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#: 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)

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# 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

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: 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.

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:

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

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

CaseF2:III-1: Female, Italy

CasePresentingHPOs: N/A

CaseAddInfo: Proband for F2

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#: 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

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

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

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

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#: 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

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.

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.

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

Article is a PDF, so annotating here.

Case#: OAK 96

DiseaseAssertion: clinical dx of adOA based on ophthalmological examination

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: All 30 coding exons of the OPA1 gene were amplified from genomic DNA by means of PCR. PCR and RT-PCR products were sequenced employing BigDyeTerminator Chemistry (Applied Biosystems, Darmstadt, Germany) and separated on an ABI 3100 DNA Sequencer

PreviouslyPublished: n/a

Variant: c.1705+1G>T (p.V556fsX596)

CAID: CA10576007

SupplementalData:

AdditionalInfo: Generation of minigene constructs and heterologous expression in COS7 cells allowed for cDNA analysis of the c.1705+1G>T mutation. This revealed a deletion of the last 40 nucleotides in exon 17 resulting from a splicing event that involves a cryptic splice donor site within exon 17 resulting in a frameshift and premature translation termination (p.V556fsX596).

Case3: Male, 27 years report, 20 years diagnosis, Germany

CasePresentingHPOs: HP:0002878 (Respiratory failure)

HPOsFreeText: 6-min walk test at 201 (m)

CaseNotHPOs:

NotHPOsFreeText: Not wheelchair bound

CaseAddInfo: 7 years on ERT

Case: Zampieri SD9, Female

DiseaseAssertion: Sandhoff Disease

FamilyInfo: patient's genotype was confirmed in parents

CasePresentingHPOs: HP:0000007, HP:0033978

CaseHPOFreeText: neurological symptoms (unspecified)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Patients presented with neurological symptoms and diagnosis was confirmed by the demonstration of reduced Hex A and Hex B activity in peripheral white blood cells or cultured fibroblasts.

GenotypingMethod: PCR

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: c.850C>T (p.R284X) same on both alleles

CAID: CA116495

gnomAD: MAF: 0.0002286 South Asian, gnomAD variant ID: 5-74009409-C-T

VariantEvidence: PMID:8162015 previously reported this variant to be associated with the infantile form of SD. A fibroblast line from this patient with the infantile form of the disease was investigated for mutations by single strand conformation polymorphism analysis and direct sequencing of PCR products. A nonsense mutation was found which generated a stop codon at codon 284. The study investigated the steady-state level of mRNA produced by cells containing stop codons using a competitive polymerase chain reaction technique and found that at codon 284, the mRNA levels were 0.8%, as percent of normal per single gene dose.

NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala)

ClinVar 224317

CAID CA10575895

gnamAD n/a

Case: Dawidziuk Proband, female, Polish, Caucasian, 10yo at report, onset at 22wks

CasePresentingHPOs: HP:0033044, HP:0034332, HP:0000817, HP:0002540, HP:0001263, HP:0002273, HP:0001252, HP:0000508, HP:0001272, HP:0002470, HP:0001298, HP:0004322, HP:0001344, HP:0100710, HP:5200044, HP:0000252, HP:0002061, HP:0000767

CasePresentingHPOsFreeText: lack of smile, “rounded” back, protruding shoulder blades, tendency to open the mouth and tilt the head back, cortico-subcortical atrophy of the cerebellum on MRI, enlargement of the 4th ventricle and widening of cerebellar sulci. Low COQ10 level tests showing 0.6 mg/l (normal range >0.67 mg/l); after 2-month treatment: 0.7 mg/l

Cardiac echocardiogram, complete blood count, electrolyte levels, CPK, liver and renal function tests, carnitine and acyl-carnitine, copper, thyroid function tests, lactate, blood amino acid profile, homocysteine, as well as urine for protein and organic acids, were within normal limits.

CaseNOTHPOs: HP:0025190, HP:0010865, HP:0001336, HP:0001250, HP:0000639, HP:0000514, HP:0000570, HP:0000657, HP:0001310, HP:0002174, HP:0002080, HP:0002353,

CaseNOTHPOSFreeText: family history of neurodevelopmental disorders. The supratentorial structures are normal. Echocardiogram, abdominal ultrasonography, and ophthalmologic investigation were also uneventful. Encephalomyopathy

CasePreviousTesting: The aCGH analysis did not show any pathogenic copy number variations. Genetic panel excluded congenital Rett, Rett-like and Angelman's syndromes, microdeletion / microduplication syndromes and genetically based lysosomal diseases

CaseGenotypingMethod: Exome sequencing, Sanger sequencing of parents to confirm biallelic origin

Variant: c.681+1G>A; c.352G>A (p.Gly118Ser) confirmed in trans

ClinVarID: or CAID: CA386577420; CA244466459

gnomAD: The splice-site variant, c.681+1G>A in exon /7, is present in gnomAD v4.1.0 with a MAF=0.00002229 (1/44868 alleles) in the East Asian population and 0 homozygotes. The missense variant, p.Gly118Ser, is present in gnomAD v4.1.0 with a MAF=0.0001650 (1/6062 alleles) in the Middle Eastern population and 0 homozygotes.

