-1

CasePresentingHPOs: HP:0001639 (hypertrophic cardiomyopathy); HP:0001645 (sudden cardiac death)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: None for the proband

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: DNA extracted from paraffin-embedded spleen tissue, taken at autopsy, was subjected to PCR-amplification of TPM1 exon 5 followed by cycle sequencing to confirm presence of the familial TPM1 variant.

Variant: NM_001018005.2(TPM1):c.554T>G (p.Leu185Arg)

ClinVar: 31881

CAID: CA019057

gnomAD: 15-63060930-T-G has no data in gnomAD v4.0.0

VariantEvidence: Chang, et al. 2005 (PMID:16043485) demonstrated in ATPase activity assays that myofibrils reconstituted with L185R mutant tropomyosin had an increased sensitivity to calcium compared to wild-type tropomyosin-reconstituted myofibrils.

CaseAddInfo: No other genes were screened for mutations in this proband.

CasePMIDs:

Case# SAL-584-005, Female, 67yo, Italian

CasePresentingHPOs HP:0001258, HP:0002070, HP:0001260, HP:0002066

CaseMethod1 Exome

CaseMethod2 Sanger

Variant NM_005186.3:c.188dup

CAID CA6092966

gnomAD 0.000009815

VariantEvidence null

CaseAddInfo in supplement, possibly consanguineous family

Case# Family R III:1, Female, 43yo, Bangladesh

CasePresentingHPOs HP:0002066, HP:0001257, HP:0002015, HP:0001260, HP:0001272

CaseMethod1 DNA SNP array

CaseMethod2 Exome sequencing

Variant NM_005186.3:c.337+1G>A

CAID CA381241741

VariantEvidence predicted null

CaseV-1: Male, 27 yrs onset, China, Asian

CasePresentingHPOs: HP:0002875, HP:0001639, HP:0002027, HP:0001712, HP:0001671, HP:0032092, HP:0001645 (Exertional dyspnea, Hypertrophic cardiomyopathy, Abdominal pain, Left ventricular hypertrophy, Abnormal cardiac septum morphology, Left ventricular outflow tract obstruction, Sudden cardiac death)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Family is consanguineous, The MYPBC3 variant was the only one to segregate with the disease, with the CACNB2 variant also being present in individuals with "severe" forms of the disease. CACNB2+ MYH7- individuals showed no symptoms of cardiomyopathy, supporting a modifying effect leading to the clinical heterogeneity of this family, MYBPC3 variant leads to a premature termination and a loss of 49 amino acids which is predicted to undergo NMD but is also associated with incomplete penetrance

CasePreviousTesting: Marked hypertrophic septum (27  mm) and a left-ventricular outflow obstruction (LVOTO) of 32  mmHg, Clinical features in Table 1, No members showed Brugada syndrome phenotypes, Proband also has polymorphisms in TGFB1 and AKAP9 but no other affected family member contains them suggesting a benign pathogenicity

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. PCR amplification was performed and sanger sequencing was performed for MYH7 and MYPBC3 mutations. After positive confirmation of the MYBPC3 mutation, RAAS genes were genotyped for a possible modifying effect. Negative findings led to a targeted NGS for the index patient using all known 104 causing/closely related genes of cardiomyopathy and chanelopathy. These variants were then filtered and analyzed for pathogenicity and confirmed in family members via Sanger sequencing.

Variant: NM_201597.3:c.1598C>T (p.Ser533Leu)

ClinVar: 190730 https://www.ncbi.nlm.nih.gov/clinvar/variation/190730/

gnomAD: 0.01004, https://gnomad.broadinstitute.org/variant/10-18828340-C-T

MultipleGeneVariants

MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.3624del (p.Lys1209fs)

ClinVar: 42727 https://www.ncbi.nlm.nih.gov/clinvar/variation/42727/

gnomAD: 0.00005140, https://gnomad.broadinstitute.org/variant/11-47354119-TG-T

DSP Variant

Variant: NM_004415.4(DSP):c.3923G>A (p.Arg1308Gln)

ClinVar: 178028 https://www.ncbi.nlm.nih.gov/clinvar/variation/178028/

gnomAD: 0.01680, https://gnomad.broadinstitute.org/variant/6-7580346-G-A

variant in trans with c.5882G>A (p.Gly1961Glu)

Patient: ID1021

Variant: c.550G > A (p.Gly184Arg)

CAID: CA219267

Functional effect: Monoallelic expression (wt only). Observed in blood.

