Case# Pat3, F, Chinese, 12day onset

CasePresentingHPOs HP:0008344, HP:0002013, HP:0011968, HP:0001250, HP:0001263

CaseNotHPOs HP:0001276, HP:0001279,

CasePreviousTesting tested for serum BCAAs

CaseMethod1 PCR

CaseMethod2 Direct

CaseGenotypingMethod exons and flanking intronic regions of the BCKDHA, BCKDHB and DBT genes were amplified using PCR and sequenced

Variant NM_000709.3:c.178G>T, NM_000709.3:c.1214_1219dup

CAID CA406004676(c.178), CA658820662(c.1214)

CaseAddInfo mutations confirmed in parents by Sanger sequencing, Her elder brother was healthy. She exhibited feeding difficulties and vomiting at 12 days of age. Severe psychomotor retardation was found at the age of 3 months. Cerebral MRI showed bilateral damage to the globus pallidus, basal ganglia, capsula interna and capsula externa. After treatment, clinical improvement was observed. Currently, she is 4 years old and has moderate psychomotor retardation.

Case# Pat1, M, Chinese, 3day onset

CasePresentingHPOs HP:0008344, HP:0008872, HP:0001250, HP:0001276, HP:0001279, HP:0001263

CaseNotHPOs HP:0002013

CaseMethod1 PCR

CaseMethod2 Direct

CaseGenotypingMethod exons and flanking intronic regions of the BCKDHA, BCKDHB and DBT genes were amplified using PCR and sequenced

Variant NM_000709.3:c.853+1delG ?

Case#: 2, female 4 days (onset), 4 y 3 mo (current), Chinese

CasePresentingHPOs: HP: 0008344, HP: 0012088, HP: 0011968, HP: 0001276, HP: 0001941, HP: 0002543, HP: 0011342 (elevated A keto acids in urine, abnormal urinary odor, feeding difficulties, hypertonia, acidosis, abnormal globus pallidus MRI signals, mild global developmental delay)

HPOsFreeText: Poor response to light and sound, abnormal MRI signals in frontal lobes, Blood ammonia: 95 uM, Hemoglobin: 117 g/L, Leucin: 745.01 uM, Valine: 526.40 uM, Isoleucine: 181.06 uM, Alloisoleucine: 69.45 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

CasePreviousTesting: n/a

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_000709.3(BCKDHA): c.659C>T (p.Ala220Val)

ClinVar: 93367

CAID: n/a (because this doesn't need to be included if it is in ClinVar right?)

gnomAD: not in gnomAD

Case#: 4, female, 5 days (onset), 3 y 11 mo (current), Chinese

CasePresentingHPOs: HP: 0008344. HP: 0012088, HP: 0001279, HP:0001254, HP: 0011968, HP: 0001942, HP: 001276, HP: 0002543, HP: 0011344 (elevated A keto acids in urine, abnormal urinary odor, unconsciousness, lethargy, feeding difficulties, metabolic acidosis, hypertonia, abnormal globus pallidus, severe global developmental delay)

HPOsFreeText: liver damage, blood ammomia: 129 uM, Hemoglobin: 59 g/L, Leucin: 1155.27 uM, Valine: 848.19 uM, Isoleucine: 374.34 uM, Alloisoleucine: 128.73 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: unsure whether cis or trans

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_000709.3:c.178G>T (p.Glu60Ter), NM_000709.3c.491T>C (p.Leu164Pro),

ClinVar: n/a

CAID: CA406004676, CA406010453

gnomAD: not found

Case# Pat4, F, Chinese, 5day onset

CasePresentingHPOs HP:0008344, HP:0002013, HP:0011968, HP:0001250, HP:0001276, HP:0001279

CasePreviousTesting Tested serum BCAAs

CaseMethod1 PCR

CaseMethod2 Direct

CaseGenotypingMethod exons and flanking intronic regions of the BCKDHA, BCKDHB and DBT genes were amplified using PCR and sequenced

Variant NM_000709.3:c.178G>T, NM_000709.3:c.491T>C

CAID CA406004676(c.178), CA406010453(c.491)

CaseAddInfo mutations confirmed in parents by Sanger sequencing, Her elder brother was healthy. This patient presented with lethargy and feeding difficulty when she was 5 days old. She was admitted because of unconsciousness at the age of 5 months, and she was diagnosed with MSUD accompanied by metabolic acidosis, liver damage and hypermyotonia. Cerebral MRI showed abnormal signals in the left and right globus pallidus. Clinical improvement as well as improvement in the laboratory test results was observed after treatment. She is now 3 years and 11 months old with severe psychomotor retardation. She is still unable to walk or speak.