AddCaseInfo: healthy, non-consanguineous parents

PreviouslyPublished: n/a

VariantEvidence: COQ5 mRNA (Supp.Fig.3) showed that its level is markedly diminished

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?

CaseFSIP2_4 male, 43yo report, Tunisian

CasePresentingHPOs HP:0003251, HP:0012207, HP:0012868

(male infertility, asthenospermia, sperm tail anomaly)

HPOsFreeText Sperm volume: 1.7mL, sperm concentration: 49.5 million/mL, total motility: 5h, vitality: 52%, normal spermatozoa: 0%, absent flagella: 6%, short flagella: 70%, coiled flagella: 14%, flagella of irregular caliber: 80%

CaseNotHPOs n/a

CasePreviousTesting Previous genetic analysis of DNAH1, CFAP43, and CFAP44 did not end in diagnosis. "Normal somatic karyotypes 46,XY and were negative for Y chromosome microdeletions."

Variant NM_173651.3(FSIP2):c.16393_16396del (p.Asn5465Glufs)

ClinVar 586971

gnomAD not in gnomAD

CaseAddInfo Consanguineous parents

CasePMIDs 29449551

Case#: Pedigree OA-16, North of England

DiseaseAssertion: optic atrophy

FamilyInfo: 2 additional affected individuals

CasePresentingHPOs: HP:0000648

CaseHPOFreeText: Snellen BCVA 20/200 - hand movement, mean age of onset= 3.7yrs

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: Cautious that they may overlap with the individuals from Hudson et al since both are from England, but the author notes that they "checked against the eOPA1 database (http://lbbma.univ-angers.fr/eOPA1/, Accessed 10-12-09) to determine whether they had been described in previous mutational reports."

GenotypingMethod: The entire coding region of the OPA1 and OPA3 genes was amplified by PCR and sequenced. Variants were confirmed by reverse sequencing.

Variant: c.1635C>G; p.S545R

ClinVar: 30461

CAID: CA10575554

SupplementalData:

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#: MD-0242, onset at 18yo, 24yo at report

DiseaseAssertion: STGD1

FamilyInfo: Segregation noted, but no specific details provided

CasePresentingHPOs:

CaseHPOFreeText: VA loss, BCVA=0.1/0.1, "STGD1 was determined according to initial symptoms of VA loss; fundus images showing orange-yellow flecks in the retina, a beaten-bronze appearance; and normal or cone-altered ffERG results"

CaseNotHPOs:

CaseNotHPOFreeText: VF loss, abnormal ERG

GenotypingMethod:

PreviouslyPublished: n/a

Variant: c.1715G>C p.(Arg572Pro); c.5242G>A p.(Gly1748Arg)

ClinVar: 99073

CAID: CA226919

SupplementalData: Table S1

Case#: Patient #13

DiseaseAssertion: STGD1

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: RPE atrophy (clearly demarcated definitely decreased fundus autofluorescence (FAF) under short-wavelength excitation light (488 nm) in combination with hypertransmission in optical coherence tomography (OCT)) areas ≥0.05 mm2 secondary to STGD1 or AMD. diagnosis of STGD1 was based on (1) a compatible phenotype (yellow-white flecks that correlated with hyperautofluorescent flecks on FAF imaging) and (2) the presence of at least one mutated ABCA4 allele as well as the absence of mutations in peripherin-2 (PRPH2). Minimum age of onset (first reported subjective symptoms) of 45 years.

CaseNotHPOs:

CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting visual function or image quality (e.g., significant media opacity, amblyopia or optic nerve disease) led to exclusion from the study. “diffuse-trickling geographic atrophy”

GenotypingMethod: Analysis of all coding exons of the ABCA4 and PRPH2 genes was done by either direct chain-terminating dideoxynucleotide Sanger sequencing, a custom-designed GeneChip CustomSeq Resequencing Array, or NGS

PreviouslyPublished: possible since the study was at the same university with the same first author as PMID: 33214501

Variant: c.3468C>G/p.(Tyr1156*) and c.5059A>T/p.(Ile1687Phe)

ClinVar: n/a

CAID: CA341290648

SupplementalData: supplement 1 has the genotype for probands

Case#: STGD102, 10-14yo at onset, German

DiseaseAssertion: STGD

FamilyInfo: segregation in family

CasePresentingHPOs:

CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing

PreviouslyPublished: n/a

Variant: R572Q-2588G→C IVS35+2T→A in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"

ClinVar: 7900

CAID: CA226918

SupplementalData: n/a

Annotating here since the full text is a PDF.

