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11 pages, 1406 KiB

Open AccessArticle

A Novel Transcriptome Approach to the Investigation of the Molecular Pathology of Vitreous and Retinal Detachment

by Mel Maranian and Martin Snead

Genes 2022, 13(10), 1885; https://doi.org/10.3390/genes13101885 - 18 Oct 2022

Viewed by 2152

Retinal detachment (RD) is one of the most common, sight-threatening ocular conditions requiring emergency intervention. Posterior vitreous detachment (PVD) occurs in the majority of an aging population whereby the vitreous body separates from the retina. It is well established that PVD is the [...] Read more.

Retinal detachment (RD) is one of the most common, sight-threatening ocular conditions requiring emergency intervention. Posterior vitreous detachment (PVD) occurs in the majority of an aging population whereby the vitreous body separates from the retina. It is well established that PVD is the common precursor to the most common forms of RD; however, it remains unknown why in most individuals PVD will cause no/few complications (physiological PVD) but in a small percentage will cause retinal tears and detachment (pathological PVD). Despite over 100 years of scientific research, the anatomical definitions of PVD and its pathogenesis remain controversial. Recent research has identified a novel cell population (laminocyte), present at significantly higher numbers in pathological PVD when compared to physiological PVD. We review and summarise the seven distinct clinical sub-groups of retinal breaks and focus on the role of the laminocyte in those secondary to PVD and the transcriptomic profile of this unique cell. Provisional whole transcriptome analysis using bulk RNA-Seq shows marked differentially expressed genes when comparing physiological PVD with PVD associated with RD. The limitations of bulk RNA-Seq are considered and the potential to address these using spatial transcriptomics are discussed. Understanding the pathogenesis of PVD-related retinal tears will provide a baseline for the development of novel therapeutic targets and prophylactic treatments. Full article

(This article belongs to the Special Issue Genetics in Stickler Syndrome)

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9 pages, 3442 KiB

Open AccessArticle

Prevention of Blindness in Stickler Syndrome

by Philip Alexander and Martin P. Snead

Genes 2022, 13(7), 1150; https://doi.org/10.3390/genes13071150 - 26 Jun 2022

Cited by 5 | Viewed by 2791

Abstract

Stickler syndromes are inherited conditions caused by abnormalities of structural proteins in the eye, inner ear and cartilage. The risk of retinal detachment, particularly due to the development of giant retinal tears, is high. Stickler syndrome is the most common cause of childhood [...] Read more.

Stickler syndromes are inherited conditions caused by abnormalities of structural proteins in the eye, inner ear and cartilage. The risk of retinal detachment, particularly due to the development of giant retinal tears, is high. Stickler syndrome is the most common cause of childhood retinal detachment. Although retinal detachment surgery in the general population has a high success rate, outcomes from surgical repair in Stickler syndrome patients are notoriously poor, providing a strong argument for prophylactic intervention. Variable case selection, absence of molecular genetic sub-typing and inconsistent treatment strategies have all contributed to the historic uncertainty regarding the safety and efficacy of prophylactic treatment. This paper reviews the major published clinical studies that have evaluated different methods and strategies for prophylaxis. Based on the current body of literature, there is extremely strong evidence from cohort comparison studies demonstrating the efficacy and safety of prophylactic retinopexy to reduce, but not eliminate, the risk of retinal detachment in Stickler syndrome patients. It is vital that this body of evidence is provided to Stickler syndrome patients, to enable them to make their own fully informed choice about whether to receive prophylaxis for themselves and particularly on behalf of their affected children, to reduce the risk of retinal detachment. Full article

(This article belongs to the Special Issue Genetics in Stickler Syndrome)

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Review

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13 pages, 998 KiB

Open AccessReview

Orofacial Clefts: Genetics of Cleft Lip and Palate

by Arwa Babai and Melita Irving

Genes 2023, 14(8), 1603; https://doi.org/10.3390/genes14081603 - 09 Aug 2023

Cited by 3 | Viewed by 4074

Abstract

Orofacial clefting is considered one of the commonest birth defects worldwide. It presents as cleft lip only, isolated cleft palate or cleft lip and palate. The condition has a diverse genetic background influenced by gene–gene and gene–environment interaction, resulting in two main types, [...] Read more.

