Case#: proband, F, Age of Report: 11 y.o., Ethnicity: European ancestry.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0000662 (Nyctalopia), HP:0007737 (Bone spicule pigmentation of the retina), HP:0001250 (Seizure)

CaseHPOFreeText: The proband of European ancestry was referred at the age of 11 yr for a recent diagnosis of retinitis pigmentosa (II:3). She reported a several-year history of nyctalopia. At her initial visit, her VA was 20/20 in both eyes [oculus uterque (OU)]. GVF testing was unreliable at this visit, and results are not shown. ERG testing showed barely recordable responses in both eyes. Fundus examination showed early optic nerve pallor and surface gliosis, vascular attenuation, depressed foveal reflex, and fine retinal pigment epithelium (RPE) granularity. Peripheral retina showed a few areas of bone spicule-like pigmentation and a coarse RPE granularity. When re-evaluated at the age of 17 yr, her vision was reduced to 20/30 OU and visual fields were constricted (Fig. 1D, i and ii). Testing at the age of 24 yr demonstrated further reduction of VA to 20/50 right eye [oculus dexter (OD)] and 20/30 left eye [oculus sinister (OS)] with greatly constricted visual field (Fig. 1D, iii and iv). Fundus examination showed heavy bone spicule pigmentation in the equatorial region OU (Fig. 1C). Medical history was significant for a history of petit mal seizures beginning at the age of 8 yr, which were controlled with medication.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WGS.

Variant: Variant 1: NM_021831.6:c.841C>T (p.Arg281Cys). Variant 2: NM_021831.6:c.1459C>T (p.Arg487Ter).

ClinVar: Variant 1: 1036269. Variant 2: N/A.

CAID: Variant 1: CA1567739. Variant 2: CA1567876.

gnomAD: Variant 1: Frequency: 0. Link: https://gnomad.broadinstitute.org/variant/chr2-27055186-C-T?dataset=gnomad_r4. Variant 2: Frequency: 0.000003590. Link: https://gnomad.broadinstitute.org/variant/chr2-27056716-C-T?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband's brother (II:2) was initially evaluated at the age of 15 yr. He also reported a history of impaired night vision. His visual acuities were 20/15 OD and 20/20 OS. GVF testing showed full fields with the V4e isopter, but constriction to 30 degrees centrally with the I4e isopter. The scotopic ERG was barely recordable and photopic responses showed 50% reduction of amplitude and normal waveform. Fundus examination showed slight optic disc pallor and gliosis. Vessels were attenuated. The foveal reflex was intact in both eye, and the RPE was intact in both maculae. The peripheral retina showed fine bone spicule pigmentation and fine granularity to the RPE. Aside from the history of seizures as a child in the proband, these patients reported no other ocular or nonocular abnormalities and had a diagnosis of recessive retinitis pigmentosa.

CasePMIDs: N/A.

Case#: Patient F1-IV:3, M, Age of Report: 32 y.o., Ethnicity: N/A.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0011505 (Cystoid macular edema/cystoid maculopathy), HP:0007663 (Reduced visual acuity), HP:0500081 (Pseudophakia),

CaseHPOFreeText: Patient F1-IV:3 was referred to the Rotterdam Eye Hospital at age 32 with end-stage RP complicated by cystoid maculopathy. Visual acuity at presentation was hand movements in the right and light perception in the left eye. He was pseudophakic (cataract extraction performed at age 29), and retrospective data on visual acuity and visual fields were not available. The cystoid maculopathy was responsive to subcutaneous octreotide, but visual acuity did not improve. Through the years the cysts disappeared and atrophy of the macular region developed (Figs. 2A, 2B). He was also suffering from Behcet's disease, but did not have a history of recurring uveitis.

Stratus OCT of the right eye in F1-IV:3 (B) at age 34 showed large cysts at the macula comprising several retinal layers with cysts in the inner nuclear layer of the paramacular region (upper). In the lower scan (at 39 years), complete atrophy of retinal layers at the fovea can be observed.

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients developed posterior subcapsular cataract.

CaseNotHPOs: N/A.

CaseNotHPOFreeText:N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.1775G>A (p.Trp592Ter).

ClinVar: N/A.