Case#: Family AR263 proband, male, US, 9yo at onset

DiseaseAssertion: Stargardt

FamilyInfo: 3 generations, no other affected members in the pedigree

CasePresentingHPOs:

CaseHPOFreeText: The essential and defining features of STGD were (1) pedigrees with at least one living affected individual compatible with autosomal recessive inheritance; (2) an ophthalmoscopically characteristic retinal disorder in families with both parents living; (3) bilateral central visual loss with both “beaten metal” elliptical foveal dystrophy and temporal pallor of the optic discs, documented by retinal color photography, with or without yellow-pigment epithelial flecks in the macular and/or retinal “near periphery”; and (4) the characteristic fluorescein angiographic feature of a dark choroid (Blacharski 1988).

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.6445C>T (p.Arg2149Ter); c.6079C>T (p.Leu2027Phe). Heteroduplex and SSCP analyses were used to screen the 50 exons of ABCA4

ClinVar: 99460

CAID: CA227404

SupplementalData: n/a

annotating here since the article is a PDF

Case#: Duno Patient D015, Danish

DiseaseAssertion: Stargardt flavimaculatus phenotype

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: The diagnosis was based on standard ophthalmological examinations including fundus photography, colour vision assessment, dark adaptometry, and full field ERG.

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: ABCA4 mutation microarray and High-resolution melting (HRM) in patients in whom the array analysis identified either a heterozygous mutation (n = 50) or no mutation (n = 30).

PreviouslyPublished: n/a

Variant: c.1654G>A p.V552I; c.6478A>G p.K2160E; c.3380G>A p.G1127E phase unknown

CAID: CA239745

SupplementalData:

Case#: Muller Subject #8, 34yo, qAF=590

DiseaseAssertion: ABCA4-related retinopathy

FamilyInfo: mother was 59yo at report with qAF=399

CasePresentingHPOs:

CaseHPOFreeText: "ABCA4-related retinopathy was diagnosed based on characteristic findings on indirect ophthalmoscopy, optical coherence tomography, and conventional fundus AF imaging. The clinical diagnosis was confirmed by the presence of biallelic mutations in ABCA4, and segregation analysis was carried out with samples of the parents."

CaseNotHPOs:

CaseNotHPOFreeText: age ≥ 65 years, ethnicity other than Caucasian, significant lens opacities, dilated pupil diameter below 7 mm, unstable fixation, refractive error > ±6 diopters (spherical equivalent), and any other additional known ocular pathology or prior intraocular surgery.

GenotypingMethod: ABCA4 sequence analysis of all coding exons and flanking splice junctions was performed either by Sanger chain-terminating dideoxynucleotide sequencing after PCR amplification, by multiplex ligation-dependent probe amplification (MLPA) analysis (performed when only a single mutation was detected), or by next-generation sequencing (NGS) including a quantitative readout to detect large structural rearrangements using a gene panel covering 120 genes associated with inherited retinal disease as described previously.23 Validation of identified putatively pathogenic variants and segregation analysis were carried out by conventional sequencing

PreviouslyPublished: n/a

Variant: maternal allele: [c.1622T>C (p.Leu541Pro); c.3113C>T (p.Ala1038Val)]; paternal allele: c.1654G>A (p.Val552Ile); c.4771G>A (p.Gly1591Arg)

CAID: CA239745

SupplementalData:

This variant was found on one allele of a Stargardt patient, but no additional details are provided about the patient or the other allele. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to evaluate the entire exonic and flanking intron sequence of the ABCA4 gene

c.1989G>CA (p.Trp663Ter) variant was found on one allele of a Stargardt patient, but no additional details are provided about the patient or the other allele. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to evaluate the entire exonic and flanking intron sequence of the ABCA4 gene

This variant was found on one allele of a Stargardt patient, but no additional details are provided about the patient or the other allele. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to evaluate the entire exonic and flanking intron sequence of the ABCA4 gene

PMID: 10612508

Gene: ABCA4

Case#: Patient 1, 40-year-old female

DiseaseAssertion: STGD1

FamilyInfo: One of four affected siblings in a family of eight. Segregation consistent with autosomal recessive inheritance.

CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0000612 — Central scotoma HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology

CaseHPOFreeText: Progressive decline in visual acuity since age 15. Best-corrected visual acuity RE 20/400, LE 20/150. Central scotomas reported. Fundus exam showed bilateral central macular atrophy (worse in right eye), pigment deposits at the level of the retinal pigment epithelium, and numerous yellow flecks in the midperiphery. Fluorescein angiography demonstrated central hypofluorescence corresponding to atrophy with surrounding hyperfluorescence and peripheral dark choroid.

CaseNotHPOs: HP:0000662 — Night blindness (absent)

CaseNotHPOFreeText: Patient denied nyctalopia.

GenotypingMethod: PCR amplification and direct sequencing of all 50 exons of ABCA4 following SSCP screening.

