OBJECTIVE: To explore the genetic etiology of a fetus with cryptophthalmos detected by prenatal ultrasonography.
METHODS: A fetus undergoing induced labor at 32nd gestational week due to absence of bilateral eye fissures detected by prenatal ultrasonography in January 2017 was selected as the study subject. Umbilical cord blood sample from the fetus and peripheral blood samples from its parents were collected for the extraction of genomic DNA. Pathogenic variants were screened through whole exome sequencing (WES) and verified by Sanger sequencing. Pathogenicity of candidate variants was verified by bioinformatic analysis and protein structure simulation. Based on the results of genetic testing, prenatal diagnosis was provided to the couple upon their subsequent pregnancy.
RESULTS: The couple had four adverse pregnancies previously. The aborted fetus was the fifth, with fused bilateral upper and lower eyelids, poorly developed eyeballs, adhesion of the cornea with the upper eyelid, low-set ears, and abnormal plantar creases, and was diagnosed with cryptophthalmos. WES and Sanger sequencing revealed that the fetus has harbored compound heterozygous variants of the FREM2 gene, namely c.4537G>A (p.D1513N) and c.7292C>T (p.T2431M). Both variants were unreported associated with cryptophthalmos previously. Protein structure simulation showed that they may lead to loss of hydrogen bonds in the protein product. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1_Supporting+PM2_Supporting+PM5+PP3+PP4; PM2_Supporting+PM3+PP3+PP4). The mother was performed prenatal diagnosis in her sixth pregnancy based on the variants detected in this family, and delivered a daughter with normal phenotype.
CONCLUSIONS: The FREM2: c.4537G>A and c.7292C>T compound heterozygous variants probably underlay the pathogenesis of cryptophthalmos in this fetus. Above finding has enriched the mutational spectrum of the FREM2 gene.

BACKGROUND: Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes.
METHODS: The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.
RESULTS: A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.
CONCLUSIONS: Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.

Recent studies have uncovered that noncoding sequence variants may relate to Axenfeld-Rieger syndrome (ARS), a rare developmental anomaly with genetic heterogeneity. However, how these genomic regions are functionally and structurally associated with ARS is still unclear. In this study, we performed genome-wide linkage analysis and whole-genome sequencing in a Chinese family with ARS and identified a heterozygous deletion of about 570 kb (termed LOH-1) in the intergenic sequence between paired-like homeodomain transcription factor 2 (PITX2) and family with sequence similarity 241 member A. Knockout of LOH-1 homologous sequences caused ARS phenotypes in mice. RNA-Seq and real-time quantitative PCR revealed a significant reduction in Pitx2 gene expression in LOH-1-/- mice, while forkhead box C1 expression remained unchanged. ChIP-Seq and bioinformatics analysis identified a potential enhancer region (LOH-E1) within LOH-1. Deletion of LOH-E1 led to a substantial downregulation of the PITX2 gene. Mechanistically, we found a sequence (hg38 chr4:111,399,594-111,399,691) that is on LOH-E1 could regulate PITX2 by binding to RAD21, a critical component of the cohesin complex. Knockdown of RAD21 resulted in reduced PITX2 expression. Collectively, our findings indicate that a potential enhancer sequence that is within LOH-1 may regulate PITX2 expression remotely through cohesin-mediated loop domains, leading to ARS when absent.

BACKGROUND: Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome) is a severe multi-systemic developmental disorder, caused by variants in the SON gene. A patient diagnosed with ZTTK syndrome who carried a de novo SON mutation and exhibited recurrent myocardial injury was described in this case.
METHODS: A 7-year-old girl was admitted to the Cardiology Department of Beijing Children\'s Hospital in November 2019 due to myocardial injury following respiratory infection. She displayed elevated myocardial enzymes and severe T-wave changes on electrocardiogram. Over the past three years, she had experienced myocardial injury on three occasions. Additionally, she exhibited intellectual disability, congenital amblyopia, and dysmorphic facial features. Genetic analysis revealed a de novo heterozygous mutation c.3852_3856delGGTAT in the SON gene, which was confirmed by Sanger sequencing of her parents. She received anti-infection treatment and was administered metoprolol orally. Her condition was stable at the time of discharge. Over a 42-month follow-up period at the outpatient clinic, she complained intermittent fatigue and palpitation.
CONCLUSIONS: The identified SON mutation, which plays a crucial role in heart development and mitochondrial function, may be associated with an increased susceptibility to myocardial injury or cardiomyopathy. This case report contributes novel insights into this rare condition and suggests the expansion of the ZTTK syndrome phenotype.

