前眼部形成異常

Congenital eye malformations represent a clinically and genetically heterogeneous group of disorders. Despite advances in genetic testing, fewer than half of affected patients receive a definitive molecular diagnosis. However, obtaining a molecular diagnosis is crucial for these patients and their families. Whole genome sequencing (WGS) is now standard practice in the genetic investigation of patients, but its contribution has not been extensively evaluated in patients with ocular malformations. In this work, we performed short-read WGS in a cohort of 100 families presenting with eye developmental disorders, including microphthalmia-anophthalmia spectrum (M/A), coloboma, anterior segment dysgenesis, congenital cataracts and/or foveal hypoplasia. Prior to WGS, 47 individuals had undergone targeted next-generation sequencing (NGS) of genes panels related to ocular development, 11 had chromosomal microarray analysis (CGH-array) and 20 had a combination of both. None had received a definitive genetic diagnosis. WGS identified a (likely) pathogenic variant in eighteen patients. In addition, candidate variants of uncertain significance were detected in nine patients. Notably, fourteen of these variants would have been missed by conventional genes panels or CGH-array, underscoring the broader diagnostic scope of WGS. Our findings demonstrate that short-read WGS significantly improves diagnostic yield in patients with congenital eye malformations, including those previously undiagnosed despite NGS panel testing. These results support the integration of WGS in the genetic evaluation of ocular developmental disorders.

PRCIS: Axenfeld-Rieger syndrome (ARS) is a rare genetic disorder characterized by anterior segment dysgenesis and secondary glaucoma, often accompanied by systemic defects. This study investigated the clinical and genetic features in four Chinese families with ARS. PURPOSE: To characterize the clinical phenotypes and identify the causative genetic mutations in four unrelated Chinese families with ARS. METHODS: Affected individuals from four Han Chinese families underwent comprehensive clinical and ophthalmological examinations. Genetic analysis was performed using whole-exome sequencing (WES) and validated by copy number variation sequencing (CNV-seq) and qPCR. RESULTS: All affected individuals exhibited anterior segment dysgenesis. Secondary glaucoma was present in seven of them. Systemic manifestations, including dental and umbilical abnormalities, were observed in all affected individuals. Genetic analysis identified novel heterozygous PITX2 mutations in all four families: three distinct microdeletions (ranging from 206 bp to 449.97 kb) and one nonsense mutation (p.Phe140*) , with all predicted to cause haploinsufficiency. CONCLUSIONS: Four novel PITX2 mutations, including microdeletions, were identified in Chinese ARS families. The 206-bp genomic DNA deletion appeared to be an essential region (chr4: 111543411-111543616) for PITX2 function in ocular and systemic development, underscoring the necessity of full gene dosage.

BACKGROUND: Juvenile-onset open-angle glaucoma (JOAG) is a heterogeneous early-onset glaucoma subtype. Axenfeld-Rieger syndrome (ARS) is an autosomal dominant disorder caused by FOXC1 variants, which may present with severe early-onset glaucoma and can be clinically mistaken for JOAG. This study aimed to determine the genetic cause and clarify the clinical diagnosis in a Chinese family initially diagnosed with JOAG. METHODS: A 15-year-old male proband and his family members received detailed ophthalmic and systemic evaluations. Whole-exome sequencing was performed in the proband, and candidate variants were verified by Sanger sequencing. Bioinformatic tools were used to evaluate variant pathogenicity. RESULTS: The proband and his elder sister initially presented with severe early-onset glaucoma and were diagnosed with JOAG at an outside hospital. After systemic evaluation, they were found to have anterior segment dysgenesis and characteristic facial features, including midface hypoplasia, hypertelorism, and saddle nose deformity, supporting a revised diagnosis of ARS. A novel heterozygous missense variant c.311T>G (p.Ile104Ser) in FOXC1 was identified. This variant was absent from the East Asian population in gnomAD and was predicted to be highly deleterious. It co-segregated with the disease phenotype and showed incomplete penetrance in the unaffected father. CONCLUSION: We identified a novel FOXC1 variant responsible for ARS in a Chinese family. ARS-associated glaucoma can closely mimic JOAG, leading to initial misdiagnosis. The observation of incomplete penetrance in an unaffected carrier father underscores the phenotypic complexity of this disorder. Our findings expand the genotypic spectrum of FOXC1-related disorders and highlight the importance of systemic evaluation and genetic testing in patients with early-onset glaucoma.

PURPOSE: To determine the indications, practice pattern of immunomodulation (IM), and outcomes of repeat optical penetrating keratoplasty (OPK). METHODS: Of 4454 OPKs performed from 2016 to 2023, 259 (5.81%) were OPK following previous failed OPKs (OPK/OPK) and these were included in the study; those with follow-up <1 m were excluded. Indications for primary, last graft, risk factors, and IM use were recorded. Hazard's ratio of factors for graft failure was computed. Graft survival (clear graft at last follow-up) and graft survival time were analyzed. RESULTS: Prior OPK failed twice in 69 (26.64%), thrice in 41 (15.83%), and >4 times in 13 (5.01%). Indications for repeat graft included rejection (83.78%), HSV (14.67%), and infection (13.90%). Pre-op IM was used in 18.91%, while post-op was in 7%. Younger age, prior therapeutic PK, corneal scars post infections, anterior segment dysgenesis, >2 quadrants deep vascularization, and >2 failed grafts increased risk of graft failure. Visual acuity improved at 1 month and declined after 3 months. 39% of grafts survived until last follow-up (mean 31.5 m), and the median survival time was 36 m (CI: 30.2 to 45.8 m). CONCLUSION: OPK/OPK subset constitutes close to 6% of all OPKs performed, and 39% of these regrafts remain clear over a mean follow-up of 31 m. Half regrafts fail 36 m post-OPK. More than 80% of these grafts fail post rejection, and one-third post infection. Males undergo repeat OPKs more. Younger age, deep vessels, previous infections, and >2 grafts pose higher risk of failure to subsequent grafts. Current IM use is limited to 7-20% with pre-existing high risk and needs further studies to enhance graft survival in these complex situations.