Case#: IV-2, M, Age of Diagnosis: 33 y.o., Ethnicity: Arab-Muslim origin.

CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0100014 (Epiretinal membrane), HP:0001696 (Situs inversus totalis), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: Proband has consanguineous parents.

Proband was noted to find have visual acuity of 0.2 in the right eye (RE) and 0.4 in the left eye (LE), and his Goldmann visual fields were constricted to 10°–12° with the V4e target.

Interestingly, all three siblings displayed a marked component of macular atrophy, including smaller and larger atrophic patches, as well as epiretinal membranes with wrinkling of the retina (Figures 2A–2D). Neither photopic nor scotopic electroretinogram (ERG) responses were detectable.

Audiometric testing was within normal limits in all three siblings, and computed-tomography imaging revealed full thoracic and abdominal situs inversus in individuals IV-1 and IV-2 but normal situs composition (situs solitus) in individual IV-3.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Homozygosity mapping.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: NM_012106.4:c.101-1G>C.

ClinVar: 65473.

CAID: CA10575604.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: "When she was 36 years old, his older sister (IV-1; Figure 1A) had severely impaired vision: she could detect hand motion in the RE and had bare light perception in the LE. There were no significant refractive errors. Mild posterior subcapsular cataracts were present, and fundoscopy revealed optic-disc pallor, mild-to-moderate bone-spicule-like pigmentation in the midperiphery, and attenuated retinal blood vessels, all typical signs of RP. Interestingly, all three siblings displayed a marked component of macular atrophy, including smaller and larger atrophic patches, as well as epiretinal membranes with wrinkling of the retina (Figures 2A–2D)."

Case#: 46-year-old, M, Age of report: 46 y.o., Ethnicity: Han Chinese.

CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0001696 (Situs inversus totalis), HP:0003251 (Male infertility), HP:0000662 (Nyctalopia/Night blindness), HP:0012207 (Reduced Sperm Motility), HP:0011109 (Chronic sinusitis), HP:0000458 (Anosmia/Permanently impaired olfactory sensation), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)

CaseHPOFreeText: Proband has consanguineous family.

The proband complained of pronounced vision decline over the last 2 years. He had experienced night blindness over the last decade and was diagnosed with RP at age 33. His best-corrected visual acuity (BCVA) was 0.6 in both eyes, with −3.75-0.75 × 85 OD and − 3.25-1.25 × 65 OS.

Dilated fundus examination revealed sparse bone spicule pigment deposits, widespread mottled pigmentation in the mid-peripheral retina, and attenuated retinal vessels (Figure 1A). Fundus autofluorescence imaging exhibited hypofluorescence outside the vascular arcades and a characteristic hyperfluorescent ring around the fovea (Figure 1B). Optical coherence tomography (OCT) images showed a retained central island within the outer nuclear layer and ellipsoid zone (Figure 1C). Electroretinography indicated extinguished responses.

Four-year follow-up data combined with past medical history revealed slow vision degeneration. BCVA in both eyes was 0.1 at age 41, 0.8 at age 44, and 0.5 at age 50. Fundoscopy demonstrated larger, more peripheral retinal pigment epithelium atrophy with age, corresponding to hypofluorescent patches in fundus autofluorescence (Figure 1B). OCT images demonstrated ellipsoid zone peripheral loss, which progressed to the central fovea over time (Figure 1C). The severe peripheral visual field constriction observed in his forties worsened considerably with age. At age 50, all peripheral visual fields outside the central 5° were bilaterally lost (Figure 1D).

A review of his medical history during the second visit revealed full thoracic and abdominal situs inversus (Figure 1E). Routine semen analysis found that sperm motility was severely reduced, resulting in infertility (Table 1). Furthermore, this patient had chronic sinusitis, and olfactory sensation was permanently impaired following a severe cold at age of 49.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: Next-generation sequencing. Sanger sequencing and segregation analysis indicated his siblings carried the same heterozygous variant (Figure 2A, B).

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: Whole exome sequencing (WES) for proband and his siblings

Variant: NM_012106.4:c.22_23del.

ClinVar: N/A.

CAID: CA495624174.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: N/A.

CasePMIDs: N/A.

Case#: LL89, F, Age of Diagnosis: 36 y.o., Ethnicity: Portuguese origin.

CasePresentingHPOs:HP:0000613 (Photophobia), HP:0000662 (Nyctalopia/Night blindness), HP:0030786 (Photopsia), HP:0001133 (Constriction of peripheral visual field), HP:0007663 (Reduced visual acuity), HP:0000551 (Color vision defect/loss of color vision), HP:0012508 (Metamorphopsia), HP:0000543 (Optic disc pallor/pale optic discs), HP:0000533 (Chorioretinal atrophy/generalized chorioretinal atrophy), HP:0002076 (Migraine)

CaseHPOFreeText: Proband was born a from consanguineous union between first degree cousins of Portuguese origin. She was diagnosed with a classical form of retinitis pigmentosa at the age of 36 years.

Initial visual complaints started with photophobia at 11 years of age and progressed to night blindness and photopsia by the age of 25. Constriction of the peripheral visual field was noted at the age of 28. Disease progression led to a sharp reduction in visual acuity at age 38 and to loss of color vision by the age of 40. The patient underwent cataract surgery at age 40 and 48. At 50 she developed metamorphopsia in the OS.

At the last ophthalmologic examination, patient P2 showed a BCVA of 0.3 in the OD, 0.16 in the OS, and severe constriction of the peripheral visual field, with bilateral tunnel-like vision, restricted to the 5 degrees central. Dilated fundus examination revealed attenuated retinal vessels, pale optic discs (Fig 2B) and a marked generalized chorioretinal atrophy in the posterior pole and in the periphery, with areas of complete atrophy in the inferior peripheral region of the right eye. Mild to moderate mottled pigment deposition in the retinal periphery, along with some irregular white patches in the posterior pole near the superior vessels, was also observed. Fundus autofluorescence was notable for generalized hypo-autofluorescence with a wide hyper-autofluorescent ring in the posterior pole (Fig 2D). SD-OCT revealed pronounced atrophy of the outer retinal layers and the presence of a foveal cyst (Fig 2F).

P2 gave birth to two children.

P2 displays a pale optic disc, vascular thinning and marked retinal changes, with opalescent areas of the retinal tissue in the periphery and central atrophic lesion. Scarse pigment deposition can also be found adjacent to the optic nerve head and periphery.

P2 suffered from frequent migraines and recently underwent a cerebral CT imaging examination, which revealed normal ventricular volumes and absence of other morphological anomalies.

CaseNotHPOs: N/A.

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A.

CaseMethod2: N/A.

CaseGenotypingMethod: WES and Sanger.

Variant: NM_012106.4:c.33_36del.

ClinVar: 2577503.

CAID: CA2580617535.

gnomAD: N/A.

VariantEvidence: N/A.

CaseAddInfo: Patient P2’s paternal aunt (P3) and her uncle (P4) were also diagnosed with RP, showing similar progression and manifestations. Specifically, P3 began to be visually impaired in her 20s with the onset of night blindness. Her visual field progressively shrank for both eyes and considerably worsened after the birth of her two daughters in her 30s, evolving to a state of complete blindness by the age of 50.

There is no clinical history of other ciliopathic disorders in this family, with the exception of P4, who suffered from chronic bronchitis. This latter patient died of multiple myeloma prior to this study, thus preventing further clinical analysis. Interestingly, P4 never conceived any offspring in spite of multiple attempts (as reported by his sister, patient P3), whereas both female patients P2 and P3 had two healthy children.

CasePMIDs: N/A.