OBJECTIVE: This study aimed to ascertain the occurrence of foveal hypoplasia (FH) in individuals diagnosed with familial exudative vitreoretinopathy (FEVR).
METHODS: Retrospective cohort study.
METHODS: In this study, FEVR families and sporadic cases were diagnosed at the Eye and ENT Hospital, Fudan University, between 2017 and 2023. All patients attended routine ophthalmologic examinations and genetic screenings. The classification of FH was determined using optical coherence tomography (OCT) scans. The FH condition was classified into 2 subgroups: group A (FH being limited to the inner layers) and group B (FH affecting the outer layers). A total of 102 eyes from 58 patients were suitable for analysis.
RESULTS: Forty-nine mutations in LRP5, FZD4, NDP, TSPAN12, KIF11, CTNNB1, and ZNF408 were examined and detected, with 26 of them being novel. Forty-seven eyes (46.1%) revealed FH. The majority (53.2%) were due to the typical grade 1 FH. Patients with mutations in LRP5 and KIF11 were found to exhibit a higher prevalence of FH (P = .0088). Group B displayed the lowest visual acuity compared with group A (P = .048) and the group without FH (P < .001). The retinal arteriolar angle in group B was significantly smaller than in group A (P = .001) and those without FH (P < .001).
CONCLUSIONS: This study offers a new diagnostic approach and expands the spectrum of FEVR mutations. LRP5 and KIF11 were found to be more susceptible to causing FH in patients with FEVR. FEVR eyes with FH exhibited both greater visual impairment and reduced retinal arteriolar angles. The assessment of foveal status in patients with FEVR should be valued.

BACKGROUND: The structural features have an impact on the surgical prognosis for congenital corneal opacity (CCO). The structural classification system of CCO, however, is lacking. Based on data from ultrasound biomicroscopy (UBM) findings in infants and toddlers with CCO, this research proposed a classification system for the anterior segment structure severity.
METHODS: Medical records, preoperative UBM images and slit-lamp photographs of infants and toddlers diagnosed with CCO at University Third Hospital between December 2018 and June 2022 were reviewed. According to the anterior segment structural features observed in UBM images, eyes were classified as follows: U1, opaque cornea only; U2, central anterior synechia; U3, peripheral anterior synechia combined with angle closure; and U4, aniridia or lens anomaly. The opacity appearance and corneal vascularization density observed in slit-lamp photographs were assigned grades according to previous studies. The extent of vascularization was also recorded. The corresponding intraocular anomaly classifications and ocular surface lesion severity were analysed.
RESULTS: Among 81 eyes (65 patients), 41 (50.6%) were right eyes, and 40 (49.4%) were left eyes. The median age at examination was 6.91 months (n = 81, 1.00, 34.00). Two (2.5%) of the 81 eyes were classified as U1, 20 (24.7%) as U2, 22 (27.2%) as U3a, 11 (13.6%) as U3b and 26 (32.1%) as U4. Bilateral CCO eyes had more severe UBM classifications (P = 0.019), more severe dysgenesis (P = 0.012) and a larger angle closure (P = 0.009). Eyes with more severe UBM classifications had higher opacity grades (P = 0.003) and vascularization grades (P = 0.014) and a larger vascularization extent (P = 0.001). Eyes with dysgenesis had higher haze grades (P = 0.012) and more severe vascularization (P = 0.003 for density; P = 0.008 for extent), while the angle closure range was related to haze grade (P = 0.013) and vascularization extent (P = 0.003).
CONCLUSIONS: This classification method based on UBM and slit-lamp photography findings in the eyes of CCO infants and toddlers can truly reflect the degree of abnormality of the ocular surface and anterior segment and is correlated with the severity of ocular surface anomalies. This method might provide meaningful guidance for surgical procedure design and prognostic determinations for keratoplasty in CCO eyes.

Joubert syndrome (JBTS) is a systematic developmental disorder mainly characterized by a pathognomonic mid-hindbrain malformation. All known JBTS-associated genes encode proteins involved in the function of antenna-like cellular organelle, primary cilium, which plays essential roles in cellular signal transduction and development. Here, we identified four unreported variants in ARL13B in two patients with the classical features of JBTS. ARL13B is a member of the Ras GTPase family and functions in ciliogenesis and cilia-related signaling. The two missense variants in ARL13B harbored the substitutions of amino acids at evolutionarily conserved positions. Using model cell lines, we found that the accumulations of the missense variants in cilia were impaired and the variants showed attenuated functions in ciliogenesis or the trafficking of INPP5E. Overall, these findings expanded the ARL13B pathogenetic variant spectrum of JBTS.

