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‘‘Genomic Insights into Knobloch Syndrome: A Meta-Analytical Perspective’’
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05 February 2024
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06 February 2024
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Abstract
A rare genetic disorder caused by col18.a1 mutations, inherited mostly in autosomal recessive and rarely in autosomal dominant pattern, giving rise to ocular abnormalities and other associated disorders, the condition is referred to as Knobloch syndrome. This paper overviews the anterior and posterior ocular symptoms in Knobloch patients, thus demonstrating the major findings in Knobloch cases including the mutational analysis which discusses the proteins involved and exon number on which mutations are detected. Animal modeling done by knocking out col18.a1 has also been discussed to determine the functions of this gene which have been identified based on anomalies found in knock-out mice.
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Subject: Biology and Life Sciences - Biology and Biotechnology
Introduction
Knobloch syndrome is an autosomal recessive disorder characterized by abnormalities most commonly in ophthalmic regions. The most common symptoms of Knobloch syndrome include retinal detachment, occipital encephaloceles, and high myopia (1). Apart from ocular and occipital skull abnormalities, Knobloch syndrome can give a range of phenotypic discoveries like lung hypoplasia, hyperextensible joints, duplication of the renal collecting system, epilepsy, neuronal migration abnormalities, and dysmorphic findings such as midface hypoplasia, high-arched palate, micrognathia, flat nasal bridge, and dental abnormalities (4). It is a genetic disorder that is caused by mutations in the gene Col18A1 and is inherited in an autosomal recessive pattern. This condition is acquired in an autosomal latent example, which implies that mutations have occurred in both duplicates and copies of every cell's gene. One copy of a mutated gene will be present in both parents of the person with an autosomal recessive condition means the parents are a carrier, however, they commonly don't give indications and manifestations of their condition. This syndrome is named after one of the two authors named W.H Knobloch who first reported this disease along with his companion in a family where five out of ten siblings were affected. Their parents had a non-consanguineous marriage. To date, three types of Knobloch syndromes have been reported. Type 1 is because of mutations in the col18A1 gene however the causative genes for type 2 and 3 have still not been identified. Influenced people may likewise have irregularities in the focal space of the retina, called the macula. The macula is accountable for sharp focal vision, which is required for point-by-point errands like perusing, driving, and perceiving faces. Because of irregularities in the retina, vitreous, and macula, individuals with Knobloch syndrome can raise visual deficiency or blindness in one or both eyes. Knobloch syndrome occurs due to biallelic mutations in Col18A1 (2). Col18A1 is associated with Knobloch syndrome. Collagen XVIII is a non-fibril-framing. It is more like a short isoform communicated in epithelial and endothelial base layers all through the body however especially in the eye, where it plays a significant formative part (3). Knobloch disorder is an uncommon condition. Although, the specific prevalence of the condition is obscure. The countries from where Knobloch cases were reported; are shown by red dots in the map given below.
SYSTEMATIC ANALYSIS OF SYMPTOMS
Table 1 shows the data of case reports of Knobloch patients reported to date. The symptoms are divided based on an anterior and posterior division of the eye and other clinical observations and associations found in those patients such as skeletal abnormalities, facial dysmorphisms, neurological disorders, and other interlinked malformations. Each row individually represents the records of a single research publication and includes all the cases discussed in that paper.
Causes
Mutations in COL18.A1 are the novel cause of this syndrome. This gene plays its role in the building of collagen XVIII which is an important structural protein found in the body’s connective tissues. Collagen produces endostatin, endostatin is a signaling molecule and it retards the proliferation and migration of endothelial cells. (5) Presence of collagen in appropriate amounts is very significant for normal eye development. 21q22.3 was the very first locus identified for Knobloch syndrome in 1996 in 11 affected people in a Brazilian family by sertie et al. (6) Recently mutations in another gene have been identified in Knobloch type 2 patients which is PAK 2 in two affected siblings with unaffected parents. They confirmed the mutant variant in affected children with the help of Sanger sequencing. PAK2 gene plays its role in cell growth, survival, and migration (7). Homology modeling of the PAK 2 gene showed that Glu435, Ser371, and Trp409 are present in the catalytic active site of the gene. These residues are significant for the correct conformation and stability of helical structures. A point mutation in (Glu435Lys) which is present at the active region domain of the PAK2 gene seems important for the kinase activity of the gene because this mutation has led to a decrease in phosphorylation at the catalytic site (8). Nonfunctional or haploinsufficiency of the PAK2 gene has resulted in patients with autism-related behaviors, cytoskeleton impairment, dysplasia+, bifid thumb growth delay, and related neurological disorders (9)(10)(11). All these clinical findings are also seen in patients with Knobloch syndrome having mutational COL18.A1 gene which provides clear evidence of a strong association between the two genes. Antonarakis et al hypothesized that some functional correlation might exist between COL18.A1 and PAK2 because both work in association with integrins and are activated by RAC1 which is involved in the regulation of many cell processes in the body (8).
SYSTEMATIC ANALYSIS OF MUTATIONS
Following is the table designed by analyzing the previously present data about the mutations reported in patients of Knobloch syndrome:
Table 2 discusses the type of mutations identified after genome sequencing of Knobloch patients. A total of 65 mutations have been reported in Col18.a1 and PAK2 gene, being a cause of Knobloch syndrome. Out of which, 28 were deletions, 6 were insertions, 5 were duplications and 26 were substitutions. Within the insertion and deletions, 28 were frameshift.
Methodology
A review of the literature was conducted from 1992 to 2021 and all the papers accomplishing the inclusion criteria and published by the International scholars were considered. The search strategy adopted was an article title/keyword/abstract-based search using the following key terms: ‘Knobloch/recessive and dominant’, ‘Knobloch/congenital’, ‘Knobloch /congenital ophthalmological disorders’. KNO1 reported under the study title of birth defects, ophthalmological disorder, and congenital ocular deformities were included. PubMed, Science Direct, and Google Scholar were the search engines employed for literature search. The appropriate information including authors, institute, study site, time, sample size, age group, objectives, and management strategy, was extracted. Data were maintained in excel sheet.