CAID: CA1567964.

gnomAD: Frequency: 2.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27058503-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: His older sister (F1-IV:2) was examined only once, at the age of 43. She also presented with end-stage RP. She was pseudophakic, and visual acuity was hand movement and counting fingers. Her fundus examination revealed optic disc pallor, attenuated vessels, macular atrophy, midperipheral and peripheral RPE atrophy, and heavy bone spicule pigmentation but no cystoid macular edema (not shown). The DNA sample of this patient was not available.

CasePMIDs: N/A.

Case#: F3-II.1, F, Age of Report: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0032037 (Mildly reduced visual acuity),

CaseHPOFreeText: Very limited photoreceptor preservation for F3-II.1

Patients from families 2 and 3 initially developed nyctalopia, with a range of onset from 9 to 30 years before subsequent development of peripheral visual field loss. At last review (age range, 24–45 years), there was mild visual acuity loss with best-corrected visual acuity mean 0.34 logMAR (range, 0.30–0.48). There were fundus abnormalities consistent with RP including attenuated vessels, macular and midperipheral RPE mottling/atrophy, and peripheral intraretinal pigment migration, most prominent in the proband of family 3 (Fig. 2I). A partial ring of reduced autofluorescence in F3-II:1 (Figs. 2D, 2G, 2J).

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients developed posterior subcapsular cataract.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WGS.

Variant: Variant 1: NM_021831.6:c.752T>G (p.Val251Gly). Variant 2: NM_021831.6:c.1504dup (p.Ala502GlyfsTer15).

ClinVar: Variant 1: N/A. Variant 2: N/A.

CAID: Variant 1: CA346174950. Variant 2: CA2586968850.

gnomAD: Variant 1: Frequency: 2.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27053509-C-G?dataset=gnomad_r4. Variant 2: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: F2-II:1, F, Age: N/A, Ethnicity: N/A.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0032037 (Mildly reduced visual acuity), HP:0001328 (Specific learning disability/earning difficulties)

CaseHPOFreeText: FAF imaging in three patients demonstrated a ring of increased autofluorescence parafoveally in F2-II:1

OCT imaging also demonstrated loss of outer retina with partial preservation of the inner segment ellipsoid band in patient F2-II:1

Patients from families 2 and 3 initially developed nyctalopia, with a range of onset from 9 to 30 years before subsequent development of peripheral visual field loss. At last review (age range, 24–45 years), there was mild visual acuity loss with best-corrected visual acuity mean 0.34 logMAR (range, 0.30–0.48). All patients developed posterior subcapsular cataract. Patient F2-II:1 had learning difficulties but no other symptoms suggestive of syndromic disease. There were fundus abnormalities consistent with RP including attenuated vessels, macular and midperipheral RPE mottling/atrophy, and peripheral intraretinal pigment migration, most prominent in the proband of family 3 (Fig. 2I). Fundus autofluorescence imaging demonstrated a ring of increased autofluorescence parafoveally in F2-II:1

On OCT, there was outer retinal atrophy with variable preservation of photoreceptors most apparent in F2-II:1 with a centrally preserved inner segment ellipsoid band (Fig. 2D). Optical coherence tomography imaging demonstrated intraretinal cysts of the inner nuclear layer, which responded to topical carbonic anhydrase inhibitors (Figs. 2E, 2H, 2K). Electrophysiology demonstrated rod and cone system dysfunction (Table 1).

Two affected siblings from family 2 (GC15894) were homozygous for the missense variant c.323C>G:p.(Pro108Arg).

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients had midperipheral reduced autofluorescence in keeping with regions of RPE atrophy and increased pigmentation.

All patients developed posterior subcapsular cataract.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.323C>G (p.Pro108Arg).

ClinVar: 1184585.

CAID: CA346170082.

gnomAD: Frequency: 2.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27053509-C-G?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Affected sister F2-II:3 was noted to have the following:

Focal parafoveal increased autofluorescence in F2-II:3 (G), likely representing cystoid macular edema.

Very limited photoreceptor preservation for F2-II.3

Focally increased autofluorescence corresponding to macular edema in F2-II:3

CasePMIDs: N/A.

