PMID: 22863181

Gene: ABCA4

HGNC ID: 34

PMID: 31879568

Gene: ABCA4

Disease: ABCA4-Related Retinopathy

PMID: 26720470

Gene: ABCA4

Disease: retinopathy

This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.

This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.

PMID: 36471740

Gene: ABCA4

HGNC ID: 34

Unable to find this variant in the text or supplementary even though Mastermind says it's in supplemental MOESM1

Case#: Patient 225, Female, age of onset 7 y.o, Poland

DiseaseAssertion: STGD-1

FamilyInfo: no given family information.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.[1622T>C;3113C>T]

ClinVar: 99067, 7894

CAID: n/a

gnomeAD 0.0001266 allele frequency

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

PMID:39967245

Gene: ABCA4

HGNC ID: 34

Case#:39 man

DiseaseAssertion:NA

FamilyInfo:NA

CasePresentingHPOs:Snellen in both eye, visual impairment with night blindnessisual acuity was 20/20Snellen in both eyes, with a minor correction for astig-matism. The anterior segment and intraocular pressurewere within normal limits. On fundus examination, dif-fuse fleck-like lesions were scattered both inside and out-side the arcades, while sharply demarcated areas ofmacular atrophy with foveal sparing, more pronouncedin the left eye, were visible.

CaseHPOFreeText:NA

CaseNotHPOs:NA

CaseNotHPOFreeText:

Genotyping Method:Next-Generation Sequencing (NGS), using theTruSight One Clinical Exome sequencing panel on anIllumina NexSeq500 platform, enriching for 4800 genesincluding ABCA4, CNGB3, ELOVL4, PROM1, and PRPH2

PreviouslyPublished:Under refernces?

Variant:WDR19 variants:the novel deletion at c.1777 + 1 within the donor splicingsite (class 4) and the rare c.1430 G>T variant causing theamino-acid substitution p.(Arg477Leu) (class 3) in the putative protein. Additionally, a heterozygous c.1793A>G(class 3) variant in the CDH23 gene was found, though it was deemed as not contributive to the patient’s clinical phenotype. All reported variants were confirmed throughSanger sequencing

ClinVar:NA

CAID:NA

SupplementalData:NA

PMID: 32843395

Gene: ABCA4

Disease: Stargardt

Case#: Family 12 Proband, male, 43yo at onset, Portuguese

DiseaseAssertion: Stargardt

FamilyInfo: no affected family members in pedigree (Fig. 1)

CasePresentingHPOs: HP:0007663

CaseHPOFreeText: "The criteria for STGD phenotype included bilateral central vision loss and pigmentary macular lesions, normal caliber of retinal vessels, absence of pigmented bone spicules, and compatibility with recessive mode of inheritance." Moderate central retinal changes, decreased mfERG responses exclusively in the central 15 degrees

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: p.Glu1574X; p.Val931Met. Several other polymorphisms also reported. ABCR400 gene chip microarray, DHPLC

ClinVar: 1460063

CAID: CA341283936

SupplementalData: n/a

PMID: 35120629

Gene: ABCA4

Disease: Stargardt disease

PAPER USED TO SCORE PS4

PMID: 12796258

Gene: ABCA4

Disease: autosomal recessive cone-rod dystrophy

PMID: 23949494 HGNC: 34 Gene: ABCA4 DiseaseAssertion: Stargardt Disease

Annotating here since the full text is a PDF.

Case#: Family AR321 proband, US, 6yo at onset

DiseaseAssertion: Stargardt

FamilyInfo: proband and two other siblings are affected

CasePresentingHPOs: 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).

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: (1) evidence of autosomal dominant inheritance; (2) any history of night blindness, loss of peripheral vision, or "retinitis pigmentosa"; (3) cataracta complicata or cells in the vitreous; (4) substantially abnormal electroretinographic or electrooculographic responses; (5) no fluorescein angiography performed or no dark choroid documented; (6) neurological disease (including loss of cognition or seizures); 7) drug exposures (especially to antimalarial and agents known to cause crystalline retinopathies); or (8) any "atypical" maculopathies in which a unique diagnosis of STGD could not be established.

PreviouslyPublished: PMID: 8533764

Variant: c.3113C>T p.A1038V; c.1715G>C p.R572P . Heteroduplex and SSCP analyses were used to screen the 50 exons of ABCA4. Linkage analysis and haplotype analysis were previously performed

ClinVar: 99073

CAID: CA226919

SupplementalData: n/a

PMID: 32845050

Gene: ABCA4

Disease: Stargardt Macular Degeneration

Case#: Bryant Subject JB260, US

DiseaseAssertion: Stargardt

FamilyInfo:

CasePresentingHPOs: "Stargardt disease is a childhood-onset macular degeneration and is most commonly caused by mutations in ABCA4. Characteristic yellow flecks are typically seen under the macula during a fundus exam."

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: WES; previously screened using arrayed primer extension (APEX) multigene panels for the relevant disease and no disease-causing variants had been identified; PCR and Sanger for verification

PreviouslyPublished: n/a

Variant: c.6119G>A p.Arg2040Gln; c.2879del p.Ala960Aspfs*17

CAID: CA232815

SupplementalData:

PMID: 17296903

Gene: ABCA4

Disease: hereditary retinal disease

PMID:39215425

Gene: ABCA4

HGNC ID: 34

case27-year-old male, the brother of case 1

DiseaseAssertion: Table 1 The summary of the clinical assessment of IRD patients’ family in this research fro there down they did a whole pannel on the family

Pedigree one can be fore form the beggginnings of case presention section?

CasePresentingHPOs: Case 2, a 27-year-old male, the brother of case 1 had blurry vision which was not corrected with an eyeglass and inconveniences under bright light starting from 14 years ago. Case 2 also underwent a fundus examination after finding that case 1 was RP. In further examination of those patients and their family members found that case 1 was confirmed as RP and case 2

CaseHPOFreeText:NA

CaseNotHPOs:NA

CaseNotHPOFreeText:NA

Genotyping Method:NA

PreviouslyPublished:NA

Variant:NA

ClinVar:

CAID:NA

SupplementalData:NA

Inheritance pattern Autosomal Recessive

Case#: Patients were identified from the inherited retinal disease (IRD) database at UC San Diego (UCSD).