Clinical Techniques
Radiological examinations, CT scan, Optical Coherence Tomography (OCT), Anomaloscope plate test-5, histological examinations, ophthalmic evaluation, magnetic resonance imaging MRI, chest radiography, Echocardiogram, intelligence tests, abdominal ultrasounds, renal and cranial ultrasounds, ELISA to measure plasma concentrations, urinary tract ultrasound scan, vertebral column radiography, slit-lamp biomicroscopy, fundus photography, B scan ultrasonography, Goldmann kinetic perimetry dark adaptometry, Ganzfeld ERGs, LKC technologies, skull radiography, ocular examinations, fluorescein angiography, ultra-sonographic investigations during pregnancy, pathological analysis, psychometric evaluations, retinopathy, teeth examinations, fundus finding after pars plana vitrectomy, DNA extraction, electroencephalography, retinoscopy, vitreoretinopathy, goniotomy, trabeculotomy, auditory screening, gonioscopy were used to determine the clinical symptoms in Knobloch patients.
Genetic Molecular Techniques
RNA purification by Guanidium isothiocyanate method, PCR , silver staining for PCR production visualization, genotype analysis using polymorphic markers, dbEST database searching, bidirectional sequencing through PCR, SSCP analysis of chromosomes, DNA sequencing through Dye Deoxy Terminator Cycle Sequencing, RFLP analysis, Pyrosequencing, flanking primers through primer 3 for mutational analysis, standard chromosome testing, fish analysis, CD68 staining, direct sequencing of COL18.A1 exons, surface plasma resonance assays, immunohistochemistry, RT PCR analysis, BLAST (NCBI) for sequence retrieval, PFAM, GenBank, knockout analysis to determine if knocking out of the gene COL18.A1 has any outcome on expression, autozygosity mapping along with exome sequencing, SNP genotyping, RNA in situ hybridization, Illumina sequencing, whole-genome genotyping, confirmatory sanger sequencing, genotyping and linkage analysis, mitochondrial DNA sequencing, segregation analysis, western blotting procedures were used for the mutational analysis of patients’ genome.
Mouse Modelling
In recent years, mouse modeling has been performed for the functional analysis of COL18.A1 which is a causative gene for Knobloch syndrome, confirmed through genomic molecular analysis of several Knobloch patients. Col18.a1 directs the conformation of the protein to make a protein named collagen. Absence of collagen and its derivative endostatin results in the underdevelopment of retina and retinal vessels as well as blood vessels in the ophthalmic vitreous region. Dissociation of hyaloid vessels from the surface of the retina, leading to retinal vasculature (13)(15), and absence of VHP capillaries was evident in col18.a1 null mice which were homozygous mutant. Similarly, collagen 18 null mice also showed signs of structural anomalies along inner eye membranes and delayed expression of vascular endothelial growth factors in the retina (12). Ocular examination of Col18.a1 null mice at the age of 22 months showed varied phenotypes and irregularities when compared with wild-type species. Abnormalities included a detachment of layers of IPE cells from the iris, abnormal developmental pattern, and irregular bending of retinal vessels. Mutant mice also showed an unusual increase in thickness of BM zone present in the anterior region of iris (13)(14)(15). Ophthalmic studies along with fluorescence angiography in Col18.a1null mice also showed pigmented regions formed by the migration of cells from iris stroma leading to cluster formation and giving the appearance of iris clumps, thus blocking light from retinal vessels (13)(15). Utrianen et al in 2004 experimentally showed that Col18.a1 null mice also exhibit abnormal skull enlargements as well as irregularities associated with renal structure and functions (14). The latest evidence also shows the signs of iris atrophy and ciliary body abnormalities in collagen 18 null mice which are evident symptoms in Knobloch patients (15). Col18a1 mice and Hspg2 mutant mice were taken under observation out of which col18a1 mice have raised plasma triglycerides comparatively to that of wild type. Hypertriglyceridemia is encountered in mice due to deficiency of col18. Hypertriglyceridemia was developed due to amended extrahepatic clearance triglyceride-rich lipoproteins. In col18a1 mice, the level of lipoprotein lipase (lpl) is notably low in comparison to wild-type mice. Since the Col18a1 mice had hypertriglyceridemia, and a decrease in plasma and endothelium-bound Lpl levels in their blood; this evoked to be tested on human patients who had Col18-deficiency (16). Several anomalies were observed in collagen 18 null mouse eyes. The excessive protrusion was visible from the anterior side of the lens capsule. An examination through a Transmission electron microscope indicated an uncontrolled fibrillar stuff accumulation in an aqueous medium besides the ciliary body of transgenic mice also some inflammation was seen in the fibrillar space on top of the lens capsule. Some retinal and vitreous anomalies were suspected and encountered too. Shortage of collagen 18 resultantly gives led to enlarged eyes, lens subluxation, and lower intraocular pressure. Knobloch sufferers generate truncated protein as a result of missense mutations; they might be deleterious and harmful, this is all disclosed due to the transgenic mice’s study in which overexpression of the Tsp-1 domain or the C-terminal endostatin domain was seen (17).
Treatment
Moreover, some common abnormalities in patients with Knobloch syndrome-like cataracts, encephaloceles, blurred vision, etc. can be treated accordingly. Cataract surgery was performed on a Caucasian boy aged 12 years reported with Knobloch syndrome which improved its visual acuity in the right eye to 20/200 (18). Similarly high myopic conditions can be treated with eye surgeries to enhance vision but require proper evaluation from patient to patient (19). Likewise, Ebrahimiadib et al reported a case of an Afghani girl aged 7 years who was suffering from Knobloch syndrome confirmed through genetic testing having severe retinal detachment, underwent medical treatment including scleral buckling surgery and cryotherapy in her left eye. She showed signs of effective retinal detachment repair and improved visual impairment a few months post-surgery (20). Alsulaiman et al in 2019 published a paper that discusses the surgical treatments given to patients having retinal detachment within the timeframe of 7 years (January 2012 till December 2018). Different treatment procedures included silicone oil tamponade with scleral buckling surgery or devoid of it, pars plana vitrectomy (PPV), endolaser photocoagulation, retinectomy, triamcinolone-assisted posterior hyaloid peeling, and vitrectomy. 7 out of 9 eyes underwent operative treatments, which couldn’t be performed on the rest of two because one had a retinal detachment that was restricted to the atrophic lesion and in the other case, the parent’s consent was not available. Post-surgical procedures, 5 out of 9 eyes showed re-attachment of the retina, and two eyes showed re-detachment (21).