PreviouslyPublished: Yes

Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)

ClinVar: Not reported

CAID: Not reported

SupplementalData: Segregation demonstrated in pedigree (Figure 1); mutation confirmation by sequencing (Figure 4)

Case#: Patient 4, Female, Caucasian, 33yo

DiseaseAssertion: STGD1

FamilyInfo: One of eight siblings; four affected. Disease segregates with ABCA4 variants consistent with autosomal recessive inheritance. Parents are deceased and can't be tested.

CasePresentingHPOs: HP:0007663, HP:0007754, HP:0025147, HP:0007924, HP:0011507

CaseHPOFreeText: gradual decline in visual acuity over 9 years, BCVA 20/300 OU, bilateral beaten-bronze appearance of the macula, numerous perimacular yellow flecks, fluorescein angiography showing hyperfluorescence in the posterior pole and dark choroid in the periphery

CaseNotHPOs: N/A

CaseNotHPOFreeText: absence of central hypofluorescence on fluorescein angiography (present in affected siblings but not this patient)

Genotyping Method: SSCP analysis; Taq Dyedeoxy Terminator Cycle Sequencing kit

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.2588G>C (p.Gly863Ala), NM_000350.3(ABCA4):c.161G>A (p.Cys54Tyr)

ClinVar: ClinVarID:7879, ClinVarID:99065

CAID: N/A

SupplementalData: Segregation and sequencing data (Figures 1, 4)

PMID: 10612508

Gene: ABCA4

Case#: Patient 2, 46-year-old female

DiseaseAssertion: STGD1

FamilyInfo: One of four affected siblings in a family consistent with autosomal recessive inheritance.

CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology

CaseHPOFreeText: Progressive visual decline since age 16. Best-corrected visual acuity 20/400 in both eyes. Fundus examination showed bilateral symmetrical central chorioretinal atrophy (~3 disc diameters) with prominent pigment deposits and numerous yellow flecks in the posterior pole. Fluorescein angiography demonstrated central hypofluorescence with surrounding hyperfluorescence and peripheral dark choroid.

CaseNotHPOs: Not reported

CaseNotHPOFreeText: Not reported

GenotypingMethod: PCR amplification and direct sequencing of ABCA4 after SSCP screening

PreviouslyPublished: Yes

Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)

ClinVar: Not reported

CAID: Not reported

SupplementalData: Segregation and sequencing data shown in Figures 1 and 4

Case#: Patient 3, 37-year-old female

PMID: 10612508

DiseaseAssertion: STGD1

FamilyInfo: Affected sibling in autosomal recessive family.

CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology

CaseHPOFreeText: Gradual visual decline beginning at age 12. Visual acuity 20/400 in both eyes. Fundus examination revealed bilateral macular atrophy with pigment deposits and numerous yellow flecks in the posterior pole and midperiphery. Fluorescein angiography showed large hypofluorescent regions with surrounding hyperfluorescence and peripheral dark choroid.

CaseNotHPOs: Not reported

CaseNotHPOFreeText: Not reported

GenotypingMethod: PCR and direct sequencing of ABCA4

PreviouslyPublished: Yes

Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)

ClinVar: Not reported

CAID: Not reported

SupplementalData: Segregation and sequencing data (Figures 1, 4)

Case#: STGD113, 20-24yo at onset, German

DiseaseAssertion: STGD

FamilyInfo: segregation in family

CasePresentingHPOs:

CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing

PreviouslyPublished: n/a

Variant: L541P-A1038V; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"

ClinVar: 7879

CAID: CA119128

SupplementalData: n/a

Case#: STGD138, 15-19yo at onset, German

DiseaseAssertion: STGD

FamilyInfo: segregation in family

CasePresentingHPOs:

CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing

PreviouslyPublished: n/a

Variant: IVS13+1G→A; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"

ClinVar: 7879

CAID: CA119128

SupplementalData: n/a

Case#: STGD87, 10-14yo at onset, German

DiseaseAssertion: STGD

FamilyInfo: segregation in family

CasePresentingHPOs:

CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing

PreviouslyPublished: n/a

Variant: Q1750X; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"

ClinVar: 7879

CAID: CA119128

SupplementalData: n/a

Case#: STGD47/164, 10-14yo at onset, German

DiseaseAssertion: STGD

FamilyInfo: segregation in family

CasePresentingHPOs:

CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing

PreviouslyPublished: n/a

Variant: IVS13+1G→A; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"

ClinVar: 7879

CAID: CA119128

SupplementalData: n/a

Case#: Sporadic Case #4, Mexican

DiseaseAssertion: Stargardt

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosis based on: "onset of symptoms in childhood or early adulthood (before 20 years of age), bilateral central vision loss (central and peripheral visual field computerized testing), a retinal “beaten-bronze” foveal appearance and/or yellow-whitish flecks from the posterior pole to the mid periphery, normal caliber of the retinal vessels, no pigmented bone spicules in the retinal periphery, a normal to subnormal electroretinogram, and a typical dark choroid in fluorescein angiography."