DiseaseAssertion: RP with macular edema

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: Dx of RP based on "a history of progressive peripheral vision loss or nyctalopia, and ocular examination findings of RP including bone spicule pigmentation, disc pallor and attenuated vessels and genetic confirmation."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Next-generation sequencing (NGS), exome sequencing, and/or targeted Sanger sequencing were the primary genetic testing approaches.

PreviouslyPublished: PMID:10206579 is referenced but it seems a reference to the variant and not the proband

Variant: c.6383A>G (p.His2128Arg); c.3G>T (p.Met1?). phase unknown

ClinVar: 99455

CAID: CA227399

SupplementalData: Variant is found in table S2

another patient with the 541 variant potentially not in cis with ala1038val. G1961E has been classified as pathogenic by the ABCA4 VCEP

another patient with the 541 variant potentially not in cis with ala1038val. F655C is path/LP in clinvar

Case#: Patient 13, 35yo

DiseaseAssertion: STGD

FamilyInfo: Family 8

CasePresentingHPOs:

CaseHPOFreeText: Visual acuity=0.017. OCT ft (μm)=163. MP (dB)=0. Fundus=3(extensive atrophic-appearing RPE changes). ERG=3(abnormal responses involving both rods and cones). mfERG=4(subnormal mfERG in the entire test field (0°–30°) plus pathologic Ganzfeld ERG).

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: PCR of coding regions, intron/exon boundaries, and 5′ and 3′ regions of ABCA4; Standard cycle-sequencing reactions with BigDye Terminator

PreviouslyPublished:

Variant: L541P; R1098C

CAID: CA226911;

SupplementalData: n/a

Case#: 4, 34 year old male

DiseaseAssertion: Stargardt Disease

FamilyInfo: NR

CasePresentingHPOs: NR

CaseHPOFreeText: NR

CaseNotHPOs:

CaseNotHPOFreeText: NR

Genotyping Method: Analyzing the ABCA4 gene

PreviouslyPublished: NR

Variant: 4469G>A

ClinVar: NR

CAID: NR

SupplementalData: NR

PMID: 23949494 HGNC: 34 Gene: ABCA4 DiseaseAssertion: Stargardt Disease

gnomad 0.0001 frequency

I don't understand what this means, but how I interepret it is if an homozygous STGD1 variant appears at a lower frequency that it is less severe.

I don't understand what this means, but how I interepret it is if an homozygous STGD1 variant appears at a lower frequency that it is less severe.

SupplementalData:

SupplementalData:

This variant was found in Patient 074752 in cis with a nonsense (c.6088C>T) and in trans with an intronic variant (c.4253+43G>A); neither of which has been curated yet by the ABCA4 VCEP

Not sure if this variant is c.1988G>A or c.1989G>A.

This variant is listed for Stargardt DNAID#067322 in trans with c.5603A>T p.(Asn1868Ile). No phenotype information provided.

Case#: Female, family #5, Patient #20

DiseaseAssertion: STGD

FamilyInfo: Proband's sister presented with same clinical prognosis. Sister diagnosed with pattern dystrophy and photoaversion at age 57, with difficulty seeing at night. Sister has nuclear sclerotic and cortical cataracts in both eyes.

CasePresentingHPOs: HP:0000662, HP:0000603, HP:0000603, HP:0000493

CaseHPOFreeText: Proband presented with localized blur at age 62, (late onset) in her left eye. BVCA 20/20-3 and 20/20-2 at age 70. Also has macular lesions with stage 2 fundus flecks.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Genotyping performed at Columbia University, sequencing technology used is not disclosed.

PreviouslyPublished: n/a

Variant: p.N18681, IVS36:c.5196+1G>A

ClinVar: M2) 99067, M6) 99351

CAID: N/A

SupplementalData: Fig 1: Pedigree illustrating ABCA4 variants and the associated Stargardt phenotype for 5 families. Proband Labeled w/ white arrow for each family. Fig 2: retinal scan measuring melanin in 4 patients of family 2. Panel shows bull's-eye ring of RPE atropy. Fig 3: Macular SD-OCT line profile from b-scans. Reflectivity plotted against function of retinal depth. Table 1: table shows patients with p.N18681 variant, type of mutation, and pathogenicity class. Table 2: Patients, age on-set and first symptom

Case#: Patient 225, Female, age of onset 7 y.o, Poland

DiseaseAssertion: STGD-1

FamilyInfo: no given family information.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.[1622T>C;3113C>T]

ClinVar: 99067, 7894

CAID: n/a

gnomeAD 0.0001266 allele frequency

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

It is known that patients harbouring p.(Gly1961Glu) or p.(Asn1868Ile) allele share some common clinical characteristics and present with a milder disease phenotype than patients carrying other alleles. A typical feature of patients with p.(Gly1961Glu) is BEM, which is otherwise present in around 20% of all STGD1 patients.

It is known that patients harbouring p.(Gly1961Glu) or p.(Asn1868Ile) allele share some common clinical characteristics and present with a milder disease phenotype than patients carrying other alleles. A typical feature of patients with p.(Gly1961Glu) is BEM, which is otherwise present in around 20% of all STGD1 patients.

ABCA4 variant revealed but not target of research and doesn't seem to amount to anything Variantc.3113C>T p.(Ala1038Val)

ABCA4 variant revealed but not target of research and doesn't seem to amount to anything Variantc.3113C>T p.(Ala1038Val)

PatientID: 10

KindredID: 10

Case: M, 22Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: Positive family history.

CohortInfo: Case series of 14 patients with definite or presumed von Hippel-Lindau disease and retinal vascular proliferation.

CasePresentingHPOs: HP:0002011, HP:0001732, HP:0007850, HP:0012210, HP:0009711 (Morphological central nervous system abnormality, abnormality of the pancreas, retinal vascular proliferation, abnormal renal morphology, retinal capillary hemangioma)

CaseHPOFreeText: At age 12, his left eye had a large juxtapapillary vascular complex extending from the nerve along the superior arcade that was associated with dense fibrovascular tissue. During the next 29 months, this fibrovascular complex enlarged, extending into the center of the macula and causing a decrease in visual acuity to 20/80. The patient underwent pars plana vitrectomy and membrane peel. When the patient was reexamined 7 years after his surgery, there was no recurrence of the lesion. In the patient's contralateral right eye, 3 typical peripheral RCHs were observed during this 7-year follow-up. At age 14 years, he was also noted to have a small patch of superficial retinal vessels in the inferior retinal quadrant near the equator of the right eye that resembled an arteriovenous anastomosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Partial Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName:Null (Partial deletion)