Discussion
The relationship of occipital encephaloceles and vitreoretinal degeneration with high nearsightedness and retinal separation was portrayed first by Knobloch and Layer in 1971. As they reported 5 siblings out of 10 in a family showed the above-mentioned conditions i.e. occipital encephaloceles and vitreoretinal degeneration with high myopia. The vitreoretinal degeneration with high nearsightedness and inevitable retinal separation or say detachment are all universally inclusive in this syndrome. The study inferred that innate occipital scalp defects in preference to genuine encephaloceles may, as is valid at times of Meckel condition, go with Knobloch syndrome (22). Clinical flexibility is available in the appearance of this syndrome’s condition (23). COL18A1 is situated on the long arm of chromosome 21 (chr21q22.3) and is made out of 43 exons. It encodes the collagen XVIII protein, which has been disclosed to be a significant part of base films (24). COL18A1 has no less than three particular isoforms of various lengths. Regardless of the fact that COL18A1 is pervasively communicated or expressed, its isoforms have distinctive tissue and formative circulation. In expansion to these three isoforms, COL18A1 can create endostatin through proteolytic cleavage. Endostatin is a gesturing molecule known to hinder the relocation and expansion of endothelial cells and is fit for stifling angiogenesis (25)(26). Through genetic investigations it has been noticed that most common mutations occur at exons 30 through 42 of COL18A1; in Knobloch condition patients. In any case, there stays a lot of heterogeneity in mutational site conveyance (27). With advancements in research recently it has also been observed that germline compound heterozygous mutations were likewise portrayed in patients with Knobloch condition (28). Some accessory anomalies in certain patients have been noticed by Caglayan A. O et al 2014; anomalies included atrial septal imperfections, seizures, and minor dysmorphic discoveries/findings. These findings foreground the huge phenotypic range that the Knobloch condition can include and can further represent the significance of type XVIII collagen in the typical improvement of various organ frameworks (29). In this study, we have thoroughly considered case reports of Knobloch syndrome patients till now. We deliberated the reports being mentioned in research papers from 1982 to 2021 and from those cases the symptoms were extracted out as shown in the table. This is collective data that is representing the most common and least commonly occurring symptoms in people being affected by Knobloch syndrome. Not only symptoms, but our analysis also highlights the major causes of Knobloch syndrome and techniques that have been used to track out this syndrome. By performing throughout analysis of all cases; the basic understanding of this syndrome is described in our study. Knobloch syndrome is a condition that is comprised of various ocular defects as well as several clinical abnormalities.
Results
A total of 83 articles have been published on Knobloch syndrome since 1971 out of which we reviewed the cases reported in patients to date. To the best of our knowledge, 49 case reports have been published in literature which reports a total of approximately 240 patients of this ophthalmic disorder up till now. Molecular techniques that were involved in determining the clinical findings in the patients of Knobloch syndrome included clinical molecular techniques and genetic molecular techniques.
Future Recommendations
As it is evident that Knobloch syndrome involves ocular abnormalities that vary among patients but high myopia, encephaloceles, and occipital defects are the most common symptoms of this condition (30). Because a lot of mutations are a cause of this particular disorder, there is no specific treatment introduced to tackle these kinds of mutations, however, genome sequencing can tell us about the faulty gene and precautions can be taken in this regard. The incidence of inherited genetic disorders among children from a consanguineous marriage is double the rate of children from parents that are not related to each other (31). Consanguinity can be eluded to avoid such genetic disorders.
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| Sr. no | Refrences | No of Patients | Age | Ethnicity | Anterior Symptoms | Posterior Symptoms | Associations | Journals | Journals' Country | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Czeizel et al 1992 | 2 | 6-14 years | hungarian family | blurred vision, enlarged pupil, lens dislocation, | macular atrophy, high myopiacharacteristic vitreo-retinal degeneration, white cataractretinal detachment, retinal thinning, vitreous haze, Posterior synechiae, pigmented degenerative macula | occipital bone abnormality, meningocele, occipital dermal sinus tract, occipital scalp defects, skull abnormalities, spina bifida occulta, carious teeth, asymmetric chest, unusual palmar creases, nail hypoplasia, renal abnormalitieshetrotropic neuronal tissue | American journal of medical genetics | United States | ||||