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: allele 1: c.1804C>T (p.R602W) and c.2828G>A (p.R943Q) allele 2: c.2453G>A (p. G818E); direct sequencing of exons of ABCA4

ClinVar: 99135

CAID: CA227000

SupplementalData: n/a

Case#: Familial Case #8, Mexican

DiseaseAssertion: Stargardt

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosis based on: "onset of symptoms in childhood or early adulthood (before 20 years of age), bilateral central vision loss (central and peripheral visual field computerized testing), a retinal “beaten-bronze” foveal appearance and/or yellow-whitish flecks from the posterior pole to the mid periphery, normal caliber of the retinal vessels, no pigmented bone spicules in the retinal periphery, a normal to subnormal electroretinogram, and a typical dark choroid in fluorescein angiography."

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: allele 1: c.2453G>A (p. G818E) allele 2: c.4249_4251 delTTC (p.F1417del); direct sequencing of exons of ABCA4

ClinVar: 99135

CAID: CA227000

SupplementalData: n/a

Case#: Sporadic Case #10, Mexican

DiseaseAssertion: Stargardt

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosis based on: "onset of symptoms in childhood or early adulthood (before 20 years of age), bilateral central vision loss (central and peripheral visual field computerized testing), a retinal “beaten-bronze” foveal appearance and/or yellow-whitish flecks from the posterior pole to the mid periphery, normal caliber of the retinal vessels, no pigmented bone spicules in the retinal periphery, a normal to subnormal electroretinogram, and a typical dark choroid in fluorescein angiography."

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.2453G>A (p. G818E) homozygous; direct sequencing of exons of ABCA4

ClinVar: 99135

CAID: CA227000

SupplementalData: n/a

Case#: Sporadic Case #16, Mexican

DiseaseAssertion: Stargardt

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosis based on: "onset of symptoms in childhood or early adulthood (before 20 years of age), bilateral central vision loss (central and peripheral visual field computerized testing), a retinal “beaten-bronze” foveal appearance and/or yellow-whitish flecks from the posterior pole to the mid periphery, normal caliber of the retinal vessels, no pigmented bone spicules in the retinal periphery, a normal to subnormal electroretinogram, and a typical dark choroid in fluorescein angiography."

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: allele 1: c.2453G>A (p. G818E); c.5824G>C (p. E1942Q) allele 2: c.6384A>G (p.H2128R) direct sequencing of exons of ABCA4

ClinVar: 867010

CAID: CA957117

SupplementalData: n/a

Case#: Sporadic Case #15, Mexican

DiseaseAssertion: Stargardt

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosis based on: "onset of symptoms in childhood or early adulthood (before 20 years of age), bilateral central vision loss (central and peripheral visual field computerized testing), a retinal “beaten-bronze” foveal appearance and/or yellow-whitish flecks from the posterior pole to the mid periphery, normal caliber of the retinal vessels, no pigmented bone spicules in the retinal periphery, a normal to subnormal electroretinogram, and a typical dark choroid in fluorescein angiography."

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: allele 1: c.6221G>T (p.G2074V) allele 2: c.2453G>A (p. G818E); direct sequencing of exons of ABCA4

ClinVar: 99135

CAID: CA227000

SupplementalData: n/a

Case#: Family MD-0560 Proband, 16yo at onset

DiseaseAssertion: AR Stargardt

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal electroretinogram (ERGs)." VA loss, VF loss, BCVA=0.1/0.1

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.6410G>A (p.Cys2137Tyr); c.3386G>T (p.Arg1129Leu) found by ABCR400

ClinVar: 2202779; 99224

CAID: CA341277358; CA227116

SupplementalData:

Case#: MD-0170 Proband, 14yo at onset

DiseaseAssertion: STGD

FamilyInfo: Family MD-0170

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Haplotype analysis, ABCR400

PreviouslyPublished: unclear

Variant: c.4457C>T (p.Pro1486Leu); c.1222C>T (p.Arg408*)

ClinVar: 99283

CAID: CA227192

SupplementalData: n/a

Case#: Family MD-0084 Proband, 7yo at onset

DiseaseAssertion: AR Stargardt

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)." VA loss, VF loss, BCVA=<0.05/<0.05

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: PMID: 16917483 (variant not found in this paper); PMID: 19959634

Variant: c.6410G>A (p.Cys2137Tyr) homozygous, found by ABCR400 + dHPLC + HRM + MLPA

ClinVar: 2202779

CAID: CA341277358

SupplementalData:

Case#: Family MD-0242 Proband, 18yo at onset, Spanish

DiseaseAssertion: AR Stargardt

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Haplotype analysis, ABCR400 microarray, direct sequencing for confirmation

PreviouslyPublished: n/a

Variant: c.1715G>C p.Arg572Pro

ClinVar: 99073

CAID: CA226919

SupplementalData:

Case#: MD-0324 Proband,

DiseaseAssertion: STGD

FamilyInfo: Family MD-0324

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Haplotype analysis, ABCR400, NGS

PreviouslyPublished: n/a

Variant:c.3386G>T p.Arg1129Leu; c.3G>A p.Met1Ile

ClinVar: n/a

CAID: CA341289040

SupplementalData: n/a

This variant was found in 6 different families (F32, F33, F40, F41, F42, and F43).