MultipleGeneVariants: N/A

GroupID/ KindredID: 28

PatientID: II

Case: 24Y0M, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: Family 28 consisted of 4 members; one relative (age 27Y) was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs, another (40Y) diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs, and a final relative (62Y), diagnosed with a single HAB.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: Patient was diagnosed with a single cerebellar HAB at 24Y

GroupNotHPOs: HP:0009713; HP:0009711; HP:0005584 (spinal hemangioblastoma, retinal capillary hemangioma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: complete deletion of VHL gene

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Haplotype analysis information in Table 3

MutationType: deletion

CivicName: deletion

MultipleGeneVariants: N/A

GroupID/ KindredID: 22

Case: Age unknown, Sex unknown, Chinese

DiseaseAssertion: hemangioblastoma

FamilyInfo: No family history. Genetic testing of their parents confirmed a de novo mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666; HP:0005584; HP:0009711; HP:0001732 (pheochromocytoma; renal cell carcinoma; retinal capillary hemangioma; pancreatic lesion)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 1 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: unknown (brother)

KindredID: A

Case: M (deceased), Age unknown, Turkish

DiseaseAssertion: assumed VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. This patient and his one brother were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0002666; HP:0005584 (retinal capillary hemangioma; pheochromocytoma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A

GroupID/ KindredID: F28

Case: Sex unknown, 23Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found; unknown of any additional features of index case relatives

CasePresentingHPOs: HP:0000107; HP:0009711; HP:0006880; HP:0006770; HP:0002666 (renal cysts, retinal capillary hemangioma, cerebellar hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma)

CaseHPOFreeText: unilateral pheo, bilateral ccRCC and multiple lesions were found with the patient’s renal cysts. Age of onset is 23Y0M.

CaseNotHPOs: HP:0001737 (pancreatic cysts)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: rearrangement (unspecified)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Southern blot positive

MutationType: rearrangement_region

CivicName: Rearrangement

MultipleGeneVariants: N/A

PatientID: 246

KindredID: 246

Case: Sex Unknown, 26Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0006770 (Hemangioblastoma, Retinal capillary hemangioma, Clear cell renal cell carcinoma)

CaseHPOFreeText: CNS and retinal hemangioblastoma and clear cell renal cell carcinoma.

CaseNotHPOs: HP:0002666; HP:0000107; HP:0001732 (Pheochromocytoma, Renal cyst, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Partial Deletion (0.7kb)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Partial deletion of 0.7kb

MultipleGeneVariants: N/A

PatientID: IX-I

KindredID: 9

Case: M, 68Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history reported.

CasePresentingHPOs: HP:0006748; HP:0002668; HP:0030405; HP:0001737; HP:0006880 (adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, cerebellar hemangioblastoma)

CaseHPOFreeText: Patient presented with adrenal pheochromocytoma, paraganglioma, pancreatic endocrine tumor, pancreatic cyst, and cerebellar hemangioblastoma at age 55Y0M and was diagnosed with VHL type 2A (see table 2).

CaseNotHPOs: HP:0000107; HP:0005584 (renal cyst; renal cell carcinoma)

CaseNotHPOFreeText: Patient negative for renal cell carcinoma and renal cysts.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: complete deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: NULL (deletion)

MultipleGeneVariants: N/A

Performed a meta-analysis of all data published on the rs2710102 CNTNAP2 variant up to 2015, and included Anney et al, 2012 (PMID: 20663923), Toma et al., 2013 (PMID: 23277129), Sampath et al, 2013 (PMID: 24147096), Poot et al., 2014 (PMID: 25337070 ), plus there current cohort.

No significant increase in cases vs controls for CNTNAP2 rs2710102

While this data does help support Contradictory evidence for CNTNAP2 involvement in autism, the lack of reporting of the total number of controls, as well as the number of cases and controls with the SNP prevents me from curating this information within the ClinGen gene curation interface.

Performed a meta-analysis of all data published on the rs7794745 CNTNAP2 variant up to 2015, and included Arking et al., 2008 (PMID:18179894), Li et al 2010 (PMID: 20414140), Anney et al, 2012 (PMID: 20663923), Toma et al., 2013 (PMID: 23277129), Sampath et al, 2013 (PMID: 24147096), plus there current cohort.

No significant increase in cases vs controls for CNTNAP2 rs7794745

Genotyped for the two common SNPs in CNTNAP2 rs2710102 rs7794745

CaseControlLabel: Toma 2013 CNTNAP2 rs7794745 analysis

CaseCohortLabel: 322 Autism patients

ControlCohortLabel: 524 controls

CaseCohortDisease: MONDO:0005260 (Autism)

CaseCohortPhenotype:

CaseCohortPhenotypesFreeText: Authors indicate that all individuals fulfilled DSM-IV criteria for autism or Asperger disorder. Additionally, some cases included where diagnosed with pervasive developmental disorder they may or may not have been characterized based on ADI-R and ADOS-G.

CaseControlNOTPhenotype:

CaseControlNOTPhenotypeFreeText:

CaseDemographics: 269 men, 53 women, Average age= = 17y.o. of Spanish and/or Caucasian descent.

ControlDemographics: controls were noted to be sex-matched and unrelated, however no numbers or ages were indicated. Sample obtained from the Blood and Tissues Bank of Hospital Universitari Vali d'Hebron.

CaseGenotypingMethod: One SNP, rs7794745, was genotyped using PCR-RFLP, from DNA obtained from peripheral blood lymphocytes (salting out method).

ControlGenotypingMethod: One SNP, rs7794745, was genotyped using PCR-RFLP, from DNA obtained from peripheral blood lymphocytes (salting out method).

CasePower: 312/322

ControlPower: 505/524

CaseAddInfo: Other genetic variation is not noted.

ControlAddInfo: Other genetic variation is not noted.

CaseControlStudyType: Single Variant Analysis

CaseControlDetectionMethod: Cases and controls genotyped for single variant

CaseControlStats: p-value= 0.87

CaseControlBias: Cases and controls are ethinically matched, and noted to be sex-matched.

CaseControlComments:

GWAS identified rs2799573 as being associated with five disorders (autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia)

This paper is flagged in Mastermind as containing this variant. The rs12720449 ID is mentioned in the supplemental info under the controls tab, but the specific variant is not listed

Case: Multiple individuals with the same GRIN2B variant (the mean age was 76 ± 11 SD years (Range: 38–101), the mean age at PD onset was 67 ± 12 SD years (Range: 32–94), and 421 patients (63%) were male).

