Phenotypic features of CRB1-associated early-onset severe retinal dystrophy and the different molecular approaches to identifying the disease-causing variants

Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.

Download Full-text

Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects

Human Genetics ◽

10.1007/s00439-021-02284-1 ◽

2021 ◽

Author(s):

Andreas R. Janecke ◽

Xiaoqin Liu ◽

Rüdiger Adam ◽

Sumanth Punuru ◽

Arne Viestenz ◽

...

Keyword(s):

Early Onset ◽

Single Nucleotide Polymorphism Array ◽

Outer Nuclear Layer ◽

Retinal Dystrophy ◽

Geographic Origin ◽

Retinal Disease ◽

Homozygosity Mapping ◽

Rod Photoreceptor ◽

Loss Of Function ◽

Knockout Mouse Model

AbstractBiallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic—intestinal and retinal—disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

Download Full-text

Molecular Screening of 43 Brazilian Families Diagnosed with Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy

Genes ◽

10.3390/genes8120355 ◽

2017 ◽

Vol 8 (12) ◽

pp. 355 ◽

Cited By ~ 7

Author(s):

Fernanda Porto ◽

Evan Jones ◽

Justin Branch ◽

Zachry Soens ◽

Igor Maia ◽

...

Keyword(s):

Early Onset ◽

Retinal Dystrophy ◽

Molecular Screening ◽

Leber Congenital Amaurosis

Download Full-text

Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2019-314281 ◽

2019 ◽

Vol 104 (7) ◽

pp. 932-937 ◽

Cited By ~ 3

Author(s):

Ke Xu ◽

Yue Xie ◽

Tengyang Sun ◽

Xiaohui Zhang ◽

Chunjie Chen ◽

...

Keyword(s):

Early Onset ◽

Retinal Dystrophy ◽

Case Series ◽

Clinical Findings ◽

Chinese Patients ◽

Pcr Analysis ◽

Common Mutation ◽

Essential Information ◽

Leber Congenital Amaurosis ◽

Targeted Next Generation Sequencing

BackgroundLeber congenital amaurosis (LCA) and early onset severe retinal dystrophy (EOSRD) are clinically and genetically heterogeneous inherited retinal disorders that cause severe visual impairment in children. The objective of this study was to describe the mutation profile and phenotypic characteristics in Chinese patients with LCA or EOSRD.MethodsRetrospective consecutive case series (2010–2017) study was performed in 148 probands (91 with LCA and 57 with EOSRD). All patients underwent ophthalmic evaluation. Mutations were revealed using targeted next-generation sequencing, followed by Sanger DNA-sequencing and real-time quantitative PCR analysis.ResultsWe identified two diseasing-causing mutations in 88 unrelated patients, heterozygous autosomal dominant mutations in 11 probands and X-linked hemizygous mutations in 11 patients, for an overall mutation detection rate of 74.3% (110/148). We detected 158 different disease-causing mutations involving 14 LCA genes, 16 retinitis pigmentosa or cone-rod dystrophy genes and 3 syndromic retinal dystrophy genes. Of these 158 mutations, 98 were novel. The most common mutation was p.Q141X of AIPL1, with a gene-specific allele frequency of 60%. The first five most frequently mutated genes were AIPL1 (11.0%), RPGRIP1 (8.8%) and CEP290, GUCY2D and RPE65 (each 7.7%) in the patients with LCA and RPGR (12.3%), CRB1 (10.5%), RPE65 (10.5%), RDH12 (7.0%) and RP2 (5.3%) in the patients with EOSRD.ConclusionsOur results revealed that the mutation spectrum of patients with LCA differs from that of the patients with EOSRD and established the configuration of the mutation frequencies for each LCA gene in Chinese patients, thereby providing essential information for future genetic counselling and gene therapy.

Download Full-text

Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion

Genetics in Medicine ◽

10.1038/gim.2014.95 ◽

2014 ◽

Vol 17 (4) ◽

pp. 291-299 ◽

Cited By ~ 27

Author(s):

Kristof Van Schil ◽

Françoise Meire ◽

Marcus Karlstetter ◽

Miriam Bauwens ◽

Hannah Verdin ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Early Onset ◽

Autosomal Recessive ◽

Retinal Dystrophy ◽

Autosomal Recessive Cerebellar Ataxia

Download Full-text

Lack of fundus autofluorescence to 488 nanometers from childhood on in patients with early-onset severe retinal dystrophy associated with mutations in RPE65

Ophthalmology ◽

10.1016/j.ophtha.2004.01.033 ◽

2004 ◽

Vol 111 (8) ◽

pp. 1585-1594 ◽

Cited By ~ 77

Author(s):

Birgit Lorenz ◽

Bettina Wabbels ◽

Erika Wegscheider ◽

Christian P Hamel ◽

Wolfgang Drexler ◽

...

