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Axenfeld-Rieger syndrome is a genetic condition characterized by ocular and systemic features and is most commonly caused by variants in the FOXC1 or PITX2 genes. Facial dysmorphism is part of the syndrome but the differences between both genes have never been systematically assessed. Here, 11 facial traits commonly reported in Axenfeld-Rieger syndrome were assessed by five clinical geneticists blinded to the molecular diagnosis. Individuals were drawn from the Australian and New Zealand Registry of Advanced Glaucoma in Australia or recruited through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Italy. Thirty-four individuals from 18 families were included. FOXC1 variants were present in 64.7% of individuals and PITX2 variants in 35.3% of individuals. A thin upper lip (55.9%) and a prominent forehead (41.2%) were common facial features shared between both genes. Hypertelorism/telecanthus (81.8% vs 25.0%, p = 0.002) and low-set ears (31.8% vs 0.0%, p = 0.036) were significantly more prevalent in individuals with FOXC1 variants compared with PITX2 variants. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

The aim of this review is to reveal Turkey's current status of medical practice in inherited eye diseases and the necessary steps to improve healthcare services and research activities in this area. Since consanguinity rate is high, disease burden is estimated to be high in Turkey. Universal health insurance system, easily accessible medical specialists, increasing genetic test, and counseling opportunities are the key advantages of Turkey's healthcare system. However, specialized clinics for inherited eye diseases, low-vision rehabilitation services, training of ophthalmologists about the recent developments in ocular genetics, and multidisciplinary translational research are the main headlines needed to be focused for better health services and successful research in Turkey., (© 2020 Wiley Periodicals LLC.)

Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10-18 deletion., (© 2020 Wiley Periodicals LLC.)

Ophthalmic genetics is a much needed and growing area in India. Ethnic diversity, with a high degree of consanguinity, has led to a high prevalence of genetic disorders in the country. As the second most populous country in the world, this naturally results in a significant number of affected people overall. Practice involves coherent association between ophthalmologists, genetic counselor and pediatricians. Eye genetics in India in recent times has witnessed advanced research using cutting edge diagnostics, next generation sequencing (NGS) approaches, stem cell therapies, gene therapy and genomic editing. This article will highlight the studies reporting genetic variations in the country, challenges in practice, and the latest advances in ophthalmic genetic research in India., (© 2020 Wiley Periodicals LLC.)

Genetic eye diseases are phenotypically and genetically heterogeneous, affecting 1 in 1,000 people worldwide. This prevalence can increase in populations where endogamy is a social preference, such as in Arab populations. A retrospective consecutive cohort of 91 patients from 74 unrelated families affected with non-syndromic and syndromic inherited eye disease presenting to the ocular genetics service at Moorfields Eye Hospitals United Arab Emirates (UAE) between 2017 and 2019, underwent clinically accredited genetic testing using targeted gene panels. The mean ± SD age of probands was 27.4 ± 16.2 years, and 45% were female (41/91). The UAE has a diverse and dynamic population, and the main ethnicity of families in this cohort was 74% Arab (n = 55), 8% Indian (n = 6) and 7% Pakistani (n = 5). Fifty-six families (90.3%) were genetically solved, with 69 disease-causing variants in 40 genes. Fourteen novel variants were detected with large deletions in CDHR1 and TTLL5, a multiexon (1-8) duplication in TEAD1 and 11 single nucleotides variants in 9 further genes. ABCA4-retinopathy was the most frequent cause accounting for 21% of cases, with the confirmed UAE founder mutation c.5882G>A p.(Gly1961Glu)/c.2570T>C p.(Leu857Pro) in 25%. High diagnostic yield for UAE patients can guide prognosis, family decision-making, access to clinical trials and approved treatments., (© 2020 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

De novo heterozygous mutations changing R179 to histidine, leucine, or cysteine in the ACTA2 gene are associated with Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS). Characteristic hallmarks of this condition, caused only by these specific ACTA2 mutations, are congenital mydriasis (mid-dilated, non-reactive pupils), a large persistent ductus arteriosus (PDA), aortic aneurysms evolving during childhood, and cerebrovascular anomalies. We describe two patients, a 3-day-old newborn and a 26-year-old woman, with this unique mutation in association with a huge PDA and an aorto-pulmonary window. In addition, one showed a coarctation of the aortic arch and the other a complete interruption of the aortic arch type A; thereby expanding the spectrum of cardiac congenital heart defect of this syndrome. Each patient displayed a huge PDA and an extra-cardiovascular phenotype consistent with MSMDS. These observations exemplify that a functional alpha 2 smooth muscle actin is necessary for proper cardiovascular organ development, and demonstrate that a very exceptional congenital heart defect (aortopulmonary window) can be caused by a mutation in a gene encoding a contractile protein of vascular smooth muscle cells. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