Disease Assertion: Parkinson's disease

FamilyInfo: None

CasePresentingHPOs: HP:0001300

CaseHPOFreeText: Parkinson's disease

CaseNotHPOs: HP:0001250

CasePreviousTesting: Polymorphism genotyping on Sequenom iPLEX ® platform

PreviouslyPublished: No

Variant: rs7301328

ClinVarID: 129205

Case#:Not assigned

DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I

FamilyInfo:No information

CasePresentingHPOs:HP:0100543

CaseHPOFreeText:

CaseNotHPOs:HP:0032557

CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.

CaseEnzymeAssay:No information

CaseUrineGAGs:No information

CaseERT:Yes

CaseBMT:No (exclusion criterion)

Variant1:L238Q

Variant1ClinVarID:265418

Variant1CAID:

Variant2:W402X

Variant2ClinVarID:

Variant2CAID:

AdditionalVariants:N/A

ParentalGenotype:Not specified

PreviouslyPublished

Case#:Not assigned

DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I

FamilyInfo:No information

CasePresentingHPOs:HP:0100543

CaseHPOFreeText:

CaseNotHPOs:HP:0032557

CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.

CaseEnzymeAssay:No information

CaseUrineGAGs:No information

CaseERT:Yes

CaseBMT:No (exclusion criterion)

Variant1:L238Q

Variant1ClinVarID:265418

Variant1CAID:

Variant2:63delC

Variant2ClinVarID:

Variant2CAID:

AdditionalVariants:N/A

ParentalGenotype:Not specified

PreviouslyPublished

Case#:Not assigned

DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I

FamilyInfo:No information

CasePresentingHPOs:HP:0100543

CaseHPOFreeText:

CaseNotHPOs:HP:0032557

CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.

CaseEnzymeAssay:No information

CaseUrineGAGs:No information

CaseERT:Yes

CaseBMT:No (exclusion criterion)

Variant1:65delC

Variant1ClinVarID:

Variant1CAID:

Variant2:H240R

Variant2ClinVarID:947028

Variant2CAID:

AdditionalVariants:N/A

ParentalGenotype:Not specified

PreviouslyPublished

PMID:34884460

GeneName:GRIN1

ClinVarID:209159

ClinVarID:397504

ClinVarID:1076783

ClinVarID:658023

ClinVarID:430264

ClinVarID:487503

ClinVarID:691274

Case:Patient 1, Male, 4 y/o, German and Thai

DiseaseAssertion:FOXG1 syndrome

FamilyInfo: Non-consanguineous parents. De novo. Patient 1 has maternally inherited duplications at 15q21.12(47292250-47309868)x3 and Xp22.31(6451676-8115124)x3 of unknown clinical significance.

ParentalGenotype:Not provided

CasePresentingHPOs:HP:0002197, HP:0005484, HP:0011344, HP:0001252, HP:0020045,HP:0000540, HP:0010808, HP:0002019, HP:0003781, HP:0012741, HP:0002421, HP:0000748, HP:0003763, HP:5200017, HP:0025112, HP:0000957

CaseHPOFreeText: At 19 months, could not sit independently and no speech development. Stereotypic hand and head movements. High pain tolerance. X-ray at age 2 showed broad ribs. Improved head control by age 4.

CaseNotHPO:HP:0410263, HP:0002376

CaseNotHPOFreeText:Dysmorphic features. breathing abnormalities

CasePreviousTesting:No previous testing

PreviouslyPublished:Not previously published

GenotypingMethod:Mate-pair sequencing, Sanger sequencing

Gene:FOXG1

Variant:46,XY,t(9;14)(q22.3;q11.2)dn

HGVS:Not provided

ClinVarID:426096

gnomAD:Not provided

Case:Patient 3, Male, 1 y/o, Brazilian

DiseaseAssertion: FOXG1 syndrome

FamilyInfo: Non-consanguineous parents

ParentalGenotype: No family testing mentioned.

CasePresentingHPOs: HP:0000252, HP:0001252, HP:0000486

CaseHPOFreeText: Developed microcephaly within 1 year. Developmental delay, unable to sit without assistance at 1 year old. Central Nervous System (CNS) MRI showed a volumetric reduction of the cerebral parenchyma, hypomyelination, and hypoplasia of corpus callosum mainly involving the anterior part and prominent lateral ventricles

CaseNotHPO: HP:0030917

CaseNotHPOFreeText: Normal length, weight, HC at birth. No retinal abnormalities.

CasePreviousTesting: Not asserted.

PreviouslyPublished: Not previously published.

GenotypingMethod: Sanger sequencing, mate-pair sequencing

Gene: FOXG1

Variant: 46,XY,t(2;14)(q37;q11.2)dn

HGVS: Not provided.

ClinVarID:426094

gnomAD:Not provided

Case:Patient 2, Female, 5 y/o, Brazilian

DiseaseAssertion:quadriplegic cerebral palsy with axial hypotonia and distal spasticity

FamilyInfo: Non-consanguineous parents. Parents had normal karyotypes. Older sister was clinically normal.

ParentalGenotype: Normal karyotypes for both parents.

CasePresentingHPOs: HP:0002098, HP:0010959, HP:0008755, HP:0002090, HP:0032661, HP:0001274, HP:0011344, HP:0001249, HP:0001344, HP:0000748, HP:0034435, HP:0000486, HP:0000483, HP:0200136

CaseHPOFreeText: Dilated superficial blood vessels seen on brain MRI.

CaseNotHPO:N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Not asserted

PreviouslyPublished: Not previously published

GenotypingMethod:Mate-pair sequencing, Sanger sequencing, chromosome analysis

Gene: FOXG1

Variant: 46,XX,t(4;14)(q27;q13)dn

HGVS: Not provided

ClinVarID: 426095

gnomAD: Not provided

EXTL3, HGNC:3518

Neuro-immuno-skeletal Dysplasia Syndrome

OMIM: 617425

Selection A- Gene with same function implicated in disease

ExperimentName: Moye et al. 2018

GOterm: GO:0051179 (localization)

FunctionalEvidence: It was discovered that without ARL2BP, the photoreceptor OS does not develop normally or have correct DMT formation, axoneme extension, and disk alignment.