Patient: ID408

Variant: c.686-12A > G

CAID: CA2580612032

Functional effect: Normal exon inclusion *, use of de novo splice site: c.686-11. Observed in blood.

Case# Christensen B

CasePresentingHPOs HP:0011675 Arrhythmia, HP:0010872 T-Wave Inversion, HP:0005133 Right Ventricular Dilation, HP:0031317 Fatty replacement of ventricular myocardial tissue

CasePreviousTesting amplicons were pre‐screened on a LightScanner High‐Resolution Melting Curve Analysis System

CaseMethod1 PCR

CaseGenotypingMethod (PCR) amplification was performed for all TMEM43 exons and flanking introns.

Variant NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu)

ClinVar 734

VariantEvidence Is there any??????

Case# Christensen A, 59 diagnosis, male

CasePresentingHPOs HP:0004756 Ventricular Tachycardia, HP:0010872 T-Wave Inversion, HP:0005133 Right Ventricular Dilation, HP:0031317 Fatty replacement of ventricular myocardial tissue

CasePreviousTesting amplicons were pre‐screened on a LightScanner High‐Resolution Melting Curve Analysis System

CaseMethod1 PCR

CaseGenotypingMethod (PCR) amplification was performed for all TMEM43 exons and flanking introns.

Variant NM_024334.2(TMEM43):c.705+7G>A

ClinVar 46152

gnomAD 0.0007554 link

VariantEvidence N/A

MonDO: MONDO:0032706

Case: Chinese male. Onset at age 30 years with mild dysarthria with progressive worsening.

DiseaseAssertion: Cerebellar ataxia

FamilyInfo: No history of neurological disease and consanguinity was documented in the family. Delivery and perinatal events were unremarkable.

CasePresentingHPOs: HP:0001260, HP:0002141, HP:0002061, HP:0009046 (Dysarthria, Gait imbalance, Lower limb spasticity, Difficulty running

CaseHPOFreeText: Difficulty writing, Increase in bilateral knee reflexes

CaseNOTHPOs: HP:0003487 (Babinski sign)

CasePreviousTesting: His clinical examination displayed cerebellar ataxia with abnormal finger-to-nose and heel-knee-shin tests. Bilateral knee reflexes were symmetrical increased (+++) and Babinski signs were negative. Cranial nerves, muscle strength and sensory examinations were normal. Mild cognitive decline with a Mini-Mental State Examination (MMSE) of 24/30, a Scale for the Assessment and Rating of Ataxia (SARA) score of 17.5/40 and International Cooperative Ataxia Rating Scale (ICARS) score of 46/100. Brain MRI revealed cerebellar atrophy (Fig. 1A).

GenotypingMethod: WES with Sanger confirmation and co-segregation analysis. Genetic testing for spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7, 12, 17 and dentatorubral-pallidoluysian atrophy (DRPLA) were negative.

VariantEvidence: Wildtype and mutant plasmids were transfected into SH-SY5Y cells. The mRNA level of frameshift variant p.Thr442fs7 was almost same with the level of wild-type, whereas nonsense variant p.Arg253 was even increased, thus they might escape NMD. As a result, p.Gln316 and p.Ser436fs36 mutant GDAP2 proteins were barely detectable, p.Thr442fs7, p.His400fs15 and p.Arg253 generated truncated proteins. Western blot analysis indicated that the GDAP2-Arg253 and GDAP2-Thr442fs*7 were C-terminal deletion mutants.