| 2 | Seaver et al 1993 | 2 | 11 y, 2 y | posterior perinuclear lens opacity, upslanting palpebral fissures, | severe retinal pigment epithelial atrophy, high myopia,characteristic vitreo-retinal degeneration, retinal detachment, abnormal vitreous,macular hypoplasia, blonde funduselevation of optic disc | occipital bone abnormality,facial dysmorphisms, occipital scalp defects, spina bifida occulta, Ectatic venular structures, central cutaneous dimple, cavernous hemangioma, midfacial hypoplasia, generalized hyperextensibility, defective neuroectodermal morphogenesis, temporal crowding of vessels | American journal of medical genetics | United States | |||||
| 3 | Bueno et al 1994 | 11 Cases | 24 y, 18y, 31y | blurred vision, lens dislocation, iris transillumination, optical phthisis, Band keratopathy, neovascular glaucoma | retinal detachment, retinal thinning,macular hypoplasia, | polymicrogyria, occipital bone abnormality, occipital dermal sinus tract, extracranial lesion, atretic cephalocele | American journal of medical genetics | United States | |||||
| 4 | Sertie et al 1996 | 11 cases | Brazilian family | iris transillumination | macular atrophy, high myopia, retinal detachment | Encephalocele | Human molecular genetics | United Kingdom | |||||
| 5 | Wilson et al 1998 | 2 cases | 9 months, 1 month | Caucasion family | nystagmus, perinuclear lens opacity | high myopia, retinal detachment, retinal degeneration, peripheral retinopathy | Encephalocele, unusual pulmonary lymphatic condition, alveolar hyperinflation, pleural thickeningventricular septal defect, patent ductus arteriosis, vomiting, pyloric stenosis, biventricular hypertrophydolichocephalic skull with micrognathia, pulmonary lymphatic dilation, telecanthus | American journal of medical genetics | United States | ||||
| 6 | Sertie et al 2000 | 24 cases | Brazilian family | lens subluxation, corneal edema | high myopia, retinal degeneration, cataract, macular pigmentation loss | chronic cardiac hypertension, facial dysmorphisms, spina bifida occulta, midfacial hypoplasia, patent ductus arteriosis, pyloric stenosis, occipital lobe defects, kidney defects, bifid ureter, lung hypoplasia, neural tube closure defects, generalized hypertensibility, unusual palmar creases | Human molecular genetics | United Kingdom | |||||
| 7 | Suzuki et al 2002 | 14 cases | 3 days -33 yrs | Brazilian, North American, Canadian-Haitian origin, Hungarian families | Blurred vision | high myopia, retinal degeneration, retinal detachment, macular degeneration | Epilepsy, Encephalocele, occipitalscalp defects, ocular alterationsdevelopmental delay, telecanthus | American journal of human genetics | United States | ||||
| 8 | Kleimann et al 2003 | 4 cases | 11y, 7y, 19y,13y | exotropia, nystagmus, esotropia, band keratopathy, partial blindness | retinal pigment epithelial atrophy, high myopia, cataract, retinal detachment, optical phthisis, macular hypoplasia, macular degeneration, exophthalms, myopic degeneration, myopic astagmatism | epilepsy, mental delay, pleural thickening ventricular septal defectpatent ductus arteriosis, ventricular dilatation, retrocerebeller arachnoid cyst, hemangioma | American journal of medical genetics | United States | |||||
| 9 | Sarra et al 2003 | 4 cases | Eastern Switzerland | Retinal pigment epithelium atrophy, retinal staphylomas, optical phthisis, retinal atrophy, viterous detachment, clumps in retina, lattice degeneration, glaucomatous excavation in optic disc | Archives of ophthalmology | United States | |||||||
| 10 | Menzel et al 2004 | 4 cases | Hungarian and New Zealandfamilies | Lens abnormalities, no light perception | macular atrophy, high myopiacataract, retinal detachment, retinal opacities, flat retina | Encephalocele, mental delay, meningocele, unusual pulmonary lymphatic condition, autistic disorder, tuft of dark hair in occipital region, pulmonary vasculature, changes in bronchial wall thickening | Human mutation | United States | |||||
| 11 | Duh et al 2004 | 1 case | 16 months | American Indian, African American ancestry | hypoplastic iris crypts, bilateral leukocoria, no light perception | cataract, tasellated fundus, retinal staphylomas, irregular choriocapillaries, foveal hypoplasia,viterous detachment, posterior fetal vasculature, vasa hyaloidea propria, retinal vessel thinning | occipital scalp defects, crow's feet, | Ophthalmology | United States | ||||
| 12 | Keren et al 2007 | 2 cases | 2 years | Algerian family | nystagmus, loss of vision | high myopia, retinal detachment, peripheral vitriretinopathy, chorioretinal leision, retinal vessel rigidity, retinal coloboma heterotropia | Encephalocele, neurodevelopmental disorders, ccipital bone abnormality,learning and language difficulties, facial dysmorphism, meningocele, skull abnormalities, mesencephalic lesions, CNS abnormalities, vermian agenesis, mesencephalic hamartoma, temporal narrowing, microcephaly, enlarged neck, occipital lobe abnormalities, retroganthia, cerebellar malformations, isthmic dysplasia | American journal of medical genetics | United States | ||||
| 13 | Khaliq et al 2007 | 5 cases | 18y, 10 y, 16y, 15y, 9y | Pakistani Family | nystagmus, optical phthisis, night blindness, glaucoma, loss of vision, lens subluxation | high myopia, retinal degeneration, macular degeneration, retinal atrophy, clumps in retina, retinal vasculature, choroidal sclerosis, viterous haemorrage, peripapillary atrophy | Occipital focal skin defect, swolen purplish hairless patch | American journal of medical genetics | United States | ||||