HGNC: HGNC:10295 (RPGR), HGNC:10263 (RP1), HGNC:6816 (MAK)

GeneEvidence: ARL2BP, RPGR, RP1 and MAK are all localized within the ciliary basal body and rootlet.

SharedGeneImplication: RPGR was classified as having a "definitive" relationship with RP 15 by the Retina GCEP. Refer to the curation for further details. RP1 was classified as having a "definitive" relationship with RP1 by the Retina GCEP. Refer to the curation for further details. MAK was classified as having a "definitive" relationship with MAK-related retinopathy by the Retina GCEP. Refer to the curation for further details.

Selection A- Gene with same function implicated in disease

ExperimentName: Aprea et al. 2023

GOterm: GO:0001535 (radial spoke head)

FunctionalEvidence: Taken together, our results indicate that the ruler proteins CCDC39 and CCDC40, the radial spoke head proteins RSPH1 and RSPH9 as well as the central pair associated apparatus proteins SPEF2 and HYDIN have a similar functional role in motile cilia and sperm flagella, as hypothesized in Figure 1.

HGNC: HGNC:12371

GeneEvidence: PMID: 24518672 documents how RSPH1 and RSPH9, which encode homologs of components of the ‘head’ structure of ciliary radial spoke complexes identified in Chlamydomonas, cause clinical phenotypes that appear to be indistinguishable except at the gene level. They both also have a relationship with PCD.

SharedGeneImplication: The gene-disease relationship between RSPH1 and PCD has been established and published in multiple papers. See Motile Ciliopathy GCEP curations of RSPH1 for more information.

Selection A- Gene with same function implicated in disease

ExperimentName: Wilken et al. 2024

GOterm: GO:0036156 (inner dynein arm).

FunctionalEvidence: Both DNAH6 and DNAH1 are both IDA components and localized to the same region.

HGNC: HGNC:2940 (DNAH1).

GeneEvidence: Both DNAH6 and DNAH1 are both IDA components and localized to the same region.

SharedGeneImplication: DNAH1 was classified as having a "limited" relationship with PCD 37 and a “defintive” relationship with spermatogenic failure 18 by the Motile Ciliopathy GCEP. Refer to the curation for further details.

Selection A - Gene with same function implicated in disease

ExperimentName: Shapiro 2007 et al.

GOterm: GO:0051179 (localization)

FunctionalEvidence: RSPH3 and RSPH9 are both localized to radial spoke heads and have a similar phenotype profile.

HGNC: HGNC:21057.

GeneEvidence: PMID: 20301301 documents how RSPH9 and RSPH3, which encode homologs of components of the ‘head’ structure of ciliary radial spoke complexes identified in Chlamydomonas, cause clinical phenotypes that appear to be indistinguishable except at the gene level. They both also have a relationship with PCD.

SharedGeneImplication: The gene-disease relationship between RSPH9 and PCD has been established and published in multiple papers. See Motile Ciliopathy GCEP curations of RSPH9 for more information.

PMID: 8541851

GeneName: GARS1

HGNC: HGNC:4162

Disease: CMT2D

MonDO ID:

Inheritance: Autosomal Dominant

The source focuses on the clinical, immunological, and molecular features of Severe Combined Immune Deficiency (SCID) based on a multi-institutional experience from India. The specific gene studied in this case is IL2RG. The HGNCID for this gene is HGNC:6016. The sources provide information about a 6-month-old male patient with SCID. The patient's family history suggests a possible X-linked inheritance pattern. The sources note the absence of autoimmunity and malignancies in the patient. Information regarding the patient's variant, previous testing, and publication history is not available in the sources.

Case#:Patient 52, female, 3 years old

DiseaseAssertion:Neonatal/Infantile Epileptic Encephalopathy (NIEE)

FamilyInfo:DeNovo. The family is Chinese

ParentalGenotype:The authors only conducted singleton and not trio-based exome sequencing so the parents' exomes were not sequenced.

CasePresentingHPOs:HP:0011344, HP:0002069, HP:0007359, HP:0011097, HP:0100704, HP:0001332, HP:0002072, HP:0012171.

CaseHPOFreeText:Patient 52 presents with severe global developmental delay and epilepsy.

Patient 52 has generalized tonic/clonic/tonic-clonic seizures, focal seizures and spasms. Patient 52's seizure onset occurred at 3 months old.

Patient 52 has cortical visual impairment (CVI), dystonia, chorea, and hand-washing sterotypies.

Patient History

@ 3 months - Patient 52 had generalized tonic/clonic/tonic-clonic seizures.

Patient 52 was on 3 antiepileptic drugs at most recent follow-up visit which reduced seizure frequency by >50%.

CaseNotHPOs:Not provided

CaseNotHPOFreeText:Not provided

CasePreviousTesting:The authors selected a cohort of 31 patients with seizure cryptogenic Neonatal/Infantile Epileptic Encephalopathy (NIEE) and seizure onset before 24 months.

Exclusion criteria included: (1) Patients with a definite history of brain insult, malformation of cortical development, neurocutaneous and syndromal disorders, and confirmed or highly suspected neurometabolic disorders based on clinical and biochemical markers. (2) Patients with Dravet syndrome and epilepsy at infancy with migrating focal seizure were also excluded because the majority of variants are detected in the SCN1A (>85%) and KCNT1 (approximately 50%) genes.

Formal neuropsychological testing or best clinical assessment was used to classify patient development or intelligence.

PreviouslyPublished:Not previously published

GenotypingMethod:Whole Exome Sequencing (WES) variant results were filtered in a panel of 430 epilepsy-associated genes. After selection of variants from the 430-gene panel, the synonymous variants, variants with variant frequency <10%, and variants with allele frequency >1% were removed.

Gene:CDKL5

Variant:NM_003159.2 c. 1849delC (p. Arg617Valfs*4)

The authors state that the variant is a heterozygous frameshift deletion.

The authors state that this is a novel variant and is pathogenic.

HGVS:Not provided

ClinVarID:Not found

CAID:Not found.

gnomAD:Not found

MultipleGeneVariants:Not provided

Case#:Patient 7, male, 5 years old

DiseaseAssertion:Neonatal/Infantile Epileptic Encephalopathy (NIEE)

FamilyInfo:The family is French/Chinese

ParentalGenotype:The variant was inherited from Patient 7's asymptomatic mother.

CasePresentingHPOs:HP:0010864, HP:0012758, HP:0000729, HP:0007359, HP:0002069, HP:0032794, HP:0001250, HP:0000252.