Case#: P9-CH, M, Age of Report: 39 y.o., Ethnicity: Switzerland.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0008527 (Congenital sensorineural hearing impairment/congenital hearing loss/bilateral sensorineural hearing loss), HP:0000667 (Phthisis bulbi), HP:0001105 (Retinal atrophy), HP:0000523 (Subcapsular cataract),

CaseHPOFreeText: P9-CH is a 39-year-old male patient diagnosed with RP and congenital hearing loss.

At the time of the first referral to the clinic, the patient presented with a monocular situation after enucleation of the right eye due to painful phthisis bulbi, which he developed after multiple surgeries to treat retinal detachment when he was 18 and 20 years old. Fundus examination of the left eye revealed typical RP with waxy optic nerve head pallor, attenuated arteries, and peripheral BSP and retinal atrophy (Fig. 2f). No CME was observed at the most recent visit or previously described in his medical history. The patient had a visual field of <10° as assessed with a microperimetry device (Nidek MP3), which corresponds well to the margins of the retinal degeneration. He also presented subcapsular cataract and received cataract surgery. Following the surgery, his BCVA in the left eye increased from 0.3 D to 1.5 D. The patient reported hearing impairment since childhood (Fig. 3). Audiological testing indicated a bilateral sensorineural hearing loss with a flat audiogram.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.908G>A (p.Arg303His).

ClinVar: 1044022.

CAID: CA1567753.

gnomAD: Frequency: 0.00001995. Link: https://gnomad.broadinstitute.org/variant/chr2-27055253-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband has an affected brother and an unaffected sister (Fig. 1f). The brother (II.1) was not available for the study, but the proband mentioned that his brother was less severely affected than him despite being 15 years older.

CasePMIDs: N/A.

Case#:P3-ES; II.3, F, Age of report: 58 y.o., Ethnicity: Spanish.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0005101 (High-frequency hearing impairment/non-progressive hearing loss at high frequencies), HP:0000543 (Optic disc pallor/pale optic disc), HP:0500081 (Pseudophakia), HP:0012832 (Bilateral),

CaseHPOFreeText: F3 is a consanguineous family (parents are second cousins) of Spanish origin with three affected and two unaffected siblings (Fig. 1c).

The index case (P3-ES; II.3) is a 58 years-old female with a typical RP and a late-onset, moderate, non-progressive hearing loss at high frequencies (Fig. 3). She had a BCVA of 0.3 D with a 10° central visual field in either eye, and presented a typical RP fundus with a pale optic disc, vessel attenuation, and pigment deposits in the periphery (with alterations of the RPE at the macular area). She had bilateral pseudophakia and did not present CME (Table 2).

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Custom panel of 117 genes associated with IRDs and WES.

Variant: Variant 1: NM_021831.6:c.1565del (p.Gly522AspfsTer4). Variant 2: NM_021831.6:c.908G>A (p.Arg303His).

ClinVar: Variant 1: N/A. Variant 2: 1044022.

CAID: Variant 1: CA3051368245. Variant 2: CA1567753.

gnomAD: Variant 1: N/A. Variant 2: Frequency: 0.00001995. Link: https://gnomad.broadinstitute.org/variant/chr2-27055253-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband's affected brothers were not collaborative for clinical examination in this study, but the proband referred that her elder brother (II.1) uses hearing aids and her younger brother (II.5) has a mild hearing impairment, both presenting also RP. Her unaffected siblings (II.2, II.4) do not present RP or hearing impairment. The three affected members were initially referred for genetic testing in 2015 with a clinical diagnosis of isolated RP. One of them (II.3, P3-ES) was analysed using a custom panel of 117 genes associated with IRDs, but no pathogenic variants were identified [27]. Subsequently, WES performed in two affected siblings (II.3, II.5) revealed compound heterozygous pathogenic variants in AGBL5 (Table 1) which segregated with the disease in the family (Fig. 1c).

CasePMIDs: N/A.

Case#: P6-PS, F, Age of Report: 26 y.o., Ethnicity: Palestinian origin.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0011505 (Cystoid macular edema), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0008542 (Low-frequency hearing loss), HP:0012713 (Moderate hearing impairment),

CaseHPOFreeText: P6-PS is a 26-year-old male patient and was the only affected individual in a consanguineous family of Palestinian origin (Fig. 1d).