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

GroupPresentingHPOs: HP:0008344 (elevated A keto acids in urine)

HPOsFreeText:

GroupNotHPOs:

NotHPOsFreeText:

NumberMales: 4

NumberFemales: 4

CountryOrigin: mainland China

Ethnicity:

Race: Chinese

AgeRange: 2 y 3 mo- 4 y 3 mo (present age)

TotalNumber: 8

VariantCount: 8 (subunits of BKDC: either BCKDHA, BCKDHB, or DBT)

NonVariant: 0

OtherVariant: 0

GroupPreviousTesting: n/a

GroupMethod1: PCR

GroupMethod2: Multiple sequence alignments

GroupGenotypingMethod: genomic DNA extracted from peripheral blood lymphocytes of patients and parents using TIANamp Blood DNA Kit. Exons and flanking intronic regions of BCKDHA, BCKDHB, and DBT were amplified with PCR and sequenced. Results compared with reference sequences in UCSC genome (BCKDHA (NM_000709), BCKDHB (NM_183050), DLD (NM_000108), DBT (NM_001918)), and compared with integrated set of variants from 1000 Genome Project to identify mutations. PolyPhen-2 and Mutationtaster program predicted the impact of missense alterations on protein function. Multiple sequence alignments obtained using BLAST.

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# Pat4, F, Chinese, 5day onset

CasePresentingHPOs HP:0008344, HP:0002013, HP:0011968, HP:0001250, HP:0001276, HP:0001279

CasePreviousTesting Tested serum BCAAs

CaseMethod1 PCR

CaseMethod2 Direct

CaseGenotypingMethod exons and flanking intronic regions of the BCKDHA, BCKDHB and DBT genes were amplified using PCR and sequenced

Variant NM_000709.3:c.178G>T, NM_000709.3:c.491T>C

CAID CA406004676(c.178), CA406010453(c.491)

CaseAddInfo mutations confirmed in parents by Sanger sequencing, Her elder brother was healthy. This patient presented with lethargy and feeding difficulty when she was 5 days old. She was admitted because of unconsciousness at the age of 5 months, and she was diagnosed with MSUD accompanied by metabolic acidosis, liver damage and hypermyotonia. Cerebral MRI showed abnormal signals in the left and right globus pallidus. Clinical improvement as well as improvement in the laboratory test results was observed after treatment. She is now 3 years and 11 months old with severe psychomotor retardation. She is still unable to walk or speak.

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

GroupPresentingHPOs: HP:0008344 (elevated A keto acids in urine)

HPOsFreeText:

GroupNotHPOs:

NotHPOsFreeText:

NumberMales: 4

NumberFemales: 4

CountryOrigin: mainland China

Ethnicity:

Race: Chinese

AgeRange: 2 y 3 mo- 4 y 3 mo (present age)

TotalNumber: 8

VariantCount: 8 (subunits of BKDC: either BCKDHA, BCKDHB, or DBT)

NonVariant: 0

OtherVariant: 0

GroupPreviousTesting: n/a

GroupMethod1: PCR

GroupMethod2: Multiple sequence alignments

GroupGenotypingMethod: genomic DNA extracted from peripheral blood lymphocytes of patients and parents using TIANamp Blood DNA Kit. Exons and flanking intronic regions of BCKDHA, BCKDHB, and DBT were amplified with PCR and sequenced. Results compared with reference sequences in UCSC genome (BCKDHA (NM_000709), BCKDHB (NM_183050), DLD (NM_000108), DBT (NM_001918)), and compared with integrated set of variants from 1000 Genome Project to identify mutations. PolyPhen-2 and Mutationtaster program predicted the impact of missense alterations on protein function. Multiple sequence alignments obtained using BLAST.