| 14 | Connell et al 2008 | 1 case | 8 y | clumps in retina | meningocele, vomiting, pyloric stenosis, nodular leisions, fibrotic lesion in lips | International journal of paediatric dentistry | United Kingdom | ||||||
| 15 | Theresa et al 2008 | 1 case | 7 y | high myopia, peripheral retinopathy | learning and language difficulties,biventricular hypertrophy, dolichocephalic skull with micrognathia, hairless scalp with one tuft, CSF leakage at tuft point | Ophthalmic genetics | United Kingdom | ||||||
| 16 | Suzuki et al 2009 | 5 cases | 1 y | Brazilian and North American families | Blindness | high myopia, enophthalmos, myopic degeneration, myopic astigmatism | Encephalocele | Molecular vision | United States | ||||
| 17 | Mahajan et al 2010 | 3 cases | 4y, 7y, 11y | Al Saluadorian family | blurred vision, nystagmus | high myopia | neurodevelopmental disorders, encephalocele, alopecia in occipital region, occipital dermal sinus tract, occipital scalp defects, occipital tissue swelling, hypotoxia, white matter loss, Frontal cortical dysplasia, mild ventriculomegaly, high signal along supratentorial sulci | American journal of medical genetics | United States | ||||
| 18 | Bongiovanni et al 2011 | 1 case | 12 y | Caucasion family | exotropia, porterior perinuclear lens opacity, lens dislocation, loss of vision, bilateral leukocoria | Fetal vasculature, macular scarring, viterous detachment, glaucomatousexcavation in optic disc, lattice degeneration, retinal atrophy, clumps in retina, retinal staphylomas, cataract,high myopia | Clinical ophthalmology | New Zealand | |||||
| 19 | Aldahmesh et al 2011 | 13 cases | 12y, 15y, 21y, 8y, 7y, 4y, 5y, 14m, 17y, 24y, 8y, 4y | Saudi origin families | ectopia lentis, lens subluxation | high myopia, retinal degeneration, cataract, retinal detachment, opticalphthisis, clumps in retina | epilepsy, mental delay, occipital bone abnormality, occipital cutis aplasia, right clavicular pseudoarthrosis | Journal of medical genetics | United Kingdom | ||||
| 20 | Khan et al 2012 | 8 cases | 4y-15y | Saudi origin families | Blurred vision, exotropia, nystagmus, esotropia, porterior perinuclear lens opacity, scattered lens opacity, ectopia lentis, aphakic dilation, traumatic pupillary block glaucoma, suprotemporal subluxation, superonasal posterior segment lens opacity, | severe retinal pigment epithelial atrophy, high myopia,characteristic vitreo-retinal degeneration, ondensations white cataract | epilepsy, mental delay, encephalocele,focal hair defect, occipital focal skindefect | The British journal of ophthalmology | United Kingdom | ||||
| 21 | Meier 2013 | 1 case | 7y | retinal detachment, abnormal vitreous, | Klinische Monatsblatter fur Augenheilkunde | Germany | |||||||
| 22 | Peluso et al 2013 | 1 case | 30y | Southern Italy | Blurred vision, exotropia, nystagmus, loss of vision, hypermetrophic refraction, | retinal dystrophy, night blindness | mental delay, cognitive delay, autisticdisorder | Orphanet journal of rare diseases, | United Kingdom | ||||
| 23 | Khan et al 2013 | 1 case | 3y | Saudi Arabian | Blurred vision, nystagmus, microphthalmia, lens subluxation, pupillary dilation | retinal atrophy | Ophthalmic genetics | United Kingdom | |||||
| 24 | Haghighi et al 2014 | 10 cases | Iranian ancestry | Blurred vision, esotropia, nystagmus,porterior perinuclear lens opacity, | macular punched out lesions, high myopia, characteristic vitreo-retinal degeneration, retinal detachment, white cataract, elevation of optic disc, retinal atrophy | PloS one | United States | ||||||
| 25 | Ahmet et al 2014 | 4 cases | 13y-22y | Turkish Family | optical phthisis, loss of vision, lens subluxation, congenital aphakia, leukoma | high myopia, characteristic vitreo-retinal degeneration, retinaldetachment,elevation of optic disc, | mental delay, encephalocele, polymicrogyria, occipital boneabnormality, facial dysmorphisms, occipital dermus sinus tract, cognitive delay, pachygyria, seizures, ventricular dilation, heterotropic grey matter in lateral ventricles, abnormal cerebellar hemisphere formation, mesencephalic lesions, slender spinal cord, brainstem volume loss, artrial septal defect | Pediatric neurology | United States | ||||
| 26 | Khan et al 2015 | 1 case | 3y | Saudi Arabian | Blurred vision, nystagmus, microphthalmia, lens subluxation, pupillary dilation, lens subluxation | tilted optic nerve, mild cone-rod dystrophy, retinal atrophy | occipita lobe defects, occipital bone abnormlity | Ophthalmic Genetics | United Kingdom | ||||
| 27 | Albakri et al 2016 | 7 cases | 6y-17y | Blurred vision, lens subluxation, | severe retinal pigment epithelial atrophy, macular punched out lesions, high myopia, retinal detachment, irregular choriocapillaris, foveal hypoplasia, retinal atrophy, choroidal sclerosis | occipital scalp defects | Ophthalmic Genetics | United Kingdom | |||||
| 28 | Hull et al 2016 | 12 cases- 7 families | 2y-38y | Indian/British/Slovak/Arab/ Northern European/African | Blurred vision, nystagmus, posterior perinuclear lens opacity, iris transillumination, lens subluxation, pupillary dilation, absent iris crypts, | severe retinal pigment epithelial atrophy, macular atrophy, high myopia, white cataract, retinal detachment, glaucomatous disc cupping | Epilepsy, mental delay, encephalocele,polymicrogyria, alopecia in occipital region, learning and language difficulties, facial dysmorphisms, meningocele, skull abnormalities, hairless scalp with one tuft, hypermobile joints, kidney defects, bifid ureter, hamstring sarcoma | JAMA ophthalmology, | United States | ||||