He presented the clinical features of RP, with vessel attenuation, RPE dystrophy without BSP, and CME in both eyes (Fig. 2d). He had a visual acuity of 0.5 D in both eyes, posterior subcapsular cataract and unrecordable ERG responses (Table 2). He also complained of mild-to-moderate hearing loss at low to mid frequencies (Fig. 3).

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.170G>A (p.Trp57Ter).

ClinVar: N/A.

CAID: CA346167763.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P1-IT, F, Age of Report: 55 y.o. Age of Onset: 14 y.o., Ethnicity: Italy.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity/hand motion visual acuity), HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0007737 (Bone spicule pigmentation of the retina/bone-spicule pigmentation), HP:0007401 (Macular atrophy), HP:0500081 (Pseudophakia), HP:0012832 (Bilateral), HP:0000365 (Hearing impairment/post-verbal hearing loss), HP:0008619 (Bilateral sensorineural hearing impairment/moderate, bilateral and symmetric sensorineural hearing loss)

CaseHPOFreeText: The patient P1-IT is a 55 year-old female sporadic case referred for genetic testing with a clinical diagnosis of Usher syndrome (Table 1). She is the second of two sisters born to reportedly non-consanguineous parents from a small local community. Her medical history is insignificant with no cases of hearing loss and/or RP in the family (Fig. 1a).

The patient presented night blindness since the age of 14 years, and received a diagnosis of RP at the age of 19 years. At the last ophthalmological examination (55 years), she had a hand motion visual acuity in both eyes, an RP fundus with bone-spicule pigmentation (BSP) in mid-periphery, and macular atrophy (Fig. 2a). FAF imaging revealed reduced autofluorescence at the posterior pole, with focal areas of absent autofluorescence surrounding the optic disc and in the macular area (Fig. 2a). SD-OCT imaging revealed a diffuse retinal pigment epithelium (RPE) dystrophy with epiretinal membranes but without cystoid macular edemas (CME) (Fig. 2a). Scotopic and photopic ERG responses were unrecordable in both eyes (Table 2), and she had bilateral pseudophakia. She also suffers from post-verbal hearing loss with a reported onset at the age of 18 years and she is currently using hearing aids (auditory prostheses). The most recent audiological examination confirmed the diagnosis of moderate, bilateral and symmetric sensorineural hearing loss (SNHL) with a Pure Tone Average (PTA) of 59 dB in both sides and a sloping audiogram at intermediate-high frequencies (500 Hz–8000 Hz) (Fig. 3). The hearing loss appeared non-progressive over the years.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Clinical exome.

Variant: NM_021831.6:c.323C>G (p.Pro108Arg).

ClinVar: 1184585.

CAID: CA346170082.

gnomAD: Frequency: 2.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27053509-C-G?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: P8-CH, F, Age or Report: 36 y.o. Age of Onset: Teens, Ethnicity: Switzerland.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0030329 (Retinal thinning/reduced retinal thickness), HP:0005101 (High-frequency hearing impairment)

CaseHPOFreeText: This proband started experiencing a decrease in visual acuity since her teens, followed by night blindness, and was referred for an ophthalmological assessment at the age of 16 years. She was from a non-consanguineous family, however both parents came from the same village (Fig. 1f).

At the first visit, her BCVA was 0.3 D in both eyes and the scotopic ERG responses were severely reduced, while the 30-Hz Flicker had reduced amplitude. At her last visit, aged 38 years, her BCVA was 0.1 D in both eyes, and the GVF was reduced to 30° bilaterally. FAF imaging showed several areas of patchy hypoautofluroescence at the posterior pole, which increased over time. The OCT scans at the last visit showed reduced retinal thickness with a severely altered layer of RPE and an absent ellipsoid layer at the posterior pole (Fig. 2f, Table 2). She never complained of hearing problems, however, the audiogram perfomed when she was 36 years old showed a reduced hearing threshold at higher frequencies (between 2000 and 4000 Hz) to 35 dB in the right ear and to 20 dB in the left side (Fig. 3, Table 2).