CaseHPOFreeText:Patient 7 presents with severe intellectual disability, developmental slowdown, and various seizure types. Patient 7 has Autistic Spectrum Disorder (ASD) and microcephaly.

Patient History

@ 12 months - Patient 7 presented with seizures.

Patient 7 developed additional seizure types including: focal seizures with/without generalization, generalized tonic/clonic/tonic-clonic seizures, myoclonic seizures, and hypomotor seizures.

Patient 7 was on two antiepileptic drugs at most recent followup visit which reduced seizure frequency by >50%.

CaseNotHPOs:Not provided

CaseNotHPOFreeText:Not provided

CasePreviousTesting:The authors selected a cohort of 31 patients with seizure cryptogenic Neonatal/Infantile Epileptic Encephalopathy (NIEE) and seizure onset before 24 months.

Exclusion criteria included: (1) Patients with a definite history of brain insult, malformation of cortical development, neurocutaneous and syndromal disorders, and confirmed or highly suspected neurometabolic disorders based on clinical and biochemical markers. (2) Patients with Dravet syndrome and epilepsy at infancy with migrating focal seizure were also excluded because the majority of variants are detected in the SCN1A (>85%) and KCNT1 (approximately 50%) genes.

Formal neuropsychological testing or best clinical assessment was used to classify patient development or intelligence.

PreviouslyPublished:Not previously published

GenotypingMethod:Whole Exome Sequencing (WES) variant results were filtered in a panel of 430 epilepsy-associated genes. After selection of variants from the 430-gene panel, the synonymous variants, variants with variant frequency <10%, and variants with allele frequency >1% were removed.

Gene:SLC9A6

Variant:Hemizygous splice site NM_001042537.1 c. 794-2A>G was assessed by the authors to be likely pathogenic.

HGVS:Not provided

ClinVarID:Not found

CAID:CA414750320

gnomAD:Not found

MultipleGeneVariants:Not provided

Case: Patient 1, female, 2 years old

DiseaseAssertion: Rett Syndrome

FamilyInfo: DeNovo. Patient 1 was the second child of a nonconsanguineous Chinese couple. Patient 1 was born at full term with a birth weight of 3.83 kg.

ParentalGenotype(s):Not provided

CasePresentingHPOs:HP:0011344, HP:0001250, HP:0001252, HP:0000252, HP:0000748, HP:0003763, HP:0005469, HP:0000486, HP:0012171.

CaseHPOFreeRext:Patient 1 presents with severe global developmental delay, epilepsy, and hypotonia. The Patient History contains all of Patient 1's phenotypes along with the progression of her condition.

Patient History

@ 3 months - Patient 1 had microcephaly (head circumference was less than 3rd percentile with a body weight and body height at 75th percentile). Patient 1 had hypotonia.

Patient 1 was given a metabolic screening, a muscle enzyme, and a brain tomography with normal results.

@ 6 months - Patient 1 had microcephaly, flat occiput, right divergent squint, and hypotonia. No syndromal diagnosis could be ascertained at that time.

@ 2 years - Patient 1 had epilepsy.

Patient 1 had severe global development delay.

Patient 1 was given an EEG which showed nonspecific background slowing, but no epileptiform abnormalities. Patient 1 was also given a brain MRI which showed mild thinning of corpus callosum without major structural defect. Patient 1 had no developmental regression but she developed stereotypical hand movements, bruxism, and occasional outburst of laughter.

Based on these phenotypes, Angelman/Rett Syndrome was suspected.

CaseNOTHPOs: HP:0002353.

CaseNOTHPOFreeText: Patient 1 was given an EEG which detected no epileptic abnormalites.

CasePreviousTesting: Genetic investigations (including methylation-specific multiplex ligation-dependent probe amplification (MS-MLLPA)) was conducted for Angelman Syndrome, UBE3A gene, MECP gene, and array CGH. These studies were negative. A FOXG1 related disease was suspected

PreviouslyPublished:Not previously published

GenotypingMethod: A FOXG1 gene test showed a de novo frameshift pathogenic mutation FOXG1 {NM_005249.3} c. 396_397ins26; FOXG1{NP_005240.3} :(p. Gly133TRPfs*68) which confirmed the diagnosis of a FOXG1 related congenital variant of Rett Syndrome.

Gene:FOXG1

Variant: (NM_005249.3) c. 396_397ins26 (p. Gly133Trpfs*68)

HGVS:Not provided

ClinVarID:Not found

CAID:Not found

gnomAD:Not found

Case:Patient 2, female, Chinese

DiseaseAssertion:Global delay

FamilyInfo:Patient 2 was the first child of nonconsanguineous Chinese couple born at 38-week gestation. The mother had gestational diabetes mellitus that required insulin therapy.

ParentalGenotype:Not provided

CasePresentingHPOs:HP:0000365, HP:0020049, HP:0000252, HP:0001263, HP:0012171, HP:0000154, HP:0000708, HP:0003763, HP:0002376, HP:0012433.

CaseHPOFreeText:

Patient History

@ birth - Patient 2 presented with mild grade bilateral hearing impairment and left divergent squint diagnosed at birth.

@ Follow-up visit - Patient 2 had microbrachycephaly and global developmental delay. Brain MRI, metabolic screening and array CGH were normal.

@ 1 year - Patient 2 had stereotypical handwashing movement.

There was no clinical or electrical seizure.

Patient 2 has craniofacial features like microbrachycephaly, wide mouth, divergent squint, and behavioral phenotype.

@ 1.5 years - Patient 2 had bruxism and developmental regression. Patient 2 also had loss of some motor and social skills.

CaseNotHPOs:HP:0001250

CaseNotHPOFreeText:Patient 2 has no seizures.

CasePreviousTesting:Not provided

PreviouslyPublished:Not previously published

GenotypingMethod:Not provided

Gene:MECP2 (MN_004992.3) (NP_004983.1)

Variant:c. 808C>T (p. Arg270*)

HGVS:Not provided

ClinVarID:Not found

CAID:CA172577

gnomAD:Not found

MultipleGeneVariants:NA

Case:Patient 1, female, 11 years old

DiseaseAssertion:Rett Syndrome - Atypical Variant

FamilyInfo:De Novo. Patient 1's parents were healthy. When Patient 1 was clinically examined, the head circumferences of her mother and father were 53 cm (P25) and 59 cm (P90), respectively. The parents had normal weight.