| 29 | Charsar et al 2017 | 2 cases | 29m | Nystagmus, esotropia, bilateral buphthalmos, amblyopia, | High myopia | Epilepsy, mental delay, polymicrogyria, seizures, brainstem volume loss | Pediatric neurology | United States | |||||
| 30 | Ebrahim et al 2017 | 1 case | 7y | Afghani | Nystagmus, anterior chamber parenthesis | severe retinal pigment epithelial atrophy, high myopia, characteristic vitreo-retinal degeneration, retinal detachment, retinal staphylomas, retinal thinning, abnormal vitreous, foveal hypoplasia, posterior synechiae, elevation of optic disc, retinal atrophy, arterial attenuation, retinal lesion | polymicrogyria, seizures | Digital journal of ophthalmology | United States | ||||
| 31 | Gradstein et al 2017 | 1 case | 2m | Blurred vision, nystagmus, esotropia | Macular atrophy, high myopia, retinal detachment, retinal atrophy, choroidal sclerosis | Polymicrogyria, cognitive delay, seizures, | Documenta ophthalmologica. Advances in ophthalmology | Netherlands | |||||
| 32 | Corbett et al 2017 | 4 cases | 41y-59y | Northern-European descent, born in Australia | Blurred vision, nystagmus, ectopia lentis, optical phthisis, microsclerocornea, neovascular glaucoma, loss of vision, pupillary dilation, no light perception, absent iris crypts, iris hypoplasia, aphakia, | High myopia, white cataract, retinal detachment, optic atrophy, fundus atrophic lesions, abnormal vitreous, macular degeneration, posterior embryotoxon | Polymicrogyria, mental delay, learning and language difficulties, seizures, myoclinic jerks, cardiovascular strokes | European journal of medical genetics | France | ||||
| 33 | White et al 2017 | 2 cases | 7m, 13y | Blurred vision, exotropia, nystagmus, esotropia, | severe retinal pigment epithelial atrophy, high myopia, macular atrophy, retinal detachent, retinal staphylomas, tessellated fundus, tilted optic nerve, mild cone-rod dystrophy, optic atrophy, retinal vascular attenuation, irregular choriocapillaris, retinal thinning | Mental delay, polymicrogyria, grey matter thickening in gyri, | BMC ophthalmology | United Kingdom | |||||
| 34 | Beshri et al 2018 | 1 case | 2m | Bilateral buphthalmos, no light perception, epiphora | High myopia, retinal detachment, elevation of optic disc, peripheral vitreoretinopathy, retinal atrophy, | Occipital bone abnormality, hypotoxia | Middle East African journal of ophthalmology | India | |||||
| 35 | Zhang et al 2018 | 3 cases | 31y,33y, demised | Chinese Family | Blurred vision, exoptropia, loss of vision, lens subluxation, | High myopia, retinal detachment, white cataract, vitreous detachment, macular scarring, | Epilepsy, frontal cortical dysplasia, cerebellar malformations | International journal of ophthalmology | China | ||||
| 36 | Suri et al 2018 | 10 cases | 41y-69y | Neovascular glaucoma | Tilted optic nerve, retinal atrophy | premature arterial contractions | Human molecular genetics | United Kingdom | |||||
| 37 | Khan et al 2018 | 5 cases | 20m-16y | Emirati family | Nystagmus, esotropia, optial phthisis, hypertelorism, neovascular glaucoma, no light perception, iris hypoplasia, aphakia, down-slanting palpebral fissures, Ahmed glaucoma valve | Macular atrophy, high myopia, white cataract, retinal detachment, abnormal vitreous, retinal dystrophy, retinal atrophy | Mental delay, occipital tissue swelling, occipital lobe defects, partially deaf, hypotoxia, diaphragmatic eventration, lung hypoplasia, omphalocele, ribs abnormalities, scoliosis | Ophthalmic genetics | United Kingdom | ||||
| 38 | Alsulaiman et al 2019 | 5 cases | 2m-5y | Blurred vision, nystagmus | Macular punched out lesions, retinal detachment, retinal staphylomas, retinal thinning | Occipital lobe defects, | Ophthalmology | United States | |||||
| 39 | Thau et al 2019 | 5 cases | Blurred vision, nystagmus, ectopia lentis, convergent strabismus, abnormal red reflux, | severe retinal pigment epithelial atrophy, high myopia, tessellated fundus, retinal vascular attenuation, retinal thinning, retinoschisis, epiretinal membrane, poor retinal lamination, myopic choroidal thinning | Alopecia in occipital region, occipital dermal sinus tract, occipital scalp defects, skull abnormalities, otitis media | Ophthalmic surgery, lasers & imaging retina | United States | ||||||
| 40 | Mayer et al 2020 | 20 cases | Arab villages of Israel and the Palestinian Authority | Blurred vision, nystagmus, microphthalmia, anterior segment disgenesis, congenital nanophthalmos, microsclerocornea, atrophic eye balls | White cataract, retinitis pigmentosa, night blindness, foveal hypoplasia, Stargardt disease, retinal dystrophy, Leber congenital amaurosis, achromatopsia, fundus albipunctatus, | Opthalmic disorder, photophobia, mental delay, osteopetrosis, Usher syndrome, hearing problems | European journal of human genetics | United Kingdom | |||||