MultipleGeneVariants:

(1) GeneName: GDAP2

(1) Variant: c.757C>T (p.Arg253*)

(1) ClinVarID or CAID: CA1031554

(1) gnomAD: Total AF 0.00001860, gnomAD v4.1 (https://gnomad.broadinstitute.org/variant/1-117899096-G-A?dataset=gnomad_r4)

(2) GeneName: GDAP2

(2) Variant: c.1323delC (p.Thr442fs*7)

(2) ClinVarID or CAID: CA2586967196

(2) gnomAD: not found in gnomAD v4.1

Case# II-1, Female, Caucasian

CasePresentingHPOs HP:0001643

CaseMethod1 WES

CaseMethod2 PCR

Variant NM_001136239.3(PRDM6):c.1385A>G (p.Gln462Arg)

ClinVar 243051

gnomAD 0.00001728 (European (Non-Finnish))

VariantEvidence no variant evidence, computational

Case# Baskin AT, Male

CasePresentingHPOs HP:0004756, HP:0002119, HP:0010872

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.169G>A (p.Ala57Thr)

ClinVar 88981

gnomAD 0.001381 link

Case#: Zahari_HA24

Demographics:

CasePresentingHPOs: HP:0003125 severe hemophiliac FVIII:C:<1%

CaseNotHPOs:

CasePreviousTesting: No

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: F8 coding regions (26 exons) including the intron/exon boundaries and the promoter regions were amplified using 26 sets of primers and subsequently sequenced.

Variant: NM_000132.3:c.3625C>T(p.Gln1209Ter)

ClinVar:

CAID: CA414895516

gnomAD: Not Found

VariantEvidence: The variant introduces a stop codon in exon 14 and premature truncation of the protein product. The variant is awarded default points

CaseAddInfo:

CasePMIDs:

unable to annotate in PDF.

Case: Farooq Family 1 Proband, Syrian, female, 11yo at report, onset at 5yo

CasePresentingHPOs: HP:0004322, HP:0001730, HP:0030044, HP:0000953, HP:0000998, HP:0000969, HP:0100651, HP:0030084, HP:0002240, HP:0001395,

CasePresentingHPOsFreeText: Hyperpigmentation on lower extremities symmetrically and bilaterally, later the genital area as well with edema.

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting:

CaseGenotypingMethod: All 6 exons including exon-intron boundaries of the SLC29A3 gene were amplified by PCR from the genomic DNA. Direct sequencing analysis. Restriction enzyme digest.

Variant: c.1+2T>G homozygous

ClinVarID: or CAID: 213676/CA377128556

gnomAD: This splice site variant, c.1+2T>G found in intron 1, is absent from gnomAD v2.1.1. It is present in gnomAD v4.0.0 with a MAF of 0.00001024 (3/292950 alleles) in the European NF population and 0 homozygotes, but there is low coverage so the AF is not reliable.

AddCaseInfo: consanguineous, heterozygous parents

PreviouslyPublished: n/a

VariantEvidence: n/a

unable to annotate in PDF.

Case: Farooq Family 2 Proband, Syrian, female, 16yo at report, onset at 1wk old

CasePresentingHPOs: HP:0030148, HP:0001629, HP:0033190, HP:0004322, HP:0012785, HP:0001730, HP:0002240, HP:0001395

CasePresentingHPOsFreeText: Hyperpigmentation on thighs and later genital area. Hearing started deteriorating progressively after an ear infection. Fasting blood glucose was elevated (350 mg/dl).

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting:

CaseGenotypingMethod: All 6 exons including exon-intron boundaries of the SLC29A3 gene were amplified by PCR from the genomic DNA. Direct sequencing analysis. Restriction enzyme digest.

Variant: p.R386Q homozygous

ClinVarID: or CAID: 39870/CA130660

gnomAD: The missense variant p.Arg386Gln is present in gnomAD v4.0.0 with a MAF=0.00003999 (3/75018 alleles) in the African/African American population and 0 homozygotes.

AddCaseInfo: Consanguineous, heterozygous parents. Proband's younger sister was also reported by the parents to be affected, but was not examined by the authors or genotyped.

PreviouslyPublished: n/a

VariantEvidence: n/a

Case: Individual 11, male, AOR= 14 years

CasePresentingHPOs: HP:0001263, HP:0000750, HP:0001256, HP:0000752, HP:0001575, HP:0000276, HP:0000286, HP:0000278, HP:0000347, HP:0001182, HP:0001763, HP:0001852, HP:0011330, HP:0001382, HP:0002719, HP:0000540, HP:0000486, HP:0002967, HP:0001065, HP:0001724, HP:0010499, HP:0000243

CasePresentingHPOText: Began walking at 24 months old.

