Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes.

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Altered Splicing of LAMP2 in a Multigenerational Family from Latvia Affected by Danon Disease.

Background and Objectives: Danon disease is a multisystemic disorder associated with variants in the LAMP2 gene, mainly affecting the cardiac muscle. Here, we report a multigenerational family from Latvia with two male patients, hemizygous for a novel splice-affecting variant c.928+3A>G. Affected patients exhibit a cardiac phenotype, moderate mental disability, and mild retinal changes. Materials and Methods: Both patients underwent either exome or hypertrophic cardiomyopathy gene panel next-generation sequencing. The pathogenic variant effect was determined using reverse transcription, Sanger sequencing, and high-resolution electrophoresis. Results: Evaluation of the splicing process revealed that approximately 80% of the transcripts exhibited a lack of the entire exon 7. This alteration was predicted to cause a shift of the reading frame, consequently introducing a premature stop codon downstream in the sequence. Conclusions: Based on our data, we propose that c.928+3A>G is a pathogenic variant associated with Danon disease.

Preliminary Results of New Modification of Vertical Muscle Transposition to Enhance Abducting Force in Sixth Nerve Palsy.

Introduction: Since 1907, multiple transposition procedures have been established for the treatment of abducens paralysis. The purpose of the study was to determine where the transposed muscle should be reattached in order to increase the tangential force necessary to improve abduction. Methods: Retrospective case review of 12 consecutive patients with abducens paralysis who underwent transposition procedures between 2016 and 2019 was conducted. Vertical rectus muscles are transposed to the insertion of lateral rectus muscle; the temporal parts are joined and sutured to the sclera on top of the lateral rectus muscle in the middle of the insertion. The nasal parts are sutured to the sclera following the spiral of Tillaux. The muscle junction suture is placed 8 mm from the insertion, with the temporal parts of the vertical muscles bellies joined and sutured to the lateral rectus muscle. A full-tendon transposition was performed on 11 patients, a half-tendon transposition procedure on 1 patient. The minimum follow-up was 3 months. Results: The mean preoperative deviation was ET of 37° (range: ET 24° to ET 51°). The mean preoperative abduction limitation was 5 mm from midline (range: 7 to 1 mm). The postoperative mean deviation was ET of 2° (range: 0° to ET 5°). The postoperative mean abduction improvement was 5 mm past midline (range: 2-6 mm). There were no complications or signs of anterior segment ischemia. Conclusion: To achieve the maximal abductive force from the transposed muscles, we suggest that the vertical muscles be reattached as close as possible to the middle of the lateral rectus insertion.

The Epidemiological and Clinical Findings from the Latvian Registry of Primary Congenital Glaucoma and Evaluation of Prognostic Factors.

Background and objectives: primary congenital glaucoma (PCG) is a rare, potentially blinding disease that affects children worldwide. The aim of the study was to describe the epidemiological and clinical characteristics, outcomes for newly diagnosed patients with PCG, as well as evaluate the prognostic factors that are related to the outcomes. Materials and Methods: a retrospective cohort study was conducted at a tertiary referral centre among patients diagnosed with PCG. Evaluation of the clinical data was performed preoperatively at three, six, and 12 months after the surgery and at the last follow-up. Results: during the 15 years of follow-ups, 24 eyes of 18 patients were diagnosed with PCG. Unilateral and bilateral PCG constituted 50% of cases each. A slight male predominance was observed (55.6% vs. 44.4%), with a relative risk of 1.3. The incidence of PCG was 1:19,033 live births. The mean age of the patients at the time of diagnosis was 10.1 ± 10.0 months, with a diagnostic delay of 2.0 ± 1.9 months. Furthermore, 75% of patients indicated an enlargement of an eyeball, followed by excessive tearing (58.3%) and corneal opacity (41.7%). After 85.9 ± 51.2 months, the mean intraocular pressure (IOP) value was 14.6 ± 4.9 mmHg. Surgical treatment provided sufficient IOP control in 75% of PCG cases at the last follow-up visit. The only prognostic factor that was related to the outcome of IOP control that was statistically significant was axial length at the time of diagnosis. Conclusions: the incidence of PCG in Latvia was 5.3 patients per 100,000 live births. PCG was more common among males than females with a relative risk of 1.3. The enlargement of an eyeball was the leading clinical sign.

Factors influencing myopic shift in children after intraocular lens implantation.