| 41 | Balikova et al 2020 | 3 cases | 2y,15y,46y | Blurred vision, nystagmus, lens dislocation, hypoplastic iris crypts, iris transillumination, correctopia, up-slanting palpebral fissures, | severe retinal pigment epithelial atrophy, high myopia, macular atrophy, macular punched out lesions, retinal detachment, retinal thinning, fundus atrophic lesions, abnormal vitreous, | Encephalocele, occipital focal skin defects, occipital bone abnormality, alopecia in occipital region, bilateral renal atrophy, chronic cardiac hypertension, dislipidemia, sleep apnoea, accessory spleen, venous insufficiency in lower limbs, atrophic skin lacerations, slow healing of wounds, congenital occipital mass with serosanguineous secretions | Ophthalmic genetics | United Kingdom | |||||
| 42 | Capurro et al 2020 | 1 case | 8y | Chile | Blurred vision, nystagmus, aphakic dilated left pupil, iris transillumination, bilateral buphthalmos, abnormal stereopsis, convergent strabismus, | high myopia, irregular choriocapillaris, abnormal vitreous, loss of neuroretinal rim in temporal optic disc, | Alopecia in occipital region, facial dysmorphism, short neck and low set of ears | American journal of medical genetics | United States | ||||
| 43 | Levinger et al 2020 | 4 cases | 1y, 3.5y, 22y, 26y | Jewish, Muslim Arab, | Nystagmus, iris transillumination, optical phthisis, | high myopia, retinal detachment, mild cone-rod dystrophy, albinotic retina, scarring of retina, retinitis pigmentosa, macular coloboma, deteriotation in photoreceptor function, | Epilepsy, polymicrogyria, alopecia in occipital region, albinism, Dandy walker malformations, meningocele, | European journal of ophthalmology | Italy | ||||
| 44 | Marzo et al 2021 | 1 case | Posterior perinuclear lens opacity, aphakic dilated left pupil, featureless iris | High myopia, fundus atrophic lesion, hypopigmented fundus, macular hypoplasia, absence of choriocapillaris, retinoschisis, posterior synechiae | Encephalocele, occipital focal skin defects | Canadian journal of ophthalmology( Journal canadien d'ophtalmologie) | United States | ||||||
| 45 | Wang et al 2021 | 6 cases | 4m-5y | Chinese Families | Convergent strabismus, loss of vision | High myopia, white cataract, tessellated fundus, mild cone-rod dystrophy, foveal hypoplasia, choroidal sclerosis, macular pigmentation loss | Mental delay, alopecia in occipital region, occipital scalp defects, skull abnormalities, cerebellar malformations, ataxia, vascular leakage, papillar dysplasia | Frontiers in cell and developmental biology | Switzerland | ||||
| 46 | Antonarkis et al 2021 | 2 cases | 24y, 26y | New Zealand family | No light perception | Characteristic vitreo-retinal degeneration, abnormal vitreous, flat retina, white cataract, retinal detachment, retinal nodular opacities | Encephalocele, learning and language difficulties, hairless scalp with one tuft, autistic disorder | Human molecular genetics | United Kingdom | ||||
| 47 | Wawrzynski et al 2021 | 2 cases | 27y, 29y | Blurred vision, optical phthisis, pupillary dilation, no light perception, corneal edema, anisometropia, acute angle closure glaucoma | High myopia, retinal detachment, retinal staphylomas, retinal pigmentosa, retinal dystrophy, elevation of optic disc, retinal atrophy | Epilepsy, occipital bone abnormality, learning and language difficulties, nausea | Journal of glaucoma | United States | |||||
| 48 | Venkateshappa et al 2021 | 1 case | 7y | High myopia, retinal detachment, white cataract | Encephalocele, polymicrogyria, occipital bone abnormality, seizures, bilateral subependymal heterotopia | Pediatric neurosurgery | Switzerland | ||||||
| Mutation NM_030582.3 | Protein | Exon number of 43 | Types of Mutation |
| In 5’ UTR (-50,112 nucleotides) | 1 | ||
| c.895delG | p.Val299Serfs*5 | 4 | Deletion, Frameshift |
| c.1469-2A>G | 7 | Substitution | |
| c.1604insC | p.Gly538Argfs*55 | 9 | Insertion, Frameshift |
| c.1761_2054del | p.Asp589_Gly686del | 9-14 | Deletion |
| c.1778-9insA | p.Asp593Glufs*58 | 10 | Insertion, Frameshift |
| c.2325_2326delCCinsA | p.Pro777Leufs*127 | 17 | Deletion, Insertion, Frameshift |
| c.2416C>T | p.Arg806* | 18 | substitution |
| c.2437-2A>G; c.3213dupC | 17?? | substitution, duplication | |
| c.2645delT | p.Leu882Profs*22 | 23 | Deletion, Frameshift |
| c.2658dupC | p.Gly887Argfs*23 | 23 | Duplication, Frameshift |
| :c.2970_2971delAGinsC | Deletion, Insertion | ||
| c.2797C>T | p.Arg933* | 26 | Substitution |
| c.3213dupC | p.Gly1072Argfs*9 | 33 | Duplication, Frameshift |
| c.3283C>T | p.Arg1095* | 35 | Substitution |
| c.3356_7insT | p.Gly1122Argfs*145 | Insertion, Frameshift | |
| c.3363_3364insC | p.Gly1122Argfs*32 | 35 | Insertion, Frameshift |
| c.3364_3371delGGCCCCCC | p.Gly1125Argfs*142 | 35 | Deletion, Frameshift |
| c.3459dupC | p.Gly1154Argfs*110 | Duplication, Frameshift | |
| c.3509-3518delCAGGGCCCCC | p.Pro1170Glnfs*38 | 36 | Deletion, Frameshift |
| c.3544+3A >C | 36 | Substitution | |
| c.3690G>A and c.4063_4064delCT | p.W1230* and p.L1355Vfs*72 | ???, 41 | Deletion, Frameshift |
| c.3811C>T | p.Gln1273* | 40 | Substitution |
| delEx41 | 41 | Deletion | |
| c.4063_4064delCT | p.Leu1355Valfs*72 | 41 | Deletion, Frameshift |
| c.4173G>A | Substitution | ||
| c.4374_4387del | p.Ser1459Alafs*9 | 43 | Deletion, Frameshift |
| c.4494_4497insTGCC | p.Ala1499Cysfs*14 | 43 | Insertion, Frameshift |
| c.4759_4760delTC | p.L1587Vfs*72 | 40 | Deletion, Frameshift |
| c.4181G>A | Substitution | ||
| c.2960_2969dup, c.3514_3515del, c.1610del and c.4492 del G | p.Gly991Argfs*96, p.Leu1172Valfs*72, Pro537Glnfs*16 and p. Glu1498Lys*fs | Duplication, Deletion, Frameshift | |
| c.5512C>G, c.5882G>A | His1838Asp, p.Gly1961Glu | Substitution | |