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# FIII.4, F, 19 day old diagnosis, Cyprus (Greek Cypriot)

CasePresentingHPOs HP:0010910, HP:0010911, HP:0010913, HP:0001254, HP:0011968, HP:0001290, HP:0001276, HP:0002789, HP:0002353,

HPOcont: Hypervalinemia, Hyperleucinemia, Hyperisoleucinemia, Lethargy, Poor feeding, Hypotonia, Hypertonia, Tachypnea, Abnormal EEG

HPOfreetext: Reduced alloisoleucine and grunting

CasePreviousTesting Tested blood BCAA (AIleu: 0, Ileu: 220 (NR: 26–100), Leu: 3270 (NR: 65–220), Val: 459 (NR: 90–300), urine organic acids (Increased:lactate, 2-keto-glutarate, 2-keto-isocaproic, 2-OH-isovaleric, 2-keto-isovaleric, 2-keto-3-methylvaleric, 4-OH-phenylacetate, 4-OH-phenylpyruvate and BCKD activity (0.03(NR: 0.4–3.4) (Fibroblasts))

CaseMethod1 PCR

CaseMethod2 Direct Sequencing

CaseGenotypingMethod Direct sequencing repeated on proband and father for deletion varaint

Variant (1) NM_000709.3(BCKDHA):c.632C>T (p.Thr211Met) (2) NM_000709.3:c.718delG

ClinVar (1) 93365

CAID (2) register link if I put that in correctly

gnomAD (1) 0.0001163(East Asian), 0.00002043 (Overall)

CaseAddInfo nonconsanguineous

Case# Lo, M, 10mo diagnosis---originally 1985

CasePresentingHPOs HP:0011968, HP:0001531, HP:0000737, HP:0007281, HP:0002013, HP:0001259, HP:0005979, HP:0001943

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod

Variant NM_000709.3:c.1265A>G(p.Lys422Arg), NM_000709.3:c.137dup(p.Ser47IlefsTer4)

CAID CA406015486(miss), CA658820686(dup)

VariantEvidence 3978850: in patient fibroblasts-rate of decarboxylation of alpha-ketoacids: alpha ketoisovalerate[0<0.31], Pyruvate[0.40>.34], alpha-ketoglutarate[0.14>0.10] (Table 1), BCKDH activity[0.0003<0.107] (Table 2), E1 subunit activity[0.6<5.9] (Table 3)--[ProbandvsNormal]

CaseAddInfo 3978850( a positive dinitrophenylhydrazine test and elevated urinary a-ketoisocaproate, a-methyl-P-OH-valerate and a-OH-isoval- erate,

CasePMIDs 3978850, 2914958

Case# GM-649, M

CaseMethod1 Sanger

CaseMethod2 PCR

Variant NM_000709.3:c.284C>A(p.Pro95His)

CAID CA406005099(p.Pro95His)

gnomAD p.Pro95His=0.0003330(African), 0.00002887(Overall)

VariantEvidence total BCKDH activity (4) in fibroblast extracts from the patient (GM649) is < 10% of normal (Table 1) in 2703538

CaseAddInfo examined patient fibroblasts here and in the previous article

CasePMIDs 2703538

RescuePatientCell CL:0000057

GeneAlteration Patient fibroblasts transfected with EBO vector containing either p.Tyr438Asn or WT cDNA.

RescuePhenotype HP:0008344

RescueMethod Measured decarboxylation rate of patient cells with various EBO vectors(empty, WT, or with variant) in comparison to an untransfected normal cell.

RescueEvidence Patient fibroblasts with the variant, empty vector, and vector containing the variant all showed virtually no decarboxylation activity. Vector containing WT restores decarboxylation rate to that of the normal cell (Figure 6). Figure 7 western blot shows that E1b subunit levels are also rescued.

RescueVariants NM_000709.3(BCKDHA):c.1312T>A (p.Tyr438Asn)

Case# GM-649, M--1989 orginally

CaseMethod1 Sanger

CaseMethod2 PCR

Variant NM_000709.3(BCKDHA):c.1312T>A (p.Tyr438Asn) , NM_000709.3:c.887_894del(p.Ile296ArgfsTer3)

CAID 100009(miss), CA658820684(del)

gnomAD miss=0.0001603(European (Non-Finnish)), 0.00007284(Overall)

VariantEvidence total BCKDH activity in fibroblast extracts from the patient (GM649) is < 10% of normal (Table 1) in 2703538

CaseAddInfo in trans

CasePMIDs 2703538, 1943689, 12888983

Case# PA7

Variant NM_000709.3(BCKDHA):c.905A>C (p.Asp302Ala)

ClinVar 93377

VariantEvidence none

Case# PA8

Variant NM_000709.3(BCKDHA):c.940C>T (p.Arg314Ter)