CaseNOTHPOs: HP:0001250, HP:0002376, HP:0012443,

CasePreviousTesting: Array-CGH (244K Agilent) normal, Fragile X syndrome (FMR1 Repeat analysis) normal, Loeys-Dietz syndrome (TGFBR1 and TGFBR2) normal and Marfan syndrome (FBN1) normal

CaseGenotypingMethod: WES (Agilent CRE and HiSeq 4000), searching for variants in FBXO11 after identification of variant in I13, Sanger confirmation to show de novo status and absence in parents. Sample identity confirmed.

Variant: hg19:chr2: g.4806002 0C>G, c.1042- 1G>C, p.(?) OR NM_001190274.1:c.1042- 1G>C(p.=)

CA ID: CA346765998

de novo splice site mutation.

gnomAD: n/a

AddCaseInfo:

VariantEvidence: The c.1042-1G>C mutation is most likely a splice site mutation. The mutation arises in exon 9 (Intron 8), and likely would disrupt exon 9 transcription. Exon 9 does not transcirbe any of the funcitonal domains, but exon 10 comprises the NosD domain, which is 5' to the first CASH domain. No functional assays or variant evidence was provided, so I have downgraded the score.

Case: Individual 2, female, AOR= 8yo

CasePresentingHPOs: HP:0001263, HP:0000750, HP:0002342, HP:0007359, HP:0002500, HP:0001290, HP:0002360, HP:0000729, HP:0000739, HP:0025269, HP:0000490, HP:0001840, HP:0000486

CasePResentingHPOText: Began walking at 22 months, first words at 2yo,. Seizure onset at 7 yo and are focal, and occur nightly. Reduced white matter bulk on MRI. Referred to as having intoeing or pigeon-toed. Low APGAR scores, brief resuscitation required

CaseNOTHPOs: HP:0002376, HP:0000202, HP:0000924, HP:0002719,

CasePreviousTesting: ArrayCGH, Fragile X (FMR1), Angelman Syndrome (methylation & UBE3A), Rett syndrome (MECP2), Pitt-Hopkins Syndrome (TCF4), and extensive metabolic screening were all normal

CaseGenotypingMethod: Trio-WES performed through the DDD consortium, 2017 PMID:PMID: 28135719.

Variant: hg19:chr2: g.48066586T>A, c.414A>T, p.(Arg138Ser) or NM_001190274.1:c.414A>T

CA ID: CA346813374

de novo Trio-WES performed by DDD so maternity and paternity could be investigated with this method.

gnomAD: n/a

AddCaseInfo: Case was part of the DDD study 2017 PMID: 28135719,

VariantEvidence: Arg138 is located N-terminal to the F-box region of FBXO11, and is conserved across species. Pathogenicity algorithms showing varying predictions, from tolerated to damaging, thus indicating a VUS. No functional assays were performed to indicate the impact of the R138S mutation on FBXO11 function.

Variant is in trans with a complex allele

Proband KH8 was 20yo at report, has the Hurler phenotype, and has this variant in compound heterozygosity with 704ins5 (CTGCT)

Proband KH9 was 11yo at report, has the Hurler phenotype, and has this variant in compound heterozygosity with 704ins5 (CTGCT)

Proband KH4 was 6yo at report, has the Hurler phenotype, and has this variant in compound heterozygosity with 704ins5 (CTGCT)

Case#: Yamagishi Case 1, female, 3yo1mo, Japanese

DiseaseAssertion: MPS1-Hurler

FamilyInfo: consanguinity

CasePresentingHPOs: HP:0001510, HP:0002240

CaseHPOFreeText: mental delay, height -1.5SD

CaseNotHPOs:

CaseNotHPOFreeText: cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5 homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: n/a

Case#: Family IV-II:1, 58 years old, male

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseHPOsFreeText: Type 2 diabetes and severe non-alcoholic steatohepatitis (NASH) with pre-cirrhotic lesions and well differentiated hepatocellular carcinoma (HCC) diagnosed on liver biopsy

CasePreviousTesting: TC 120 mg/dl, LDL-C 50 mg/dl, HDL-C 55 mg/dl, TG 89 mg/dl (see additional values in Table 1) ApoB100 19 mg/dl (normal range 49-88) (Supplemental data)

Variant: NM_000384.2:c.11153C>G (p.Ser3718Ter), heterozygous

CAID: CA345983128

gnomAD: Absent

Variant evidence: APOB- p.Ser3718* mutations lead to the formation of expected truncated ApoB forms (ApoB-81) of 418 kDa (Fig. 1C, right panel) that can be secreted by the liver and lipidated.