ParentalGenotype:Both parents were sequenced for Patient 1's mutation, and the deletion was not detected.

CasePresentingHPOs:HP:0001249, HP:0001513, HP:0001626, HP:0000256, HP:0010465, HP:0012758, HP:0000750, HP:0012433, HP:0002591, HP:0001250, HP:0020174, HP:0000316, HP:0000336, HP:0000431, HP:0000377, HP:0000470, HP:0001156, HP:0001500.

CaseHPOFreeText:

Patient history

@ birth - Patient 1 was born at 38 weeks of gestation after an uncomplicated pregnancy. Her weight was 3,390 g (P69), height 51 cm (P60), and her head circumference was 36 cm (P90).

@ 6 months - Patient 1 experienced developmental delay.

@ 9 months - Patient 1 sat without support.

@ 2 years - Patient 1 began to walk.

@ later on - Patient 1 presented with speech delay and behavioral disturbances. The behavioral disturbances were reduced by the drug risperidone.

@ early childhood - Patient 1 has been obese and appeared to display hyperphagia.

@ 8 years - Patient 1 developed precocious puberty.

@ 10 years - Patient 1 had her first epileptic seizure. Treatment with lamotrigine prevented further seizures. The seizures later became refractory to this treatment.

@ 10 years - Patient 1 presented with a height of 160 cm (P>97) and a head circumference of 59 cm (P>97). She had hypertelorism and prominent eyebrows. Her nasal bridge was broad and auricles were fleshy. In addition, Patient 1's neck was short and the fingers were short and wide.

Patient 1 has an intellectual disability, metabolic syndrome, and macrocephaly.

CaseNotHPOs:HP:0002540.

CaseNotHPOFreeText:Patient 1 sat without support at 9 months old. She walked at 2 years.

CasePreviousTesting:Patient 1 was given a conventional cytogenetic analysis. The chromosomal analyses (46,XX) and array CGH results (BlueGnome CytoChip ISCA 4×180K v1.0; Agilent Human Genome CGH Microarray 180K) were normal. Patient 1 was also given a methylation-specific MLPA to exclude a Temple syndrome, which is also characterized by weight gain and precocious puberty. In addition, Prader-Willi syndrome was ruled out by methylation testing. This syndrome is another imprinting disease causing obesity and intellectual disability.

PreviouslyPublished:Not previously published

GenotypingMethod:Whole-exome sequencing analysis of the entire exome was conducted for Patient 1. Whole-genome sequencing showed heterozygosity in Patient 1, which was confirmed by Sanger sequencing. Macrocephalic syndrome genes including PTEN, NSD1, NFIX, SETBP1, RAI1, and PHF6 were analyzed, and no additional variants of interest (pathogenic, likely pathogenic, or variants of uncertain significance) were observed.

Gene:MECP2

Variant:c. 1162_1172del (p. Pro388*), heterozygosity, frameshift.

HGVS:NM_004992.3

ClinVarID:Not found

CAID:CA1139667881

gnomAD:Not found

MultipleGeneVariants:Not provided

Case:Patient 2, female, 2.5 years old

DiseaseAssertion:CDKL5 Disorder

FamilyInfo:De Novo with an unremarkable family history.

ParentalGenotype:Not provided

CasePresentingHPOs:HP:0032792, HP:0007359, HP:0011154, HP:0002194, HP:0010862, HP:0000750, HP:0012434, HP:0000710, HP:0100023, HP:0000252, HP:0009062, HP:0010845, HP:0020174, HP:0010841.

CaseHPOFreeText:

Patient history

@ 2 months to 2.5 years - Patient 2 experienced tonic and focal seizures with autonomic symptoms.

@ 2 years - Patient 2 was diagnosed with CDKL5 disorder.

Patient 2 had severe delayed gross motor development, severe delayed fine motor development, severe delayed language development and delayed social development. Patient 2 had hyperoral and hand flapping stereotypies. She also had microcephaly (< 2 SD) and axial hypotonia.

Patient 2 was given a brain EEG which detected Delta slowing of the background followed by generalized attenuation during seizures and multifocal interictal epileptiform abnormalities.

@ 2.5 years - Patient 2 experienced seizures in clusters.

Treatments

Antiepleptic treatments included:Phenobarbital, Topirimate, Clobazam, Valproate, Keppra, Vitamin B6, Phenytoin, Lamotrigine, Nitrazepam, Oxcarbazepine, Mirtazipine, KCI, Levetiracetam, ant ketogenic diet.

Patient 2 was also treated with Carnitine. Patient 2's seizures seem to have changed in type over time but continued.

Other testing

Tests were conducted on Patient 2 to obtain data in the following areas: NBS, lactate, lipoprotein profile, plasma and urine amino acids, urine organic acids, acylcarnitine profile, total and free serum carnitine levels, plasma ammonia, total plasma homocysteine, serum CK, liver enzymes, urine alpha-AASA, creatine, biotinidase, VLCFA, Batten disease screen, CSF analysis (amino acids, lactate, glucose, protein, cell count, neurotransmitters), MRI-brain with spectroscopy, and karyotype.

CaseNotHPOs:Not provided

CaseNotHPOFreeText:Not provided

CasePreviousTesting:Patient 2 was given a gene sequence test for the genes SCNIA and MECP2. No gene mutation was found for these two genes.

PreviouslyPublished:Not previously published

GenotypingMethod:Patient 2 was given a CDKL5 gene sequence test. The test detected a mutation in the CDKL5 gene.

Gene:CDKL5

Variant:c. 2480_2486dupCAGATCT. frameshift

The authors state that CDKL5 gene sequencing detected a de novo duplication in exon 17, c. 2480_2486dupCAGATCT, resulting in a frameshift (Boston University School of Medicine, Center for Human Genetics, Boston, MA). This is a novel change that has not been reported before in ExAC. Only pathogenic point mutations in exon 17 have previously been reported. In a patient with a previously reported frameshift mutation in exon 18, a truncated CDKL5 transcript was detected. A truncated protein would lack the C-terminus and would not localize correctly in the cell, as demonstrated in vitro. Accordingly, any reading frame altering mutations proximal to exon 18 are null-variants. Therefore, this mutation is classified as pathogenic according to ACMG criteria.