ClinVar 224072

gnomAD 0.000008958(European (Non-Finnish)), 0.000004064(Overall)

Case# PA9

Variant NM_000709.3:c.1270C>T

CAID CA406015510

Case# PA6

Variant NM_000709.3:c.896A>C

CAID CA406013345

VariantEvidence none

Case# PA5

Variant NM_000709.3:c.809C>A

CAID CA406012999

VariantEvidence none

Case# PA4

Variant NM_000709.3(BCKDHA):c.661_664delTACG (p.Tyr221Glnfs)

ClinVar 203638

Case# PA3

Variant NM_000709.3(BCKDHA):c.647-1G>C

ClinVar 431985

gnomAD 0.000009079( European (Non-Finnish)), 0.000004103 (Overall)

CasePMIDs described previously in 19715473

Case# PA2

Variant NM_000709.3:c.409G>A(p.Glu137Lys)

CAID CA406007842

VariantEvidence none

Case# PA1

Variant NM_000709.3(BCKDHA):c.347A>G (p.Asp116Gly)

ClinVar 93354

VariantEvidence none

Case# 16392, Spanish, 4yo report

Variant NM_000709.3(BCKDHA):c.659C>T (p.Ala220Val), NM_000709.3(BCKDHA):c.853G>C (p.Ala285Pro)

ClinVar 93367(c.659), 93375(c.853)

gnomAD c.659=0.00005805(East Asian), 0.000008156(Overall), c.853=0.00007896(European (Non-Finnish)), 0.00003970(Overall)

VariantEvidence 4% of normal BCKD activity in patient fibroblasts

CaseAddInfo in trans

Case# 18804, Spanish, 3yo report

CaseHPOs asymmptomatic

Variant NM_000709.3:c.647C>T, NM_000709.3:c.889C>T

CAID CA9461230(c.647), CA9461294(889)

gnomAD c.647=0.0001332(African), 0.00002463(Overall), c.889=0.00006534(African), 0.00001624(Overall)

VariantEvidence reduced BCKD activity to 30% of normal in patient fibroblasts

CaseAddInfo in trans

Case# 20493, Spanish, 1yo reported

CasePresentingHPOs HP:0008344

CasePreviousTesting categorized into classical and variant phenotypes based on BCKD deficiency assessed by measuring the L-[1-14C] leucine decarboxylation rate by intact cells in absence of BCKD kinase inhibitors (Duran, et al., 1978), plasma amino acid levels, and mode of clinical presentation

CaseMethod1 Direct Sequencing

CaseMethod2 PCR

CaseGenotypingMethod direct sequencing of PCR fragments obtained after amplification of the entire coding sequence of BCKDHA, BCKDHB or DBT genes. sequenced both strands (forward and reverse) of corresponding exons and their intronic flanking sequence for confirmation.

Variant NM_000709.3:c.757G>A, NM_000709.3:c.848G>A, NM_000709.3:c.898G>A

CAID CA9461255(757), [CA406013082(848)&CA406013351(898)]

gnomAD c.757=0.00006681(European(Non-Finnish)), 0.00003236(Overall)

VariantEvidence Patient fibroblasts had <1% of normal BCKD activity

CaseAddInfo parents genotypes confirmed (in trans)

Case# 5888, Spanish, 10mo death

Variant NM_000709.3(BCKDHA):c.940C>T (p.Arg314Ter), NM_000709.3(BCKDHA):c.1037G>A (p.Arg346His)

ClinVar 224072(c.940), 93336(c.1037)

gnomAD c.940=0.000008958(European (Non-Finnish)), 0.000004064(Overall)

CaseAddInfo not confirmed in trans

Case# 16243, Spanish, 5yo reported

CasePresentingHPOs HP:0008344, HP:0001315

CasePreviousTesting categorized into classical and variant phenotypes based on BCKD deficiency assessed by measuring the L-[1-14C] leucine decarboxylation rate by intact cells in absence of BCKD kinase inhibitors (Duran, et al., 1978), plasma amino acid levels, and mode of clinical presentation

CaseMethod1 Direct Sequencing

CaseMethod2 PCR

CaseGenotypingMethod direct sequencing of PCR fragments obtained after amplification of the entire coding sequence of BCKDHA, BCKDHB or DBT genes. sequenced both strands (forward and reverse) of corresponding exons and their intronic flanking sequence for confirmation.