| c.2230C>T | p.Arg744Ter | Substitution | |
| c.2673C>A | p.Cys891Ter | Substitution | |
| c.3307G>A | p.(Gly1103Arg) | Substitution | |
| c.985G>T | p.(Gly329Cys) | Substitution | |
| c.940_942delATC | p.(Ile314del) | Deletion | |
| c.1003C>T | p.(Arg335Ter) | Substitution | |
| c.14315C>G | p.(Ser4772Ter) | Substitution | |
| c.79delA | p.(Thr27Profs*26) | Deletion, Frameshift | |
| c.1107delA | p.(Glu370Asnfs*5) | Deletion, Frameshift | |
| c.1–23706_373–709delinsTGG | Deletion, insertion | ||
| c.284G > A | p.(Arg95His) | substitution | |
| c.679C > T | p.(Arg227Trp) | substitution | |
| c.2459A > G | p.(Gln820Arg) | substitution | |
| c.1774G > A | p.(Gly592Ser) | substitution | |
| c.3514_3515delCT | p.(Leu1172Valfs*72) | Deletion, frameshift | |
| c.678delT | p.(Asn226Lysfs*38) | Deletion, frameshift | |
| c.1861C > T | p.(Gln621Ter) | Substitution | |
| PAK2 c.1303 G>A | p.(Glu435Lys) | Substitution | |
| c. 2_4del | p.? | Deletion | |
| c.718G>A | (p.Gly240Arg) | Substitution | |
| c.2134C>T | p.Arg712* | Substitution | |
| c.2673del | p.Gly892Aspfs*17 | Deletion, Frameshift | |
| c.4290_4299del | p.(Gly1431Glufs*9) | 35/41 | Deletion, Frameshift |
| c.4259-28_4265del | 34/41 | Deletion | |
| c.4759_4760del | p.(Leu1587Valfs*72) | 39/41 | Deletion, Frameshift |
| c.4579C > T | p.(Gln1527*) | 32/63 | Substitution |
| c.1487dup | p.(Asn496Lysfs*15) | 63/11 | Duplication, Frameshift |
| c.6151C > T | p.(Arg2051*) | 43/63 | Substitution |
| c.1494_1504del | p.(Gly499Valfs*8) | 63/11 | Deletion, Frameshift |
| c.4171_4172del | p.(Arg1391Glyfs*19) | 29/63 | Deletion, Frameshift |
| Mutation NM_030582.3 | Protein | Exon number of 43 | Types of Mutation |
| In 5’ UTR (-50,112 nucleotides) | 1 | ||
| c.895delG | p.Val299Serfs*5 | 4 | Deletion, Frameshift |
| c.1469-2A>G | 7 | Substitution | |
| c.1604insC | p.Gly538Argfs*55 | 9 | Insertion, Frameshift |
| c.1761_2054del | p.Asp589_Gly686del | 9-14 | Deletion |
| c.1778-9insA | p.Asp593Glufs*58 | 10 | Insertion, Frameshift |
| c.2325_2326delCCinsA | p.Pro777Leufs*127 | 17 | Deletion, Insertion, Frameshift |
| c.2416C>T | p.Arg806* | 18 | substitution |
| c.2437-2A>G; c.3213dupC | 17?? | substitution, duplication | |
| c.2645delT | p.Leu882Profs*22 | 23 | Deletion, Frameshift |
| c.2658dupC | p.Gly887Argfs*23 | 23 | Duplication, Frameshift |
| :c.2970_2971delAGinsC | Deletion, Insertion | ||
| c.2797C>T | p.Arg933* | 26 | Substitution |
| c.3213dupC | p.Gly1072Argfs*9 | 33 | Duplication, Frameshift |
| c.3283C>T | p.Arg1095* | 35 | Substitution |
| c.3356_7insT | p.Gly1122Argfs*145 | Insertion, Frameshift | |
| c.3363_3364insC | p.Gly1122Argfs*32 | 35 | Insertion, Frameshift |
| c.3364_3371delGGCCCCCC | p.Gly1125Argfs*142 | 35 | Deletion, Frameshift |
| c.3459dupC | p.Gly1154Argfs*110 | Duplication, Frameshift | |
| c.3509-3518delCAGGGCCCCC | p.Pro1170Glnfs*38 | 36 | Deletion, Frameshift |
| c.3544+3A >C | 36 | Substitution | |
| c.3690G>A and c.4063_4064delCT | p.W1230* and p.L1355Vfs*72 | ???, 41 | Deletion, Frameshift |
| c.3811C>T | p.Gln1273* | 40 | Substitution |
| delEx41 | 41 | Deletion | |
| c.4063_4064delCT | p.Leu1355Valfs*72 | 41 | Deletion, Frameshift |
| c.4173G>A | Substitution | ||
| c.4374_4387del | p.Ser1459Alafs*9 | 43 | Deletion, Frameshift |
| c.4494_4497insTGCC | p.Ala1499Cysfs*14 | 43 | Insertion, Frameshift |
| c.4759_4760delTC | p.L1587Vfs*72 | 40 | Deletion, Frameshift |
| c.4181G>A | Substitution | ||
| c.2960_2969dup, c.3514_3515del, c.1610del and c.4492 del G | p.Gly991Argfs*96, p.Leu1172Valfs*72, Pro537Glnfs*16 and p. Glu1498Lys*fs | Duplication, Deletion, Frameshift | |
| c.5512C>G, c.5882G>A | His1838Asp, p.Gly1961Glu | Substitution | |
| c.2230C>T | p.Arg744Ter | Substitution | |
| c.2673C>A | p.Cys891Ter | Substitution | |
| c.3307G>A | p.(Gly1103Arg) | Substitution | |
| c.985G>T | p.(Gly329Cys) | Substitution | |
| c.940_942delATC | p.(Ile314del) | Deletion | |
| c.1003C>T | p.(Arg335Ter) | Substitution | |
| c.14315C>G | p.(Ser4772Ter) | Substitution | |
| c.79delA | p.(Thr27Profs*26) | Deletion, Frameshift | |
| c.1107delA | p.(Glu370Asnfs*5) | Deletion, Frameshift | |
| c.1–23706_373–709delinsTGG | Deletion, insertion | ||
| c.284G > A | p.(Arg95His) | substitution | |
| c.679C > T | p.(Arg227Trp) | substitution | |
| c.2459A > G | p.(Gln820Arg) | substitution | |
| c.1774G > A | p.(Gly592Ser) | substitution | |
| c.3514_3515delCT | p.(Leu1172Valfs*72) | Deletion, frameshift | |
| c.678delT | p.(Asn226Lysfs*38) | Deletion, frameshift | |
| c.1861C > T | p.(Gln621Ter) | Substitution | |
| PAK2 c.1303 G>A | p.(Glu435Lys) | Substitution | |
| c. 2_4del | p.? | Deletion | |
| c.718G>A | (p.Gly240Arg) | Substitution | |
| c.2134C>T | p.Arg712* | Substitution | |
| c.2673del | p.Gly892Aspfs*17 | Deletion, Frameshift | |
| c.4290_4299del | p.(Gly1431Glufs*9) | 35/41 | Deletion, Frameshift |
| c.4259-28_4265del | 34/41 | Deletion | |
| c.4759_4760del | p.(Leu1587Valfs*72) | 39/41 | Deletion, Frameshift |
| c.4579C > T | p.(Gln1527*) | 32/63 | Substitution |
| c.1487dup | p.(Asn496Lysfs*15) | 63/11 | Duplication, Frameshift |
| c.6151C > T | p.(Arg2051*) | 43/63 | Substitution |
| c.1494_1504del | p.(Gly499Valfs*8) | 63/11 | Deletion, Frameshift |
| c.4171_4172del | p.(Arg1391Glyfs*19) | 29/63 | Deletion, Frameshift |
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