PP4: F32: Patient #37 is a 31yo male, ADI=4yo, dx of CRD F33: Patient #38 is a 32yo female, ADI=>32yo, dx of STGD, segregation in the family but no further details F40: Patient #45 is a 65yo male, ADI=26yo, dx of CRD, segregation of homozygous alleles with disease was demonstrated in 2 affected siblings in Family 40. F41: Patient #46 is a 38yo female, ADI=>38yo, dx of STGD F42: Patient #47 is a 45yo female, ADI=>53yo, dx of STGD F43: Patient #48 is a 55yo female, ADI=46yo, dx of STGD

PM3: In family 40, the proband was homozygous. In the other families, the variant was in compound heterozygosity with p.A1038V;p.L541P (F32); p.A1038V (F33); p.V1686M (F41); p.G1961E (F42); p.K2172R (F43).

Case#: Patient #35, male, 35yo at report, 14yo at onset,

DiseaseAssertion: STGD

FamilyInfo: family 30, segregation was noted as "yes" but no other details provided

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod:

PreviouslyPublished: n/a

Variant: allele 1: A1038V;L541P allele 2: G818E

ClinVar: 99135

CAID: CA227000

SupplementalData: supplemental table 1

Case#: Two affected sisters/Female siblings/Progressive onset initially presenting as Stargardt disease

DiseaseAssertion: ABCA4

FamilyInfo: Large American family pedigree with two affected sisters. Both sisters were compound heterozygous for two novel ABCA4 variants. Unaffected relatives carried one variant or neither variant, supporting autosomal recessive inheritance.

CasePresentingHPOs: HP:0000556, HP:0000572, HP:0007754, HP:0000648, HP:0000510, HP:0001133, HP:0000610

CaseHPOFreeText: Proband initially showed phenotype compatible with Stargardt disease with progressive central vision loss. Over several years disease advanced into severe cone-rod dystrophy with worsening retinal degeneration, abnormal visual fields, and reduced electroretinography responses.

CaseNotHPOs: n/a

CaseNotHPOFreeText: Unaffected family members with only one mutation had no retinal disease phenotype.

Genotyping Method: Genome-wide linkage analysis using 408 microsatellite markers followed by direct Sanger DNA sequencing of all ABCA4 exons and exon-intron boundaries. Segregation analysis performed in family members.

PreviouslyPublished: No, both variants were novel at time of publication.

Variant: ABCA4 (RefSeq: NM_000350.3): c.655A>T ; ABCA4 (RefSeq: NM_000350.3): c.5312+3A>T

ClinVar: 632118

CAID: n/a

SupplementalData: Variants absent in 200 unrelated controls. Clinical testing included visual acuity, fundus examination, fluorescein angiography, visual field testing, and electroretinography. Compound heterozygous state associated with severe progressive phenotype.

3 STGD patients have this variant but no specific clinical details (supplemental table s5).

Patient 79: c.1654G>A p.(V552I); c.5196+1013A>G

Patient 265: c.1654G>A p.(V552I) only

Patient 320: c.1654G>A p.(V552I); c.4254-1G>C; c.6230G>A p.(R2077Q)

This variant is found in compound heterozygosity with c.950del p.(Gly317Alafs*57) in family RP-0298 in this study. Proband is 10yo at onset of VA loss and VF loss, 8yo at night blindness, and 36yo at opthalmological exam. BCVA=HM/HM.

This variant is found in compound heterozygosity with c.2023G>A p.(Val675Ile) in family MD-1146 in this study. Proband is 46yo at onset of VA loss. 46yo at opthalmological exam. Normal ERG. BCVA=1/1. Not eligible for PP4 due to age of onset.

This variant is found in compound heterozygosity with c.4253+43G>A p.[=, Ile1377Hisfs*3] in family MD-0740 in this study. Proband is 61yo at onset of VA loss with no VF loss. 62yo at opthalmological exam. Cone pattern on ERG. BCVA=0.8/0.16. Not eligible for PP4 due to age of onset.

This variant is found in compound heterozygosity with c.6089G>A p.(Arg2030Gln) in family MD-1001 in this study. No phenotype information provided. Not eligible for PP4 due to age of onset not being provided.

This variant is found in compound heterozygosity with c.3386G>T p.(Arg1129Leu) in family MD-0723 in this study. Proband is 13yo at onset of VA loss and VF loss with night blindness. 15yo at opthalmological exam. Cone pattern on ERG. BCVA=0.2/0.2. Eligible for PP4.