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.908G>A (p.Arg303His).

ClinVar: 1044022.

CAID: CA1567753.

gnomAD: Frequency: 0.00001995. Link: https://gnomad.broadinstitute.org/variant/chr2-27055253-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: No other family member had vision problems, however her younger sister (II.3) had severe hearing impairment (Fig. 1f). The genetic testing of the proband revealed a homozygous missense variant c.908G>A, p.(Arg303His) in the AGBL5 gene (Table 1, Fig. 1f). The sister who presented isolated severe hearing loss was heterozygous for the AGBL5 variant but was found to be compound heterozygous for two variants (c.35del and c.2229T>C) in the GJB2 gene, explaining her hearing impairment (Fig. 1f). The proband did not carry any of the GJB2 variants.

CasePMIDs: N/A.

Case#: P10-GR, F, Age of Report: 63 y.o., Ethnicity: Greece.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0001133 (Constriction of peripheral visual field), HP:0000613 (Photophobia), HP:0200070 (Peripheral retinal atrophy/diffuse outer retinal atrophy), HP:0025010 (Foveal atrophy), HP:0500087 (Peripapillary atrophy), HP:0030329 (Retinal thinning), HP:0008619 (Bilateral sensorineural hearing impairment/bilateral hearing impairment/moderate SNHL)

CaseHPOFreeText: P10-GR is a 63 year-old female with adulthood-onset RP. She is the third offspring of a non-consanguineous marriage with no family history of RP or hearing loss (Fig.1g).

She reported night blindness since the age of 25 years with subsequent visual field constriction around the age of 35 and recent onset of photophobia. Her BCVA was 0.16 D in the right eye and 0.125 D in the left eye and she was pseudophakic. Fundoscopy revealed the presence of diffuse outer retinal atrophy with intraretinal pigment migration in the mid- and far-periphery along with foveal and peripapillary atrophy and vessel attenuation. FAF imaging showed areas of hypo-autofluorescence in the periphery, around the optic disc and in the fovea corresponding to the areas of retinal atrophy. SD-OCT showed retinal thinning with atrophy of outer retinal layers and foveal RPE loss (Fig. 2f, Table 2). The patient reported bilateral hearing impairment since the age of 58 years. Audiometry confirmed the presence of moderate SNHL with a flat audiogram and a PTA of 50 dB (Fig. 3).

CaseNotHPOs: N/A..

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: Variant 1: NM_021831.6:c.883G>A (p.Asp295Asn). Variant 2: NM_021831.6:c.316A>G (p.Met106Val ).

ClinVar: Variant 1: 242932. Variant 2: N/A.

CAID: Variant 1: CA10584033. Variant 2: CA346170014.

gnomAD: Variant 1: Frequency: 0.000005530. Link: https://gnomad.broadinstitute.org/variant/chr2-27055228-G-A?dataset=gnomad_r4. Variant 2: Frequency: 6.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27053502-A-G?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Molecular analysis identified two compound heterozygous variants in AGBL5: c.883G>A, p.(Asp295Asn) and c.316A>G, p.(Met106Val), that were shown to be in trans, since the unaffected daughter of the patient only carries the c.883G>A, p.(Asp295Asn) (Fig. 1g, Table 1).

CasePMIDs: N/A.

Case#: II.1, F, Age of Onset: 7-8 y.o., Ethnicity: Turkish.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa)

CaseHPOFreeText: Proband comes from a consanguineous family.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Exome sequencing.

Variant: NM_021831.6:c.883G>A (p.Asp295Asn).

ClinVar: 242932.

CAID: CA10584033.

gnomAD: Frequency: 0.000005530. Link: https://gnomad.broadinstitute.org/variant/chr2-27055228-G-A?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband has two affected siblings. They were evaluated by Sanger sequencing. II.3 had age of onset at 7-8 y.o and was noted to have mixed astigmatism and mental retardation

II.4 had age of onset at 12 y.o and was noted to have

Both siblings were homozygous for the same variant as the proband.

Since targeted analysis of all genes linked to retinal disorders did not reveal a pathogenic mutation in pedigree E, we extended our search to include the entire exomes of the two affected family members. With this approach, a homozygous missense mutation (Asp295Asn) was detected in the deglutamylase gene AGBL5 which was confirmed in all affected family members while the unaffected parents are heterozygous carriers.