HGVS:Not provided

ClinVarID:547188

NM_001323289.2 (CDKL5): c. 2480_2486dup (p. Gln830fs)

Allele ID: 538303

CAID:Not found

gnomAD:Not found

MultipleGeneVariants:Not provided

Case: Patient, Male, 4 months old <br /> DiseaseAssertion: SCID <br /> FamilyInfo: third child of non-consanguineous parents; has twin brother that is asymptomatic with no immune defects; no family history of primary immunodeficiencies <br /> CasePresentingHPOs: HP:0002014, HP:0020099, HP:0030148 <br /> CaseHPOFreeText: diarrhea, norovirus infection, heart murmur <br /> CaseNotHPOs: increased CRP <br /> CasePreviousTesting: N/A <br /> Gene: IL2RG <br /> Variant: NM_000206(IL2RG): <br /> ClinVar: <br /> CAID: <br /> gnomAD: <br /> SupplementalData:

PMID: 26986123 Gene: von Willebrand factor HGNCID: 12726 Note: reported for group analysis with no associated probands/patient

PMID: 21362127 Gene: von Willebrand factor HGNCID: 12726

PMID: 23311757 Gene: von Willebrand factor HGNCID: 12726

PMID: 18421900

Gene: SGCA

HGNCID: 10805

PMID:36685585

Gene: Adenosine Deaminase (ADA)

HGNCID: 186

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#: 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#: Hwang Case 4, male, 52yo at report, 45yo at onset

DiseaseAssertion: Stargardt

FamilyInfo: Family history was not significant for ocular disease.

CasePresentingHPOs: HP:0000545

CaseHPOFreeText: declining vision OS, BCVA was 20/100 OD and 20/70 OS. Spherical refractive error measured −3.00 OD and −3.25 OS. Posterior segment examination was significant for central atrophy and classic peripheral pisciform flecks sparing the peripapillary regions OU (Figure 4, A and B). Autofluorescence imaging demonstrated inner atrophic flecks and outer hyperautofluorescent flecks. Moderate peripapillary hypoautofluorescence, but not atrophy, was present (Figure 4, C and D).

CaseNotHPOs: HP:0500087

CaseNotHPOFreeText:

GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.

PreviouslyPublished: n/a

Variant: P1380L and S1696N

ClinVar: 7904

CAID: CA129033

SupplementalData: n/a

Case#: Hwang Case 1, US, male, 55yo at report, 18yo at onset

DiseaseAssertion: Stargardt disease

FamilyInfo: Family history was not significant for ocular disease

CasePresentingHPOs: HP:0007663, HP:0500087, HP:0000603, HP:0000512

CaseHPOFreeText: BCVA of 20/350 OD and 20/200 OS. Spherical refractive error measured −3.5 OD and −2.0 OS. Posterior segment examination and autofluorescence imaging were significant for sharply demarcated central and peripapillary zones of atrophy and the absence of fleck lesions (Figure 1, A–D). Humphrey visual fields demonstrated bilateral central scotomas with eccentric fixation at the inferior border.

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.

PreviouslyPublished: n/a

Variant: P1380L and IVS40 + 5G>A

ClinVar: 7904

CAID: CA129033

SupplementalData: n/a

Case#: Case 3, 39yo

DiseaseAssertion: BEM, RCD

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: a ring of increased AF surrounding decreased foveal AF, visual acuity= 6/6, 6/6

CaseNotHPOs:

CaseNotHPOFreeText: acquired toxic aetiology

GenotypingMethod: The entire coding sequence (50 exons), including exon–intron boundaries, of the ABCA4 gene of each patient was screened using single‐stranded conformational polymorphism (SSCP) analysis and direct sequencing.

PreviouslyPublished: n/a

Variant: Val552Ile heterozygous

CAID: CA239745

SupplementalData: n/a

PMID: 32843395

Gene: ABCA4

Disease: Stargardt

PMID: 35120629

Gene: ABCA4

Disease: Stargardt disease

PAPER USED TO SCORE PS4

PMID: 12796258

Gene: ABCA4

Disease: autosomal recessive cone-rod dystrophy

PMID: 32845050

Gene: ABCA4

Disease: Stargardt Macular Degeneration

PMID: 17296903

Gene: ABCA4

Disease: hereditary retinal disease

PMID:39215425

Gene: ABCA4

HGNC ID: 34

case27-year-old male, the brother of case 1

DiseaseAssertion: Table 1 The summary of the clinical assessment of IRD patients’ family in this research fro there down they did a whole pannel on the family

Pedigree one can be fore form the beggginnings of case presention section?

CasePresentingHPOs: Case 2, a 27-year-old male, the brother of case 1 had blurry vision which was not corrected with an eyeglass and inconveniences under bright light starting from 14 years ago. Case 2 also underwent a fundus examination after finding that case 1 was RP. In further examination of those patients and their family members found that case 1 was confirmed as RP and case 2

CaseHPOFreeText:NA

CaseNotHPOs:NA

CaseNotHPOFreeText:NA

Genotyping Method:NA

PreviouslyPublished:NA

Variant:NA

ClinVar:

CAID:NA

SupplementalData:NA

Inheritance pattern Autosomal Recessive

PMID:39967245

Gene: ABCA4

HGNC ID: 34

Case#:39 man

DiseaseAssertion:NA

FamilyInfo:NA

CasePresentingHPOs:Snellen in both eye, visual impairment with night blindnessisual acuity was 20/20Snellen in both eyes, with a minor correction for astig-matism. The anterior segment and intraocular pressurewere within normal limits. On fundus examination, dif-fuse fleck-like lesions were scattered both inside and out-side the arcades, while sharply demarcated areas ofmacular atrophy with foveal sparing, more pronouncedin the left eye, were visible.

CaseHPOFreeText:NA

CaseNotHPOs:NA

CaseNotHPOFreeText:

Genotyping Method:Next-Generation Sequencing (NGS), using theTruSight One Clinical Exome sequencing panel on anIllumina NexSeq500 platform, enriching for 4800 genesincluding ABCA4, CNGB3, ELOVL4, PROM1, and PRPH2

PreviouslyPublished:Under refernces?

Variant:WDR19 variants:the novel deletion at c.1777 + 1 within the donor splicingsite (class 4) and the rare c.1430 G>T variant causing theamino-acid substitution p.(Arg477Leu) (class 3) in the putative protein. Additionally, a heterozygous c.1793A>G(class 3) variant in the CDH23 gene was found, though it was deemed as not contributive to the patient’s clinical phenotype. All reported variants were confirmed throughSanger sequencing

ClinVar:NA

CAID:NA

SupplementalData:NA