Case#: Family ARDM-133 Proband, Spanish Retinal Dystrophy Investigation Network (EsRetNet), 8yo at onset, 42yo at report

DiseaseAssertion: arCRD

FamilyInfo: cosegregates

CasePresentingHPOs: HP:0007663, HP:0000575, HP:0007641, HP:0000613

CaseHPOFreeText: "The diagnosis of CRD was based on the following criteria: initial complaints of blurred central vision without a history of night blindness, poor visual acuity (typically 20/100 or worse, with progressive decline from an early age), impairment of color vision, funduscopic evidence of atrophic macular degeneration, peripheral disturbances including pigment clumping and/or pigment epithelial thinning, and greater or earlier loss of cone than rod ERG amplitude."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: ABCR400 microarray, PCR amplification

PreviouslyPublished: n/a

Variant: 32T→C, L11P; 2888delG

ClinVar: 99217

CAID: CA227106

SupplementalData:

This variant is mentioned for patient 5 but is likely the same proband as in PMID: 19074458 since this is the same first author and same genotype

annotating here since unable to annotate on PDF.

Case#: Stargardt patient 22, Italian

DiseaseAssertion: STGD

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: STGD criteria: "(1) juvenile to adult onset of symptoms; (2) bilateral central vision loss; (3) macular dystrophy and/or atrophy (beaten bronze appearance or large patch of atrophy); (4) normal caliber of retinal vessels; (5) absence of pigmented bone spicules. The presence of yellow-white flecks was not considered obligatory inclusion criteria, even though they could be found in most of the patients of our series. Similarly, the possible presence of the “dark choroid” phenomenon could be identified in the fluorescein angiography examinations carried out on some patients in previous clinical settings, but it was not considered significant for the recruitment."

CaseNotHPOs:

CaseNotHPOFreeText: "myopia >6 diopters, hyperopia and astigmatism >3 diopters, ocular disorders other than RP, STGD, or AMD, significant systemic diseases, a history of inflammation-associated diseases and media opacities preventing fundus examination"

GenotypingMethod: all coding exons, including intron-exon boundaries of the ABCA4 gene (NM 000350) were sequenced. PCR

PreviouslyPublished: n/a

Variant: c.5882G>A (p.Gly1961Glu); c.4450C>T (p.Pro1484Ser); c.203C>T (p.Pro68Leu)

ClinVar: 99113

CAID: CA226972

SupplementalData: Table S2

MonDO: MONDO:0019353

Case: Family SG-04 Patient II:1. Indian Male, 26 years old diagnosed with Stargardt's disease DiseaseAssertion: Stargardt disease

FamilyInfo: Only child of nonconsanguineous parents. Proband's unaffected mother (I:1) harbored only one heterozygous variant (p.Gly1961Glu) in ABCA4. His father (I:2) was clinically normal and was not included for genetic testing.

CasePresentingHPOs: HP:0001129, HP:0007401 (Large central visual field defect, Macular atrophy)

CaseHPOFreeText: atrophic macular lesions

CaseNOTHPOs: HP:0011507 (macular flecks)

CasePreviousTesting: Five clinically confirmed unrelated patients with Stargardt disease and their available family members were enrolled for genetic analysis. Study subjects underwent a complete ophthalmic examination including measurement of visual acuity, intraocular pressure, slit lamp biomicroscopy, detailed fundus examination, fundus photography, fundus autofluorescence (FAF), spectral domain optical coherence tomography (SD-OCT), and full field electroretinography (ERG). Fifty normal controls without any history of eye diseases were included.

GenotypingMethod: NGS panel testing targeting 184 genes with previously known pathogenic variations associated with multiple eye disorders. Peripheral blood samples were obtained from all subjects.

MultipleGeneVariants:

(1) GeneName: ABCA4

(1) Variant: p.Gly1961Glu

(1) CAID: CA119132

(1) gnomAD: The total minor allele frequency in gnomAD v4.1.0 is 0.003406 (5498/1614012 alleles).

(2) GeneName: ABCA4

(2) Variant: p.Tyr872X

(2) CAID: CA341276149

(2) gnomAD: Not found in gnomad v. 4.1

This variant is listed in supplementary tables S2 and S3. Proband TM-319 is a "solved" patient, meaning the phenotype matches the genotype. Compound heterozygous (c.5318C>T p.A1773V) female with Stargardt disease- all that is provided.

This variant is listed in supplementary tables S2 and S3. Proband TI-50 is a "solved" patient, meaning the phenotype matches the genotype. Homozygous female with MD/CORD- all that is provided.

This variant is listed in supplementary tables S2 and S3. Proband KN-187 is a "solved" patient, meaning the phenotype matches the genotype. Compound heterozygous (c.6290C>T p.P2097L; c.6445C>T p.R2149X) male with Stargardt disease- all that is provided.