CaseAddInfo: Son of Family IV-I:1

Case#: Family II-II:1, 41 year old, male

CaseHPOs: HP:0003563, HP:0001397 (decreased LDL cholesterol, hepatic steatosis)

CaseHPOsFreeText: Prediabetes

CasePreviousTesting: TC 113 mg/dl, LDL-C 38 mg/dl, HDL-C 69 mg/dl, TG 32 mg/dl (see additional values in Table 1). ApoB100 22 mg/dl (normal range 49-88) (Supplemental data). Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

CaseGenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation.

Variant: NM_000384.2:c.7711C>T (p.Gln2571Ter), heterozygous

CAID: CA43502110

gnomAD: Absent

Case#: Patient 2.1.1, male, 4yo, Indian

DiseaseAssertion: MPS1

FamilyInfo: No family history reported, but said not to be consanguineous

CasePresentingHPOs:

CaseHPOFreeText: Distended abdomen, developmental delay

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: NGS, Sanger

PreviouslyPublished:

Variant: c.1882C > T p. Arg628Ter homozygous

ClinVar: 550421

CAID: CA2802462

SupplementalData: n/a

Case#: Family 5 Case 1, male, 43yo, south France

DiseaseAssertion: OA plus

FamilyInfo: mother and brother also had optic atrophy, but further details such as genotype and more phenotype information were not confirmed

CasePresentingHPOs: HP:0000648, HP:0000508, HP:0000365, HP:0001251, HP:0002403, HP:0003326, HP:0009830, HP:0003200, HP:0000590, HP:0003688, HP:0003390,

CaseHPOFreeText: visual impairment since childhood, colic occlusion without any evident mechanical cause, impaired sensation to all modalities predominantly in the lower limbs, atrophy of the corpus callosum and brainstem and a mild cerebellar atrophy, bilateral basal ganglia hypointensity was detected at T2-weighted MRI scan

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished:

PreviousTesting: Direct sequencing of the complete coding region and the exon/intron boundaries of the genes POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1). mtDNA multiple deletions present.

GenotypingMethod: genomic DNA was amplified by PCR with specific primers designed to amplify all exons and flanking intronic regions and sequenced. Southern blot analysis, long-range PCR, sequencing in both directions, and quantitation of mtDNA relative to nuclear DNA was performed on mtDNA

Variant: c.1635 C > G (p.S545R)

ClinVar: 30461

CAID: CA10575554

SupplementalData:

CaseF2:III-1: Female, Italy

CasePresentingHPOs: N/A

CaseAddInfo: Proband for F2

Case# II-1, F, 13yo diagnosis, European

CasePresentingHPOs HP:0001254, HP:0001137, HP:0025404, HP:0008936, HP:0002509, HP:0025430, HP:0003739, HP:0002353, HP:0001508, HP:0000297, HP:0010804, HP:0000218, HP:0000347, HP:0001212, HP:0001864, HP:0040082, HP:0012167, HP:0030820, HP:0000276, HP:0000268, HP:0000549, HP:0000678, HP:0012166, HP:0002465

HPOcont: Lethargy, Alternating esotropia, Abnormal visual fixation, Muscular hypotonia of the trunk, Limb hypertonia, High-pitched cry, Myoclonic spasms, EEG abnormality, Failure to thrive, Facial hypotonia, Tented upper lip vermilion, High palate, Micrognathia, Prominent fingertip pads, Clinodactyly of the 5th toe, Happy demeanor, Hair-pulling, Hooded eyelid, Long face, Dolichocephaly, Abnormal conjugate eye movement, Skin-picking, Poor speech

