Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD.

Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype-phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD.

The combination of whole-exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies.

PURPOSE: To identify the accurate clinical diagnosis of rare syndromic inherited retinal diseases (IRDs) based on the combination of clinical and genetic analyses. METHODS: Four unrelated families with various autosomal recessive syndromic inherited retinal diseases were genetically investigated using whole-exome sequencing (WES). RESULTS: Two affected subjects in family MOL0760 presented with a distinctive combination of short stature, developmental delay, congenital mental retardation, microcephaly, facial dysmorphism and retinitis pigmentosa (RP). Subjects were clinically diagnosed with suspected Kabuki syndrome. WES revealed a homozygous nonsense mutation (c.5492dup, p.Asn1831Lysfs*8) in VPS13B that is known to cause Cohen syndrome. The index case of family MOL1514 presented with both RP and liver dysfunction, suspected initially to be related. WES identified a homozygous frameshift mutation (c.1787_1788del, p.His596Argfs*47) in AGBL5, associated with nonsyndromic RP. The MOL1592 family included three affected subjects with crystalline retinopathy, skin ichthyosis, short stature and congenital adrenal hypoplasia, and were found to harbour a homozygous nonsense mutation (c.682C>T, p.Arg228Cys) in ALDH3A2, reported to cause Sjögren-Larsson syndrome (SLS). In the fourth family, SJ002, two siblings presented with hypotony, psychomotor delay, dysmorphic facial features, pathologic myopia, progressive external ophthalmoplegia and diffuse retinal atrophy. Probands were suspected to have atypical Kearns-Sayre syndrome, but were diagnosed with combined oxidative phosphorylation deficiency-20 due to a novel suspected missense variant (c.1691C>T, p.Ala564Val) in VARS2. CONCLUSION: Our findings emphasize the important complement of WES and thorough clinical investigation in establishing precise clinical diagnosis. This approach constitutes the basis for personalized medicine in rare IRDs.

Elschnig's spots in the acute and remission stages in preeclampsia: spectral-domain optical coherence tomographic features.

PURPOSE: Preeclampsia is a multisystem disorder defined as new onset of hypertension and proteinuria during the second half of pregnancy. Serous retinal detachment (SRD) is a known complication of preeclampsia caused by choroidal ischemia and subsequent disruption of blood-retinal barrier. Poor perfusion of the choriocapillaris causes Elschnig's spots. We aim to describe distinctive optical coherence tomography (OCT) features of a cluster of Elschnig's spots in a patient with severe preeclampsia during the acute and remission stages. We also present a summary of OCT features of preeclampsia patients with SRD. METHODS: Descriptive case report. RESULTS: V-shaped adhesions were observed at the location of each of the Elschnig's spots, the center of which showed disruption of the outer retinal bands (external limiting membrane, inner segment/outer segment junction layer), and the V-shaped outer parts remained tethered to retinal pigment epithelium (RPE)-Bruch's complex by hyperreflective exudate on the surface of RPE. These features parallel the histopathologic features described earlier. In an experimental model, Elschnig's spots showed a gradient of RPE damage from the center to the periphery, where RPE was necrotic in the center and edematous in the periphery. Three months later, spectral-domain OCT (SD-OCT) showed focal RPE elevations at the location of each of the Elschnig's spots. CONCLUSIONS: We illustrate the distinctive SD-OCT features of a cluster of Elschnig's spots in the acute and chronic stages of preeclampsia and demonstrate the correlation with the previously described histopathologic features. Despite the favorable visual outcome, irreversible tissue damage may occur, necessitating prompt diagnosis and immediate therapeutic intervention.