Orofacial clefting is considered one of the commonest birth defects worldwide. It presents as cleft lip only, isolated cleft palate or cleft lip and palate. The condition has a diverse genetic background influenced by gene–gene and gene–environment interaction, resulting in two main types, syndromic and nonsyndromic orofacial clefts. Orofacial clefts lead to significant physiological difficulties that affect feeding, speech and language development and other developmental aspects, which results in an increased social and financial burden on the affected individuals and their families. The management of cleft lip and palate is solely based on following a multidisciplinary team approach. In this narrative review article, we briefly summarize the different genetic causes of orofacial clefts and discuss some of the common syndromes and the approach to the management of orofacial clefts. Full article

(This article belongs to the Special Issue Genetics in Stickler Syndrome)

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9 pages, 276 KiB

Open AccessReview

The Genetic Architecture of Non-Syndromic Rhegmatogenous Retinal Detachment

by Malik Moledina, David G. Charteris and Aman Chandra

Genes 2022, 13(9), 1675; https://doi.org/10.3390/genes13091675 - 19 Sep 2022

Viewed by 1569

Abstract

Rhegmatogenous retinal detachment (RRD) is the most common form of retinal detachment (RD), affecting 1 in 10,000 patients per year. The condition has significant ocular morbidity, with a sizeable proportion of patients obtaining poor visual outcomes. Despite this, the genetics underpinning Idiopathic Retinal [...] Read more.

Rhegmatogenous retinal detachment (RRD) is the most common form of retinal detachment (RD), affecting 1 in 10,000 patients per year. The condition has significant ocular morbidity, with a sizeable proportion of patients obtaining poor visual outcomes. Despite this, the genetics underpinning Idiopathic Retinal Detachment (IRD) remain poorly understood; this is likely due to small sample sizes in relevant studies. The majority of research pertains to the well-characterised Mende lian syndromes, such as Sticklers and Wagners, associated with RRD. Nevertheless, in recent years, there has been an increasing body of literature identifying the common genetic mutations and mechanisms associated with IRD. Several recent Genomic Wide Association Studies (GWAS) studies have identified a number of genetic loci related to the development of IRD. Our review aims to provide an up-to-date summary of the significant genetic mechanisms and associations of Idiopathic RRD. Full article

(This article belongs to the Special Issue Genetics in Stickler Syndrome)

9 pages, 1132 KiB

Open AccessReview

Hearing Loss in Stickler Syndrome: An Update

by Frederic R. E. Acke and Els M. R. De Leenheer

Genes 2022, 13(9), 1571; https://doi.org/10.3390/genes13091571 - 01 Sep 2022

Cited by 1 | Viewed by 4735

Abstract

Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory manifestations. Its main symptoms are high myopia, retinal detachment, joint hypermobility, early osteoarthritis, cleft palate, midfacial hypoplasia, micrognathia and hearing loss. Large phenotypical variability is apparent and partly explained [...] Read more.

Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory manifestations. Its main symptoms are high myopia, retinal detachment, joint hypermobility, early osteoarthritis, cleft palate, midfacial hypoplasia, micrognathia and hearing loss. Large phenotypical variability is apparent and partly explained by the underlying genetic heterogeneity, including collagen genes (COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3) and non-collagen genes (BMP4, LRP2, LOXL3). The most frequent type of Stickler syndrome (COL2A1) is characterized by a rather mild high-frequency sensorineural hearing loss in about half of the patients. COL11A1- and COL11A2-related Stickler syndrome results in more frequent hearing loss, being moderate and involving all frequencies. Hearing loss in the rarer types of Stickler syndrome depends on the gene expression in the cochlea, with moderate to severe downsloping hearing loss for Stickler syndrome caused by biallelic type IX collagen gene mutations and none or mild hearing loss for the non-collagen genes. Inherent to the orofacial manifestations, middle ear problems and temporary conductive hearing loss, especially at young age, are also prevalent. Consequently, hearing loss should be actively sought for and adequately treated in Stickler syndrome patients given its high prevalence and the concomitant visual impairment in most patients. Full article

(This article belongs to the Special Issue Genetics in Stickler Syndrome)

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12 pages, 1487 KiB

Open AccessReview

Molecular Basis of Pathogenic Variants in the Fibrillar Collagens

by Allan J. Richards and Martin P. Snead

Genes 2022, 13(7), 1199; https://doi.org/10.3390/genes13071199 - 04 Jul 2022

Cited by 3 | Viewed by 1798

Abstract

The fibrillar collagen family is comprised of the quantitatively major types I, II and III collagens and the quantitatively minor types V and XI. These form heterotypic collagen fibrils (composed of more than a single collagen type) where the minor collagens have a [...] Read more.