Free Text: "Birth weight, length and head circumference were 3.149 kg (−0.18SD), 51 cm (+0.99SD), and 33 cm (−0.74SD), respectively. Although she did not cry immediately and was described as sleepy and lethargic, her Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. She has had poor weight gain throughout life. By 2 months of age, she developed alternating esotropia, poor visual fixation, truncal hypotonia, upper and lower extremity hypertonia and a high-pitched cry. She also had myoclonic jerks and jerky movements of her extremities. Her weight, height and head circumference were 4.6 kg (−1.57SD), 51 cm (−3.81 SD) and 39.2 cm (+0.06SD), respectively. A head CT scan detected no anatomical anomalies. An EEG showed excessively slow background without epileptiform activity. Despite intervention, her weight gain continued to fall off, and she was diagnosed with failure to thrive. She rolled over at age 6 months, sat unsupported at 1 year. A follow-up EEG at 14 months showed a slow dysrhythmic background compatible with a seizure predisposition and diffuse cerebral dysfunction. A brain MRI at 18 months of age showed normal anatomy and myelination. In the ensuing months, she demonstrated a happy disposition, low truncal muscle tone and distal hypertonia as well as a myopathic facial appearance, a tented upper lip, a high arched palate, micrognathia, prominent finger pads and mild fifth toe clinodactyly. At age 4 years and 1 month, a developmental assessment defined her overall functioning at no more than a 12-month-old equivalent; she was not autistic. At age 6 years and 11 months, she manifested sparse hair (trichotillomania), hooded eyelids, high arched palate, thin long face and mild micrognathia. At age 12 years, she walked with the support of splints. Her height, weight and head circumference were 127 cm (−3.64 SD), 22.6 kg (−4.06 SD), and 52 cm (−0.94SD), respectively. Her features included dolicocephaly, hooded eyelids, intermittently disconjugate gaze, sparse hair, high palate and crowded dentition. Developmental assessment documented behavioral difficulties including repetitive and self-stimulatory behaviors, sensory issues such as repetitively rubbing her hands on the floor and/or licking them and mouthing objects, rigidity, communication deficits, difficulties with emotional regulation and aggression when frustrated. Her aggression included the self-injurious behaviors of dermatillomania, biting and trichotillomania. She communicated with a few words, signs, gestures and a picture exchange communication system (PECS). She developed menses at age 13 years."

CasePreviousTesting "Family history was negative for intellectual disability, multiple congenital anomalies and recurrent miscarriages. Normal genetic investigations included a karyotype (550 band resolution), subtelomeric FISH, methylation studies of SNRPN, sequence analysis of UBE3A, and DMPK repeat analysis. Normal metabolic tests included transferrin isoelectric focussing, CSF amino acids and neurotransmitters, plasma amino acids, urine organic acids, urine purines and pyrimidines, serum acylcarnitines, blood ammonia and blood lactate. She also had normal audiological testing."

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod SNP array and WES, confirmed with Sanger qt/rtPCR

Variant (1) NM_032504.1:c.3983-3_3994delinsA (p.Ser1328Argfs19), (2) NM_032504.1:c.2431C>T (p.Arg811)

CAID (1) CA658820714, (2) CA350137388

VariantEvidence skin fibroblasts from affected sister showed no unc80 mRNA.

CaseAddInfo nonconsanguineous, confirmed in trans. Affected sister with similar phenotypes died of respiratory distress at age 7.

Family Name: Family 5

FamilyPresentingHPOs: HP:0000705

FamilyNotHPOs:

CountryOrigin: Turkey

Ethnicity: Turkish

Race: n/a

FamilyPreviousTesting: candidate gene sequencing, array comparative genomic hybridization, or exome sequencing

FamilyGenotypingMethod: WES

Affected: 1

Unaffected: 4

Segregations: n/a

PublishedLOD: n/a

eLOD: n/a

AddSegregationInfo: non-consanguineous family

ProbandLabel:

Variant: NM_033068.2(ACP4):c.713C>T (p.Ser238Leu)