CasePMIDs: N/A.

Case#: 17-year-old boy, M, Age of Report: 17 y.o., Ethnicity: Indian/Pakistani descent.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0100832 (Vitreous floaters), HP:0030786 (Photopsia/ intermittent photopsia), HP:0007737 (Bone spicule pigmentation of the retina), HP:0001489 (Posterior vitreous detachment), HP:0030644 (Blind-spot enlargement),

CaseHPOFreeText: Proband came from a consanguineous family-multi-generational pedigree indicated his parents were first cousins of Indian/Pakistani descent.

A 17-year-old boy was referred for a history of pre- sumed pseudotumor cerebri associated with constricted visual fields. Prior to presenting at our clinic, he was observed to have retinal pigment and bilateral optic nerve edema. CT, MRI, and MRV were all normal. Lumbar puncture showed monocytes and lymphocytes but was otherwise normal. Given the lack of radiologic abnormalities and some recent weight gain, the diagnosis of pseudotumor cerebri was made and he was pre-scribed acetazolamide.

During the visit at our clinic, the patient reported a history of nyctalopia and some floaters in the right eye. He recalled, after starting the acetazolamide, some intermittent photopsia and visual obscurations. He was otherwise well and had lost 12 pounds over the last 2 months at the request of his doctor.

On our examination, best corrected visual acuity was 20/20–2 in each eye (−3.75 + 2.25 × 80 OD, −4.00 + 2.25 × 95 OS). Pupillary responses and eye movements were normal. Ishihara color plate testing was normal. Slit lamp examination and Goldmann applanation tonometry were normal. Fundus examination showed “bone spicule” pigmentary clumping scattered for 360 degrees in the mid periphery of each eye, internal limiting membrane irregularities over the macula, and a posterior vitreous detachment in the right eye (Figure 1a). The optic nerves were raised and irregular, consistent with optic nerve drusen (Figure 1b). There was no active edema or subretinal fluid.

OCT showed a distinct loss of photoreceptors outside the central macula. The subfoveal ellipsoid zone was also patchy in each eye (Figure 1c). Fundus autofluoresence (FAF) showed a hyperfluorescent ring within the macula and blocking of pigment beyond the macula (Figure 2a). Goldmann visual field testing showed an enlarged blind spot in each eye and generalized constriction of the isopters, in particular the I4e (Figure 2b). Multifocal electroretinogram (ERG) was severely abnormal with some central sparing. Full field ERG was isoelectric. B-scan ultra-sonography showed optic nerve drusen bilaterally (Figure 2c).

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Retinitis Pigmentosa Panel and My Retina Tracker Program Panel Plus.

Variant: NM_021831.6:c.1295A>T (p.Asp432Val).

ClinVar: N/A.

CAID: CA346180826.

gnomAD: Frequency: 6.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27056068-A-T?dataset=gnomad_r4.

VariantEvidence:N/A.

CaseAddInfo: Segregation analysis revealed that the unaffected mother and father were heterozygous for AGBL5: c.658C>T c.1295A>T, p. (Asp432Val).

CasePMIDs: N/A.

Case#: 42-year-old woman, F, Age of Report: 42 y.o., Ethnicity: Palestinian descent.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0001133 (Constriction of peripheral visual field/worsened peripheral vision), HP:0000523 (Subcapsular cataract), HP:0007737 (Bone spicule pigmentation of the retina),

CaseHPOFreeText: Proband was consanguineous - A multi-generational pedigree indicated her parents were first cousins of Palestinian descent.

A 42-year-old woman was referred for possible retinitis pigmentosa (RP). She had increasing nyctalopia since age 26. Recently, she had noticed worsened peripheral vision. She was taking ziprasidone for schizophrenia. She was otherwise well.