One set of missense mutations in the neuron specific beta tubulin isotype 3 (TUBB3) has been reported to cause malformations of cortical development (MCD), while a second set has been reported to cause isolated or syndromic Congenital Fibrosis of the Extraocular Muscles type 3 (CFEOM3). Because TUBB3 mutations reported to cause CFEOM had not been associated with cortical malformations, while mutations reported to cause MCD had not been associated with CFEOM or other forms of paralytic strabismus, it was hypothesized that each set of mutations might alter microtubule function differently. Here, however, we report two novel de novo heterozygous TUBB3 amino acid substitutions, G71R and G98S, in four patients with both MCD and syndromic CFEOM3. These patients present with moderately severe CFEOM3, nystagmus, torticollis, and developmental delay, and have intellectual and social disabilities. Neuroimaging reveals defective cortical gyration, as well as hypoplasia or agenesis of the corpus callosum and anterior commissure, malformations of hippocampi, thalami, basal ganglia and cerebella, and brainstem and cranial nerve hypoplasia. These new TUBB3 substitutions meld the two previously distinct TUBB3-associated phenotypes, and implicate similar microtubule dysfunction underlying both., (© 2015 Wiley Periodicals, Inc.)

We here report on a Japanese family with congenital fibrosis of the extraocular muscles (CFEOM) syndrome associated with slowly progressive cerebellar ataxia. The pedigree indicated autosomal dominant inheritance. All affected individuals showed a complete loss of upgaze function with ptosis, and severe or moderate restriction of downgaze function probably from the birth. Horizontal gaze function was well preserved, except for the eldest patient, who showed both eyes almost totally fixed in exotrophic position. The primary vertical and horizontal position of each eye varied from patient to patient. Aberrant eye movements were observed on attempted upgaze. They showed amblyopia and/or astigmatism, but none of them complained of diplopia. Pupillary reactions were normal, and retinal pigmentary degeneration or optic atrophy was not observed. These ophthalmological findings were consistent with the CFEOM phenotype. The two middle-aged patients, but not the two younger patients, showed slowly progressive gait ataxia with juvenile onset. Magnetic resonance images of the brain indicated cerebellar atrophy in addition to congenital hypoplasia in the cerebellar vermis. Molecular genetic analysis provided a negative linkage to the FEOM3 locus. Linkage to the FEOM1 locus could not be excluded in our family, but mutation in KIF21A, a major cause of the CFEOM1 phenotype, was not detected. We consider that this family may broaden the spectrum of the clinical features of CFEOM or the related disorders presenting with the CFEOM phenotype., ((c) 2007 Wiley-Liss, Inc.)

We describe the clinical findings in two patients with double heterozygosity, both involving Stickler syndrome. In case 1, the proposita had Albright hereditary osteodystrophy which was inherited from her mother and type 1 Stickler syndrome which was a new mutation. The combination of manifestations from the two syndromes had resulted in initial diagnostic confusion. Diagnosis of the latter syndrome was made only following ophthalmic examination which documented the presence of a membranous vitreous anomaly characteristic of type 1 Stickler syndrome. Subsequent confirmation was achieved by mutation analysis of the COL2A1 gene. The propositus in case 2 inherited Treacher Collins syndrome paternally and type 2 Stickler syndrome maternally. The overlap of facial anomalies may have resulted in a more severe phenotype for the patient. The diagnosis of Stickler syndrome in the propositus was confirmed initially by vitreous assessment and later by demonstration of mutation in the COL11A1 gene. These two patients highlight the key role of vitreous examination and vitreoretinal phenotyping in the differential diagnosis of Stickler syndrome and its subtypes in cases where the clinical picture is complicated by double heterozygosity., ((c) 2007 Wiley-Liss, Inc.)

The prevalence of mitral valve prolapse in Stickler syndrome has been reported to be much higher than in the general population. As a result, it has been recommended that all patients with Stickler syndrome undergo routine echocardiography and have antibiotic prophylaxis prior to surgery. The purpose of this study was to evaluate the prevalence of mitral valve prolapse in a large cohort of UK patients with Stickler syndrome in whom the clinical diagnosis has been confirmed by molecular genetic analysis. Probands and pedigrees were identified from the Vitreoretinal Service database according to previously published criteria. Ophthalmic, skeletal, audiometric, and orofacial features were assessed. Affected individuals underwent a full cardiological examination including auscultation and two-dimensional echocardiography. Mutation analysis of the COL2A1 and COL11A1 genes was carried out. Seventy-eight patients from 25 pedigrees were studied. Mutation analysis confirmed the clinical diagnosis in every pedigree. No patient was found to have clinical evidence of cardiovascular disease and no patient had significant mitral or other valvular prolapse on echocardiography. These data from a large cohort of UK patients with proven Stickler syndrome do not suggest an increased incidence of mitral valve prolapse over and above that found in the general population. Routine echocardiography screening and use of preoperative antibiotics are unnecessary and should be reserved for those individual cases where there is clear clinical indication., (Copyright 2002 Wiley-Liss, Inc.)