ClinVar or CAID: 374862, https://www.ncbi.nlm.nih.gov/clinvar/variation/374862/

genomAD: 8.127e-6, http://gnomad.broadinstitute.org/variant/19-51297008-C-T

FamilyAddInfo: parents unaffected

CasePresentingHPOs: HP:0006316, HP:0006297, HP:0011055, HP:0011079, HP:0011073

CasePresentingHPOTerm: wide interdental spacing due to thin enamel, missing second mandibular permanent molar, maxillary canine not yet erupted, black staining on maxillary anterior teeth and first permanent molars, brown staining on posterior teeth

CaseNotHPOs: HP:0010299

AddCaseInfo:

VariantEvidence:

Case# Postma 3:3, female, 11yo, white

CasePresentingHPOs HP:0004758, HP:0001688

CasePreviousTesting no

CaseMethod1 PCR

CaseGenotypingMethod amplified/screen of CASQ2, SCN5A, HRC, PLN, RYR2, KCNQ1, KCNH2, and KCNK1 genes

Variant NM_001232.3(CASQ2):c.97C>T (p.Arg33Ter)

ClinVar 41043 link

gnomAD 0.000008968 link

VariantEvidence not in this article

Case#: DD, 21 years, female

CasePresentingHPOsFreeText: apo-B plasma levels <2% of normal and > 50% acanthocytes; total cholesterol 1.27 (normal range 4-6.5 mmol/l), triglyceride 0.3 (normal range 0.3-1.8 mmol/l), apoB 1.5 (normal range 60-140 mg/dl), “virtually no LDL”; diagnosed with “homozygous” (i.e. biallelic) familial hypobetalipoproteinemia because both parents (AD and PD) had total plasma cholesterol and apo-B levels below the 5th percentile. Designated as the proband in the paper. However, only one variant identified (note that full gene sequencing was not performed”), and therefore PD (mother of DD) was added as the proband here as she is heterozygous for the variant and has lipid levels consistent with this.

PresentingNotHPOsFreeText: No neurological or retinal disease.

CasePreviousTesting: On Western blot a truncated species of apo-B was found in the VLDL/chylomicron fraction (fig. 3), predicted based on size to be at the 5’ end of exon 26. The protein was absent from the HDL or infranate fractions.

CaseGenotypingMethod: Genomic DNA was digested with a panel of restriction enzymes and Southern blotted. Based on truncated apoB size (detected on Western blot), the variant was predicted to be at the end of exon 26. Approximately 1.7 kb of genomic DNA including exon 26 was amplified by the polymerase chain reaction (PCR), cloned into M13, and sequenced.

Variant: Variant 1: NM_000384.3(APOB):c.5463del (p.His1822fs)

ClinVar: Variant 1 17882 Variant 2 – Not identified (not that full gene sequencing was not performed)

gnomAD: Variant 1 - 0.000008797 (European non-Finnish) Variant 2 – Not identified ((not that full gene sequencing was not performed)

CaseAddInfo: PD (mother) had the truncated apo-B (apo-B39) in both her VLDL and LDL lipoprotein fractions, but it was present at reduced levels compared to the apo-B100 arising from her one normal apo-B allele (fig. 3). Only apo-B100 and apo-B48 were detected in the father, AD.

Case1: Female, 12 yrs onset, Dutch

CasePresentingHPOs: HP:0002093, HP:0001288, HP:0003690, HP:0010628, HP:0003722, HP:0003202, HP:0003798 (Respiratory insufficiency, Gait difficulties, Limb muscle weakness, Facial muscle weakness, Neck flexor weakness, Muscle hypotrophy, Nemaline rods)

HPOsFreeText: Mild form of nemaline myopathy, Wheelchair from the age of 48, Selective hypotrophy of Type 1 muscle fibres

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: No family history of neuromuscular disorders, Variant was not detected in healthy mother or 7 unaffected siblings, Father was deceased so no sample was available

CasePreviousTesting: N/A

CaseGenotypingMethod: Genomic DNA and RNA was extracted from blood or lymphoblastoid cell lines. SSCP was used to analyze all 10 exons of TPM2. After locating the mutations, RT-PCR was used to confirm the mutated allele expression and haplotype analysis was performed on the probands and their family.