This case report presents a family with developmental glaucoma accompanied by microcornea resulting from novel mutations in the ADAMTS18 gene. The index case involves a 5-year-old twin brother, who, during a routine examination, exhibited elevated intraocular pressure persisting for over a month. The peak intraocular pressure reached approximately 25 mmHg (1 mmHg=0.133 kPa) in both eyes, with a corneal diameter of less than 10 mm. Ocular examination revealed an enlarged cup-to-disc ratio, and optical coherence tomography (OCT) demonstrated thinning of the retinal nerve fiber layer and ganglion cell layer. Ultrasound biomicroscopy combined with gonioscopy indicated partial angle closure and abnormal anterior chamber angle development. The ocular manifestations in the twin brother were consistent with those observed in the twin sister. The clinical diagnosis was bilateral developmental glaucoma with microcornea. Genetic sequencing identified two novel compound heterozygous mutations in the ADAMTS18 gene in the twins: Mutation 1 (M1) involving the variant site 1 (c.3436C>T:p.R1146W) and Mutation 2 (M2) involving the variant site 2 (c.1454T>G:p.F485C). Ocular examinations of four additional family members were normal. Genetic testing revealed that the twins\' father and sister carried M1, while the index case\'s mother and brother carried M2. This report underscores a unique association between ADAMTS18 gene mutations and developmental glaucoma with microcornea within a familial context, emphasizing the importance of genetic screening for early diagnosis and targeted management strategies.
先证者为5岁双胞胎之胞弟，体检发现双眼眼压高1个月余，双眼眼压峰值均达25 mmHg（1 mmHg=0.133 kPa）左右，角膜横径<10 mm，眼底视杯与视盘直径比（杯盘比）扩大，相干光层析成像术（OCT）显示视网膜神经纤维层和节细胞层变薄，超声活体显微镜结合房角镜检查提示部分房角关闭，前房角发育异常。胞兄眼部表现与胞弟一致。临床诊断为双眼发育性青光眼伴小角膜。经基因测序检出双胞胎同时携带有ADAMTS18基因的2个新复合杂合突变，即M1（变异位点1）：c.3436C>T：p.R1146W和M2（变异位点2）：c.1454T>G：p.F485C；家系另外4名成员眼部检查正常，基因检测发现双胞胎父亲及姐姐携带M1，双胞胎母亲及哥哥携带M2。.

OBJECTIVE: To characterize the morphology of persistent pupillary membranes (PPMs) in pediatric patients and explore the corresponding surgical approaches.
METHODS: Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
METHODS: Prospective observational study.
METHODS: Consecutive pediatric patients with PPMs who underwent surgery from April 2020 to July 2022 were included. PPM morphology was assessed and categorized according to its anatomic relationship with crystalline lens and distribution of iris strands. The surgical approaches for different morphologies of PPMs were described in detail. The visual outcome and operation-related complications were recorded.
RESULTS: 31 eyes from 19 patients were included with the mean age of 7.2 years. 3 morphological variants of PPMs were observed: type I (51.6%, 16/31), a spider-like appearance and no adhesion to the anterior lens capsule (ALC); type II (38.7%, 12/31), a loose central adherence to the ALC and partially thick iris strands attached to the iris collarette; type III (9.7%, 3/31), a tight central adherence to the ALC and only silk-like iris strands. Surgeries were performed with a natural pupil size in type I, while dilated pupil in the other types. The adhesions between PPM and the ALC were separated by viscoelastic injection in type II and by discission needles in type III. The corrected distance visual acuity was significantly improved from 0.34 ± 0.18 logMAR preoperatively to 0.17 ± 0.09 logMAR postoperatively ( P < .001). No operation-related complications were observed during 9.5-month follow-up.
CONCLUSIONS: PPMs were categorized into 3 types according to their different morphologies, which helped to determine the best surgical strategy.

BACKGROUND: Myopic maculopathy is a sight-threatening disease, which causes irreversible vision faults and central vision loss. The purpose of this study is evaluating the risk factors of the myopic maculopathy progression according to the ATN classification system.
METHODS: Clinic data of 69 high myopia patients aged older than 40 years with a follow-up time of more than 2 years, who underwent fundus photography and OCT examination were retrospectively collected. Fundus changes were evaluated with ATN classification at the first and last follow-up times. The related factors affecting progress including axial length (AL), spherical equivalence (SE), subfoveal choroidal thickness (SFCT), disc-foveal distance (DFD), optic disc tilt, and parapapillary atrophy (PPA) were analyzed.
RESULTS: This study included 69 high-myopia patients with mean age 54.29 ± 10.41 years. The progression rate of myopic maculopathy (MM) was approximately 25.56%. Elongated DFD (5.37 ± 0.11 mm vs. 4.86 ± 0.37 mm; p < 0.001) and thinner SFCT (138.52 ± 29.38 μm vs. 184.87 ± 48.72 μm; p = 0.008) at baseline were linked with MM progression. In multiple logistic regression analysis, DFD was a substantial hazard risk factor (adjusted OR = 1.672, 95% CI: 1.135-2.498, p < 0.05) after adjusting for age, AL and SFCT. Receiver operating characteristic curve showed that DFD might serve as a predictor to discriminate the MM progression with a cut-off value of 5.15 mm and a substantial receiver operating characteristic curve area (AUC: 0.794). Compared with the non-progression group, the progression group had older age (p < 0.001), longer AL (p = 0.001), higher optic disc tilt rate (p < 0.001), and higher proportion of pre-existing PPA (p = 0.038) at baseline, the differences were statistically significant.
CONCLUSIONS: Based on the ATN classification system, we found that the progression of MM was related to older age, longer AL, high disc tilt, pre-existing PPA, thinner SFCT, and longer DFD. The parameter of DFD was an important factor affecting the progression of MM, which is considered to have a higher probability of progression when the length is beyond 5.15 mm.