Case#: Family MD-0084/ARDM-84 Proband, 7yo at onset

DiseaseAssertion: AR Stargardt

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)." VA loss, VF loss, BCVA=<0.05/<0.05

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.6410G>A (p.Cys2137Tyr) homozygous, found by ABCR400 + dHPLC + HRM + MLPA

ClinVar: 2202779

CAID: CA341277358

SupplementalData: n/a

Case#: Braun Family 6 Proband (from left to right, top to bottom of available pedigrees), male

DiseaseAssertion: Stargardt

FamilyInfo: Genotypes not provided for parents. No siblings

CasePresentingHPOs:

CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer

PreviouslyPublished: n/a

Variant: c.5196+1137G>A; c.454C>T (p.R152X)

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

Case#: Braun Family 8 Proband (from left to right, top to bottom of available pedigrees), female

DiseaseAssertion: Stargardt

FamilyInfo: Unaffected carrier parents. c.5196+1137G>A maternally inherited; c.4577C>T (p.T1526M) paternally inherited

CasePresentingHPOs:

CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer

PreviouslyPublished: n/a

Variant: c.5196+1137G>A; c.4577C>T (p.T1526M)

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

Case#: Braun Family 5 Proband (from left to right, top to bottom of available pedigrees), male

DiseaseAssertion: Stargardt

FamilyInfo: Proband has 1 affected sister with the same genotype and 1 unaffected, heterozygous brother. Genotypes not provided for parents.

CasePresentingHPOs:

CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer

PreviouslyPublished: n/a

Variant: c.5196+1137G>A; c.4363T>C (p.C1455R)

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

Case#: Braun Family 1 Proband (from left to right, top to bottom of available pedigrees), female

DiseaseAssertion: Stargardt

FamilyInfo: Both parents are unaffected heterozygotes. c.4139C>T (p.P1380L) paternally inherited, c.5196+1137G>A maternally inherited. Proband has 2 unaffected, heterozygous children.

CasePresentingHPOs:

CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer

PreviouslyPublished: n/a

Variant: c.5196+1137G>A; c.4139C>T (p.P1380L)

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

Case#: Braun Family 7 Proband (from left to right, top to bottom of available pedigrees), female

DiseaseAssertion: Stargardt

FamilyInfo: Unaffected carrier parents. c.5196+1137G>A maternally inherited; c.4561-10T>C paternally inherited

CasePresentingHPOs:

CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer

PreviouslyPublished: n/a

Variant: c.5196+1137G>A; c.4561-10T>C

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

Case#: Braun Family 2 Proband (from left to right, top to bottom of available pedigrees), female

DiseaseAssertion: Stargardt

FamilyInfo: Both parents are unaffected carriers. c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variants were paternally inherited, c.5196+1137G>A maternally inherited.

CasePresentingHPOs:

CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer

PreviouslyPublished: n/a

Variant: c.5196+1137G>A; c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variant

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

Case#: Braun Family 3 Proband (from left to right, top to bottom of available pedigrees), female

DiseaseAssertion: Stargardt

FamilyInfo: Both parents are unaffected, but only mother has genotype information available since father is deceased. c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variants were maternally inherited.

CasePresentingHPOs:

CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer

PreviouslyPublished: n/a

Variant: c.5196+1137G>A; c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variant

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

Case#: Braun Family 4 Proband (from left to right, top to bottom of available pedigrees), male

DiseaseAssertion: Stargardt

FamilyInfo: Both parents are unaffected, but only mother has genotype information available since father is deceased. c.5196+1137G>A maternally inherited. c.1022-1035fs inferred to be inherited from the father since other siblings also have this variant. Proband has 1 affected sister with the same genotype, and 2 siblings that were unaffected heterozygotes

CasePresentingHPOs:

CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer

PreviouslyPublished: n/a

Variant: c.5196+1137G>A; c.1022-1035fs

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

Case#: Maia-Lopes Family 5 Proband 4514, Portuguese, 12yo at onset

DiseaseAssertion: STGD

FamilyInfo: Family 5

CasePresentingHPOs:

CaseHPOFreeText: severe central fundus changes, vision: 1/10 / 1/10

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: ABCR400 microarray, dHPLC

PreviouslyPublished: n/a

Variant: c.32T>C(1) / c.[1A>G(1)]+[6089G>A(44)]; p.Leu11Pro/p.(Met1Val)+(Arg2030Gln)

ClinVar: 99217

CAID: CA227106

SupplementalData: n/a

Case#: Maia-Lopes Family 11 Proband 4613, Portuguese, 9yo at onset

DiseaseAssertion: STGD

FamilyInfo: Family 11

CasePresentingHPOs:

CaseHPOFreeText: severe central fundus changes, vision: FC/FC

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: ABCR400 microarray, dHPLC

PreviouslyPublished: n/a

Variant: c.[4926C>G(35)]+[5041_5055del(36)] / c.32T>C(1); p.(Ser1642Arg [10])+(Val1681_Cys1685del [10])/p.Leu11Pro

ClinVar: 99217

CAID: CA227106

SupplementalData: n/a

Case#: Maia-Lopes Family 18 Proband 5709, Portuguese, 9yo at onset

DiseaseAssertion: STGD