Keyword(s):

Early Onset ◽

Fundus Autofluorescence ◽

Retinal Dystrophy

Download Full-text

Genotyp-Phänotyp-Korrelation bei Patienten mit CRB1-Mutationen

Klinische Monatsblätter für Augenheilkunde ◽

10.1055/s-0043-103961 ◽

2017 ◽

Vol 234 (03) ◽

pp. 289-302 ◽

Cited By ~ 1

Author(s):

C. Papadopoulou Laiou ◽

M. Preising ◽

H. Bolz ◽

B. Lorenz

Keyword(s):

Missense Mutation ◽

Early Onset ◽

Retinal Dystrophy ◽

Iscev Standard ◽

Sd Oct

Zusammenfassung Hintergrund Mutationen im CRB1-Gen wurden bei frühkindlicher schwerer Netzhautdegeneration (EOSRD, early-onset severe retinal dystrophy) und Stäbchen-Zapfen-Degeneration des Kindesalters identifiziert. Diese Studie beschreibt das phänotypische Spektrum bei krankheitsverursachenden CRB1-Mutationen in den ersten beiden Lebensdekaden. Material und Methoden Acht Patienten im Alter von 3 Monaten bis 20 Jahren wurden einer ophthalmologischen Untersuchung mit Prüfung des bestkorrigierten Visus (BCVA), Farbsehprüfung, Funduskopie, optischer Kohärenztomografie (SD-OCT) und Fundusautofluoreszenz (FAF) unterzogen. Die SD-OCTs wurden mit der DIOCTA-Auswertesoftware sowie manuell einer Schichtanalyse unterzogen. In Abhängigkeit von der Kooperationsfähigkeit der Patienten wurden eine Ganzfeldelektroretinografie (ffERG, ISCEV-Standard) sowie eine Goldmann-Perimetrie durchgeführt. Ergebnisse Fünf der Patienten trugen Mutationen, die zu einem Verlust des Genproduktes führten (Spleißmutationen, Nonsense-Mutationen, Leserasterverschiebungen) und zeigten bereits in den ersten Lebensmonaten ein massiv reduziertes Sehvermögen (BCVAmax: 0,04). Der 6. Patient trug eine homozygote Missense-Mutation und zeigte im Alter von 6 Jahren einen BCVAmax von 0,05. Zwei weitere Patienten mit einer hypomorphen Missense-Mutation auf mindestens einem Allel zeigten einen besseren Visuserhalt mit BCVA bis zu 0,5 im Alter von 20 Jahren. Das ffERG lag bei allen Patienten unter der Norm und war bei der Mehrheit nicht mehr ableitbar. Das Gesichtsfeld war stark eingeschränkt. Die Photorezeptorschichten waren im SD-OCT, soweit überhaupt abgrenzbar, deutlich reduziert. Die Schichtdicke der inneren Körnerschicht nahm mit zunehmender Degeneration zu. Die Analyse der A-Scans zwischen Nervenfaserschicht (RNFL) und Bruch-Membran zeigte eine besser erhaltene Netzhautschichtung bei den Patienten mit Missense-Mutationen. Schlussfolgerung Patienten mit CRB1-Mutationen zeigen in erster Linie einen schweren Phänotyp mit stark reduziertem Sehvermögen von Geburt an. Missense-Mutationen mit einer möglichen Restfunktion des Genprodukts sind mit leichteren Phänotypen assoziiert. Eine schwere und progrediente Gesichtsfeldeinschränkung war allgemein in der 1. Lebensdekade vorhanden. Die reduzierte Abgrenzbarkeit der retinalen Schichtung im SD-OCT deutet auf einen Verlust der strukturellen Integrität aller Netzhautschichten hin.

Download Full-text

An Assessment of the Apex Microarray Technology in Genotyping Patients with Leber Congenital Amaurosis and Early-Onset Severe Retinal Dystrophy

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.07-0207 ◽

2007 ◽

Vol 48 (12) ◽

pp. 5684 ◽

Cited By ~ 35

Author(s):

Robert H. Henderson ◽

Naushin Waseem ◽

Rowan Searle ◽

Jacqueline van der Spuy ◽

Isabelle Russell-Eggitt ◽

...