On examination, best corrected visual acuity was hand motion right eye and 20/50 left eye. Cycloplegic refraction was −4.00 + 1.00 × 90 OD, −3.00 + 1.00 × 90 OS. Pupillary responses and eye movements were normal. She did intermittently eccentrically fixate with the left eye. Slit lamp examination was normal with the exception of bilateral, dense, superior posterior subcapsular cataract, which did not involve the visual axis. Goldmann applanation tonometry was normal. Fundus examination showed moderate optic atrophy, moderate retinal vessel attenuation, almost 360 degrees of “bone spicule” pigmentary clumping, attenuation of the retinal vessels, and bilateral preserved central foveal islands of normal retina (Figure 4a). No optic nerve drusen were seen in the fundus examination. OCT showed an almost complete loss of photoreceptors, except for the subperifovea in both eyes (Figure 4b). FAF of the right eye was of poor quality. FAF of the left eye had marked peripapillary hypofluorescence (Figure 4c). She had maculopathy in the left eye with a central hyperautofluorescent ring inside of an area of mottled hypoautofluorescence. Visual fields were constricted to less than 10 degrees in each eye. Full field and multifocal ERG were isoelectric.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Inherited Retinal Dystrophies Sequencing Panel.

Variant: NM_021831.6:c.658C>T (p.Arg220Ter).

ClinVar: 2869501.

CAID: CA346173755.

gnomAD: N/A..

VariantEvidence: N/A.

CaseAddInfo: Segregation analysis revealed that the unaffected mother and father were heterozygous for AGBL5: c.658C>T (p.Arg220*).

CasePMIDs: N/A.

Case#: 12DG0507_III:2, M, Age: N/A., Ethnicity: N/A.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa)

CaseHPOFreeText: N/A.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_021831.6:c.826C>T (p.Arg276Trp).

ClinVar: 242933.

CAID: CA10584034.

gnomAD: Frequency: 0.000002470. Link: https://gnomad.broadinstitute.org/variant/chr2-27055171-C-T?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: The proband had two affected brothers.

CasePMIDs: N/A.

Case#: Patient 1, F, Age of Report: 32 y.o. Age of Onset: 28 y.o, Ethnicity: N/A.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0007737 (Bone spicule pigmentation of the retina), HP:0030648 (Midperipheral), HP:0000543 (Optic disc pallor/waxy pallor of the optic disc), HP:0001133 (Constriction of peripheral visual field/constricted field with a remaining small central island)

CaseHPOFreeText: 32-year-old female presented four years ago with a unilateral decrease in vision in the left eye that she had had for a number of years. There was no family history of blindness or inherited eye diseases and her parents were first cousins.

She denied a previous history of ocular trauma, surgery and ocular inflammation. Her medical and drug history were unremarkable. The patient denied any neurological or hearing problems. She had best-corrected visual acuity (BCVA) of 20/20 and 20/40 in the right and left eye, respectively. Anterior segment examination of both eyes, as well as fundus examination of the right eye were unremarkable. Fundus examination of the left eye revealed midperipheral bone spicules, attenuated blood vessels and a waxy pallor of the optic disc (Figure 1).

Fundus autofluorescence revealed hypoautofluorescence corresponding to the bone spicules and hyperautofluorescence at the macular area with preserved foveal autofluorescence. SD-OCT of the right eye was unremarkable, while the left eye showed the loss of the parafoveal ellipsoid zone. The subfoveal ellipsoid zone was minimally affected. ffERG showed responses within normal limits in the right eye and non-recordable responses in the left eye (Figure 2). The Goldman visual field was normal in the right eye, while the left revealed a severely constricted field with a remaining small central island.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: NGS.

Variant: Variant 1: NM_021831.6:c.373C>T (p.Arg125Trp). Variant 2: NM_021831.6:c.730-22_730-19dup (n.730-22_730-19dup).

ClinVar: Variant 1: N/A. Variant 2: N/A.

CAID: Variant 1: CA1567613. Variant 2: CA2586968849.

gnomAD: Variant 1: Frequency: 0.000007390. Link: https://gnomad.broadinstitute.org/variant/chr2-27053559-C-T?dataset=gnomad_r4. Variant 2: N/A.

VariantEvidence: N/A.

CaseAddInfo: Segregation analysis for parents and other family members was not possible. The patient had stable vision upon examination in both eyes during five years of follow-up visits with a stable average central macular thickness on SD-OCT (Table 2).

CasePMIDs: N/A.