Variant NM_000709.3(BCKDHA):c.117delC (p.Arg40Glyfs), NM_000709.3(BCKDHA):c.117dupC (p.Arg40Glnfs)

ClinVar 93342(del), 166741(dup)

gnomAD del=0.0007494(African), 0.0001696(Overall)

CaseAddInfo in trans

CasePMIDs duplication variant in 8037208

Case# P2, M, 1mo onset, Indian

CasePresentingHPOs HP:0001263, HP:0001250, HP:0001298, HP:0008344

CasePreviousTesting Biochemical testing (Leu + Ile- 1235 Val- 591) on Tandem Mass Spectrometry (TMS) and/or abnormal metabolites (elevated BCKAs, 2-keto isocaproate, 3-hydroxy butyrate, 2-hydroxy isovalerate, 2-hydroxy caproate, 2-keto 3-methyl valerate) on a urinary organic acid profile using Gas Chromatography Mass Spectrometry (GC–MS) was performed to make the diagnosis.

CaseMethod1 PCR

CaseMethod2 Direct

CaseGenotypingMethod Coding regions as well as flanking exon–intron boundaries of genes (BCKDHA- 9 exons, BCKDHB- 10 exons, and DBT- 11 exons) were amplified by PCR. Bidirectional Sequencing on products

Variant NM_000709.3(BCKDHA):c.844G>C (p.Asp282His)

ClinVar 204377

VariantEvidence none

CaseAddInfo consanguineous

Variant NM_000709.3:c.1267C>T(p.Gln423Ter)

CAID CA406015497

Variant NM_000709.3:c.1267C>T(p.Gln423Ter)

CAID CA406015497

Case#: Patient female, 48y, ethnicity not reported

DiseaseAssertion: Stargardt disease (STGD1) with unusual phenotype resembling pattern dystrophy

FamilyInfo: autosomal recessive inheritance; segregation analysis confirms each parent carries one variant (heterozygous). Pedigree shown in Figure 3. Proband is compound heterozygous for ABCA4 variants.

CasePresentingHPOs: HP:0007663, HP:0007754, HP:0030636, HP:0000548

CaseHPOFreeText: mild visual impairment (BCVA 20/25 and 20/20), perifoveal yellow fleck-like lesions, hyperautofluorescent lesions with lipofuscin accumulation, foveal sparing, subretinal material accumulation, phenotype resembling pattern dystrophy, bilateral macular involvement, decreased p50 values on pattern ERG

CaseNotHPOs: HP:0000510 (normal ERG responses except pattern ERG component)

CaseNotHPOFreeText: normal full-field ERG (scotopic and photopic responses), normal electrooculography, preserved outer retina structure, minimal photoreceptor disruption at fovea

Genotyping Method: targeted next-generation sequencing (Illumina NextSeq500) with SeqCap EZ enrichment panel; Sanger sequencing used for confirmation and segregation analysis

PreviouslyPublished: n/a

Variant: ABCA4 NM_000350.2: c.428C>T (p.Pro143Leu); c.3113C>T (p.Ala1038Val)

ClinVar: 99273; 7894

CAID: n/a

SupplementalData: clinical imaging and genetic/segregation data in supplemental data (Figures 1–3, Table 1)

Case#:48-year old man, onset at 13-years old

DiseaseAssertion: STGD1

FamilyInfo: n/a

CasePresentingHPOs: HP:0003621, HP:0025147, HP:0011507, HP:0030329, HP:0030610, HP:0007722, HP:0007703, HP:0007663

CaseHPOFreeText: BCVA was 20/200 bilaterally and refractive error was OD: −1.50/+0.50 × 149° and OS: −1.50/+0.25 × 161°. Hyperautofluorescent transitional zone in each eye more pronounced in right eye. The left eye showed a complete defect of the RPE-Bruch membrane complex with herniation of the outer retina. Maximum horizontal diameter of this RPE-Bruch membrane complex defect was 266um.

CaseNotHPOs: HP:0000510, HP:0000548, HP:0007984

CaseNotHPOFreeText: No defect observed in the RPE and Bruch membrane in right eye. Patient had normal cone and rod responses on ERG

Genotyping Method: ABCR 600 micro-array chip

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.4216C>T (p.His1406Tyr), NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

ClinVar: 99259, 7888

SupplementalData: n/a