Keyword(s):

Early Onset ◽

Retinal Dystrophy ◽

Microarray Technology ◽

Leber Congenital Amaurosis

Download Full-text

SRD5A3-CDG: Emerging Phenotypic Features of an Ultrarare CDG Subtype

Frontiers in Genetics ◽

10.3389/fgene.2021.737094 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nazreen Kamarus Jaman ◽

Preeya Rehsi ◽

Robert H. Henderson ◽

Ulrike Löbel ◽

Kshitij Mankad ◽

...

Keyword(s):

Early Onset ◽

Retinal Dystrophy ◽

Gastrointestinal Symptoms ◽

Skin Lesions ◽

Study Data ◽

Common Finding ◽

Mri Findings ◽

Multisystem Disorder ◽

Diagnostic Features ◽

Long Time

Background: SRD5A3-CDG is a rare N-glycosylation defect caused by steroid 5 alpha reductase type 3 deficiency. Its key feature is an early severe visual impairment with variable ocular anomalies often leading to diagnosis. Additional symptoms are still poorly defined. In this case study, we discuss 11 genetically confirmed cases, and report on emerging features involving other systems in addition to the eye phenotype.Methods: In total, 11 SRD5A3-CDG patients in five sets of sibships were included in the study. Data on 9 of 11 patients are as of yet unpublished. Patients’ results on biochemical and genetic investigations and on in-depth phenotyping are presented.Results: Key diagnostic features of SRD5A3-CDG are ophthalmological abnormalities with early-onset retinal dystrophy and optic nerve hypoplasia. SRD5A3-CDG is also characterized by variable neurological symptoms including intellectual disability, ataxia, and hypotonia. Furthermore, ichthyosiform skin lesions, joint laxity, and scoliosis have been observed in our cohort. We also report additional findings including dystonia, anxiety disorder, gastrointestinal symptoms, and MRI findings of small basal ganglia and mal-rotated hippocampus, whereas previous publications described dysmorphic features as a common finding in SRD5A3, which could not be confirmed in our patient cohort.Conclusion: The detailed description of the phenotype of this large cohort of patients with SRD5A3-CDG highlights that the key clinical diagnostic features of SRD5A3-CDG are an early onset form of ophthalmological problems in patients with a multisystem disorder with variable symptoms evolving over time. This should aid earlier diagnosis and confirms the need for long-time follow-up of patients.

Download Full-text

COG5 variants lead to complex early onset retinal degeneration, upregulation of PERK and DNA damage

Scientific Reports ◽

10.1038/s41598-020-77394-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sami Tabbarah ◽

Erika Tavares ◽

Jason Charish ◽

Ajoy Vincent ◽

Andrew Paterson ◽

...

Keyword(s):

Dna Damage ◽

Retinal Degeneration ◽

Skeletal Dysplasia ◽

Early Onset ◽

Protein Misfolding ◽

Cultured Cells ◽

Retinal Dystrophy ◽

Compound Heterozygous ◽

Cog Complex ◽

Compound Heterozygous Variants

AbstractLeber congenital amaurosis (LCA), a form of autosomal recessive severe early-onset retinal degeneration, is an important cause of childhood blindness. This may be associated with systemic features or not. Here we identified COG5 compound-heterozygous variants in patients affected with a complex LCA phenotype associated with microcephaly and skeletal dysplasia. COG5 is a component of the COG complex, which facilitates retrograde Golgi trafficking; if disrupted this can result in protein misfolding. To date, variants in COG5 have been associated with a distinct congenital disorder of glycosylation (type IIi) and with a variant of Friedreich’s ataxia. We show that COG5 variants can also result in fragmentation of the Golgi apparatus and upregulation of the UPR modulator, PKR-like endoplasmic reticulum kinase (PERK). In addition, upregulation of PERK induces DNA damage in cultured cells and in murine retina. This study identifies a novel role for COG5 in maintaining ER protein homeostasis and that disruption of that role results in activation of PERK and early-onset retinal degeneration, microcephaly and skeletal dysplasia. These results also highlight the importance of the UPR pathway in early-onset retinal dystrophy and as potential therapeutic targets for patients.

Download Full-text