Variant: NM_003289.3:c.440A>C (p.Gln147Pro)

ClinVar: 12461 https://www.ncbi.nlm.nih.gov/clinvar/variation/12461/

gnomAD: Not in gnomAD

CaseRoma: France

CasePresentingHPOs: HP:0006785, HP:0003236, (Limb-girdle muscular dystrophy, Elevated serum creatine kinase)

HPOsFreeText: Wheelchair bound before 14 yrs

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Probands are from consanguineous gypsy families supporting a founder event, This mutation segregated with the disease in 18 patients and all asymptomatic parents were heterozygous, 15 siblings were heterozygous and asymptomatic except for a moderate increase in Serum CK in some

CasePreviousTesting: Duchenne-like clinical presentation, Males and females equally affected, Normal dystrophin and decreased level of α- and γ-SG in muscle specimens

CaseGenotypingMethod: DNA was isolated from peripheral blood leukocytes and subject to PCR amplification for linkage analysis. Total RNA was extracted from muscle biopsies and cDNA synthesis was performed and amplified. This was sequenced and analyzed for mutations.

Variant: NM_000231.2(SGCG):c.848G>A (p.Cys283Tyr)

ClinVar: 2006 https://www.ncbi.nlm.nih.gov/clinvar/variation/2006/

gnomAD: 0.000008796, https://gnomad.broadinstitute.org/variant/13-23898652-G-A

Affected: 18

Unaffected: At least 29

Segregations: N/A

SegregationAddInfo: Candidate Gene Sequencing

Case2: Female, Birth onset, Germany

CasePresentingHPOs: HP:0003552, HP:0001558, HP:0002375, HP:0002747, HP:0004887, HP:0001385, HP:0001537, HP:0000023, HP:0012418, HP:0000278, HP:0000347, HP:0000470, HP:0001276, HP:0002808, HP:0001376, HP:0002063, HP:0011968, HP:0000975, HP:0003236, HP:0000938, HP:0009803, HP:0030084, HP:0001561, HP:0002828, HP:0005949, HP:0001284, HP:0003198, HP:0003557, HP:0003687, HP:0010602 (Muscle stiffness, Decreased fetal movement, Hypokinesia, Respiratory insufficiency due to muscle weakness, Respiratory failure requiring assisted ventilation, Hip dysplasia, Umbilical hernia, Inguinal hernia, Hypoxemia, Retrognathia, Micrognathia, Short neck, Hypertonia, Kyphosis, Limited joint motion, Rigidity, Feeding difficulties, Profuse sweating, Elevated serum creatine phosphokinase, Osteopenia, Shortened phalanges, Clinodactyly, Polyhydramnios, Multiple joint contractures, Apneic episodes in infancy, Areflexia, Myopathic changes, Increased variability in muscle fiber diameter, Centrally nucleated skeletal muscle fibers, Type 2 muscle fiber predominance)

HPOsFreeText: Tracheostomy performed, Bladder catheter required, Inability to sit or roll, Increased echogenicity on muscle ultrasound, Treatment with carbamazepine, benzodiazepines, and baclofen reportedly provided no substantial benefit, Difficulty sitting due to hyperactivity of hip extensors, Mini rods and z-band broadening were seen in atrophic fibers

CaseNotHPOs: HP:0100543, HP:0003730, HP:0002486, HP:0002353, HP:0002363, HP:0000496, HP:0003202, HP:0003798 (Cognitive impairment, EMG: myotonic runs, Myotonia, EEG abnormality, Abnormality of brainstem morphology, Abnormality of eye movement, Skeletal muscle atrophy, Nemaline bodies)

NotHPOsFreeText: Abnormal metabolic screening, Muscle fiber type grouping

CaseAddInfo: Case is de novo and confirmed via parental testing

CasePreviousTesting: Negative ACTA1 and CRYAB

CaseGenotypingMethod: Based on the Patient 1 results, the same region of TPM3 (Exon 6) was PCR amplified and sequenced in the proband and her parents via bidirectional Sanger sequencing.

Variant: NM_152263.4(TPM3):c.654_656AGA[1] (p.Glu219del)

ClinVar: 235144 https://www.ncbi.nlm.nih.gov/clinvar/variation/235144/

gnomAD: Not in gnomAD