The fibrillar collagen family is comprised of the quantitatively major types I, II and III collagens and the quantitatively minor types V and XI. These form heterotypic collagen fibrils (composed of more than a single collagen type) where the minor collagens have a regulatory role in controlling fibril formation and diameter. The structural pre-requisites for normal collagen biosynthesis and fibrillogenesis result in many places where this process can be disrupted, and consequently a wide variety of phenotypes result when pathogenic changes occur in these fibrillar collagen genes. Another contributing factor is alternative splicing, both naturally occurring and as the result of pathogenic DNA alterations. This article will discuss how these factors should be taken into account when assessing DNA sequencing results from a patient. Full article

(This article belongs to the Special Issue Genetics in Stickler Syndrome)

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12 pages, 1323 KiB

Open AccessReview

Autosomal Recessive Stickler Syndrome

by Thomas R. W. Nixon, Allan J. Richards, Howard Martin, Philip Alexander and Martin P. Snead

Genes 2022, 13(7), 1135; https://doi.org/10.3390/genes13071135 - 24 Jun 2022

Cited by 6 | Viewed by 2594

Abstract

Stickler syndrome (SS) is a genetic disorder with manifestations in the eye, ear, joints, face and palate. Usually inherited in a dominant fashion due to heterozygous pathogenic variants in the collagen genes COL2A1 and COL11A1, it can rarely be inherited in a [...] Read more.

Stickler syndrome (SS) is a genetic disorder with manifestations in the eye, ear, joints, face and palate. Usually inherited in a dominant fashion due to heterozygous pathogenic variants in the collagen genes COL2A1 and COL11A1, it can rarely be inherited in a recessive fashion from variants in COL9A1, COL9A2, and COL9A3, COL11A1, as well as the non-collagen genes LRP2, LOXL3 and GZF1. We review the published cases of recessive SS, which comprise 40 patients from 23 families. Both homozygous and compound heterozygous pathogenic variants are found. High myopia is near-universal, and sensorineural hearing loss is very common in patients with variants in genes for type IX or XI collagen, although hearing appears spared in the LRP2 and LOXL3 patients and is variable in GZF1. Cleft palate is associated with type XI collagen variants, as well as the non-collagen genes, but is so far unreported with type IX collagen variants. Retinal detachment has occurred in 18% of all cases, and joint pain in 15%. However, the mean age of this cohort is 11 years old, so the lifetime incidence of both problems may be underestimated. This paper reinforces the importance of screening for SS in congenital sensorineural hearing loss, particularly when associated with myopia, and the need to warn patients and parents of the warning signs of retinal detachment, with regular ophthalmic review. Full article

(This article belongs to the Special Issue Genetics in Stickler Syndrome)

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9 pages, 212 KiB

Open AccessReview

From First to Second: How Stickler’s Diagnostic Genetics Has Evolved to Match Sequencing Technologies

by Howard Martin, Allan J. Richards and Martin P. Snead

Genes 2022, 13(7), 1123; https://doi.org/10.3390/genes13071123 - 23 Jun 2022

Viewed by 1121

Abstract

Diagnostic genetics within the United Kingdom National Health Service (NHS) has undergone many stepwise improvements in technology since the completion of the human genome project in 2003. Although Sanger sequencing has remained a cornerstone of the diagnostic sequencing arena, the human genome reference [...] Read more.

Diagnostic genetics within the United Kingdom National Health Service (NHS) has undergone many stepwise improvements in technology since the completion of the human genome project in 2003. Although Sanger sequencing has remained a cornerstone of the diagnostic sequencing arena, the human genome reference sequence has enabled next-generation sequencing (more accurately named ‘second-generation sequencing’), to rapidly surpass it in scale and potential. This mini review discusses such developments from the viewpoint of the Stickler’s higher specialist service, detailing the considerations and improvements to diagnostic sequencing implemented since 2003. Full article

(This article belongs to the Special Issue Genetics in Stickler Syndrome)

12 pages, 3296 KiB

Open AccessReview

Dominant Stickler Syndrome

by Zack Soh, Allan J. Richards, Annie McNinch, Philip Alexander, Howard Martin and Martin P. Snead

Genes 2022, 13(6), 1089; https://doi.org/10.3390/genes13061089 - 18 Jun 2022

Cited by 10 | Viewed by 4270

Abstract

The Stickler syndromes are a group of genetic connective tissue disorders associated with an increased risk of rhegmatogenous retinal detachment, deafness, cleft palate, and premature arthritis. This review article focuses on the molecular genetics of the autosomal dominant forms of the disease. Pathogenic [...] Read more.

The Stickler syndromes are a group of genetic connective tissue disorders associated with an increased risk of rhegmatogenous retinal detachment, deafness, cleft palate, and premature arthritis. This review article focuses on the molecular genetics of the autosomal dominant forms of the disease. Pathogenic variants in COL2A1 causing Stickler syndrome usually result in haploinsufficiency of the protein, whereas pathogenic variants of type XI collagen more usually exert dominant negative effects. The severity of the disease phenotype is thus dependent on the location and nature of the mutation, as well as the normal developmental role of the respective protein. Full article

(This article belongs to the Special Issue Genetics in Stickler Syndrome)

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