INTRODUCTION: Intraocular lenses have always been a controversial topic in pediatric cataract surgery. In the early 1990s in the post-Soviet states of Eastern Europe, intraocular lenses promised an easier full-time correction and amblyopia treatment. Since 1991, ophthalmologists in Latvia have been implanting intraocular lenses in infants. Amount of the postoperative myopic shift and its influencing factors, analyzed in this article, are important indicators of congenital cataract treatment. MATERIALS AND METHODS: A retrospective chart review off 85 children (137 eyes) who underwent foldable posterior chamber intraocular lens implantation at the Clinical University Hospital in Riga, Latvia, from 1 January 2006 until 31 December 2016, was performed. Depending on the age at surgery, patients were divided into six groups: 1-6, 7-12, 13-24, 25-48, 49-84, and 85-216 months. RESULTS: The largest and more variable myopic shift was found in a group of diffuse/total and nuclear cataract with surgery before the age of 6 months. There was a statistically significant correlation between the acquired best-corrected visual acuity and the amount of myopic shift (rs = 0.33; p < 0.001). Comparing the amount of myopic shift in two groups of different intraocular lens implantation target refraction tactics, we did not find statistically significant differences. Comparing the amount of myopic shift and implanted intraocular lens power, a negative, statistically significant correlation was found. CONCLUSION: The earlier the cataract extraction surgery and intraocular lens implantation is performed, the larger the myopic shift. The morphological type of cataract, best-corrected visual acuity, secondary glaucoma, and intraocular lens power influence the amount of myopic shift.

Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus.

Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been linked to two loci, MCDR1 (chromosome 6q16) and MCDR3 (chromosome 5p15-p13). Recently, non-coding variants upstream of PRDM13 (MCDR1) and a duplication including IRX1 (MCDR3) have been identified. However, the underlying disease-causing mechanism remains uncertain. Through a combination of sequencing studies on eighteen NCMD families, we report two novel overlapping duplications at the MCDR3 locus, in a gene desert downstream of IRX1 and upstream of ADAMTS16. One duplication of 43 kb was identified in nine families (with evidence for a shared ancestral haplotype), and another one of 45 kb was found in a single family. Three families carry the previously reported V2 variant (MCDR1), while five remain unsolved. The MCDR3 locus is thus refined to a shared region of 39 kb that contains DNAse hypersensitive sites active at a restricted time window during retinal development. Publicly available data confirmed expression of IRX1 and ADAMTS16 in human fetal retina, with IRX1 preferentially expressed in fetal macula. These findings represent a major advance in our understanding of the molecular genetics of NCMD and provide insights into the genetic pathways involved in human macular development.

Genetic linkage studies of a North Carolina macular dystrophy family.

BACKGROUND AND OBJECTIVE: North Carolina macular dystrophy (NCMD) is a very rare autosomal dominant hereditary disease. Up to date there are three types of NCMD described and consequently named macular dystrophy, retinal: MCDR1, MCDR2 and MCDR3. The aim of this study was to perform linkage and copy number variation analysis for the family affected by NCMD followed by the selected candidate gene sequencing. MATERIALS AND METHODS: This study concerned a 3-generation, non-consanguineous Latvian family with NCMD. Genome-wide scan, copy number variation and non-parametric linkage analysis was performed. Analysis resolved the locus of interest to the 5p15.33 region. Two of the genes, iroquois homeobox 2 (IRX2) and iroquois homeobox 4 (IRX4), were selected and sanger sequencing was performed. RESULTS: Linkage analysis indicated a region on chromosome 5 for the analyzed family, corresponding to a genetic locus previously described for MCDR3 (5p15-p13). Chromosomal aberrations were not identified in the affected family members. An upstream intron variant (NM_001278634: c.-139G > A (rs6876836)) in IRX4 gene segregated with NCMD phenotype in the analyzed family. CONCLUSIONS: It is unlikely to be the causative mutation of NCMD due to its high minor allele frequency 0.3532. Therefore, the role of IRX2 and IRX4 genes in the pathogenesis of NCMD has not been proved. Considerable variability in visual acuity between individuals of the same age group in all the families examined was noted. No overlap between NCMD grade and family generation was seen in the family described in the present study.

Fabricated or Induced Illness Presenting as Recurrent Corneal Lesions, Cataracts, and Uveitis.

Two siblings with ophthalmic findings, psychomotor retardation, somnolence, and seizures underwent diagnostic studies, genetic investigations, ultrasonography, biomicroscopy, and posterior and anterior optical coherence tomography. Both siblings experienced eye problems at different times from the age of 6 months to 12 years. The family pedigree and neurological problems (ie, hypotony, seizures, sleepiness, and speech and psychomotor delay) suggested a metabolic or mitochondrial pathology. After exclusion of multiple potential diseases, a fabricated or induced illness was suspected. Fabricated or induced illness can be a cause for unusual clinical findings and should be considered in the differential diagnosis when ocular and other abnormalities cannot be explained after a comprehensive evaluation. The diagnosis of fabricated or induced illness should not be based on exclusion alone but rather on positive findings.