X-Chromosome Inactivation Is a Biomarker of Clinical Severity in Female Carriers of RPGR-Associated X-Linked Retinitis Pigmentosa

Fahim, Abigail T.; Sullivan, Lori S.; Bowne, Sara J.; Webb‐Jones, Kaylie; Wheaton, Dianna K.; Khan, Naheed W.; Heckenlively, John R.; Jayasundera, Thiran; Branham, Kari; Andrews, Chris; Othman, Mohammad; Karoukis, Athanasios J.; Birch, David G.; Daiger, Stephen P.

doi:10.1016/j.oret.2019.11.010

Cited by 39 publications

(30 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Female carriers of the RPGR mutation are usually either asymptomatic or have delayed onset of the symptoms and show a milder phenotype [ 59 ]. Skewed inactivation of the X chromosome is thought to be responsible for manifesting more severe phenotype [ 44 , 60 ], however, other modifying genetic factors have also been suggested [ 61 ]. RPGR carriers appear to have four main patterns of fundus appearance: Normal or near normal pattern, a tapetal reflex, focal or patchy pigmentary retinopathy limited to a quadrant or hemisphere, and three or more quadrants of bone spicule pigmentation or atrophy [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

Hadalin

Šuštar

Volk

et al. 2021

Genes

View full text Add to dashboard Cite

Mutations in RPGRORF15 are associated with rod-cone or cone/cone-rod dystrophy, the latter associated with mutations at the distal end. We describe the phenotype associated with a novel variant in the terminal codon of the RPGRORF15 c.3457T>A (Ter1153Lysext*38), which results in a C-terminal extension. Three male patients from two families were recruited, aged 31, 35, and 38 years. Genetic testing was performed by whole exome sequencing. Filtered variants were analysed according to the population frequency, ClinVar database, the variant’s putative impact, and predicted pathogenicity; and were classified according to the ACMG guidelines. Examination included visual acuity (Snellen), colour vision (Ishihara), visual field, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electrophysiology. All patients were myopic, and had central scotoma and reduced colour vision. Visual acuities on better eyes were counting fingers, 0.3 and 0.05. Electrophysiology showed severely reduced cone-specific responses and macular dysfunction, while the rod-specific response was normal. FAF showed hyperautofluorescent ring centred at the fovea encompassing an area of photoreceptor loss approximately two optic discs in diameter (3462–6342 μm). Follow up after 2–11 years showed enlargement of the diameter (avg. 100 μm/year). The novel c.3457T>A (Ter1153Lysext*38) mutation in the terminal RPGRORF15 codon is associated with cone dystrophy, which corresponds to the previously described phenotypes associated with mutations in the distal end of the RPGRORF15. Minimal progression during follow-up years suggests a relatively stable disease after the initial loss of the central cones.

show abstract

Section: Discussionmentioning

confidence: 99%

Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

Hadalin

Šuštar

Volk

et al. 2021

Genes

View full text Add to dashboard Cite

show abstract

“…These samples were analysed for their methylation patterns. It was found that X-inactivation ratios correlated with clinical severity and could be useful indicators for prognostic purposes [ 157 ]. Another common feature of RPGR pathogenesis is that missense variants often lack an ability to interact with other key IRD gene products which results in the failure of RPGR to correctly localise to the cilia as required [ 158 ].…”

Section: Modifiers Of Ird Phenotypesmentioning

confidence: 99%

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Dockery

Whelan

Humphries

et al. 2021

IJMS

View full text Add to dashboard Cite

Inherited retinal diseases (IRDs) represent a collection of phenotypically and genetically diverse conditions. IRDs phenotype(s) can be isolated to the eye or can involve multiple tissues. These conditions are associated with diverse forms of inheritance, and variants within the same gene often can be associated with multiple distinct phenotypes. Such aspects of the IRDs highlight the difficulty met when establishing a genetic diagnosis in patients. Here we provide an overview of cutting-edge next-generation sequencing techniques and strategies currently in use to maximise the effectivity of IRD gene screening. These techniques have helped researchers globally to find elusive causes of IRDs, including copy number variants, structural variants, new IRD genes and deep intronic variants, among others. Resolving a genetic diagnosis with thorough testing enables a more accurate diagnosis and more informed prognosis and should also provide information on inheritance patterns which may be of particular interest to patients of a child-bearing age. Given that IRDs are heritable conditions, genetic counselling may be offered to help inform family planning, carrier testing and prenatal screening. Additionally, a verified genetic diagnosis may enable access to appropriate clinical trials or approved medications that may be available for the condition.

show abstract

“…XCI status has been used to explain the wide spectrum of phenotypes observed (from asymptomatic to severe) in some X‐linked diseases in women, depending on the degree of silencing of the normal allele (Echevarria et al, 2016; Elstein, Schachamorov, Beeri, & Altarescu, 2012; Fahim et al, 2019; Juchniewicz et al, 2018). For example, the severity scores and progression phenomena in X‐linked Fabry disease caused by α‐Gal deficiency had significant correlation with XCI ratio in female patients (Echevarria et al, 2016; Elstein et al, 2012; Juchniewicz et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

De novo mutation and skewed X‐inactivation in girl with BCAP31 ‐related syndrome

et al. 2020

View full text Add to dashboard Cite

Full genome analysis of a young girl with deafness, dystonia, central hypomyelination, refractory seizure, and fluctuating liver function impairment revealed a heterozygous, de novo variant in the BCAP31 gene on chromosome Xq28 (NM_001256447.2:c.92G>A), mutations of which caused the X‐linked recessive severe neurologic disorder deafness, dystonia, and cerebral hypomyelination. Reverse transcription‐polymerase chain reaction of the patient's white blood cells showed the absence of wild‐type BCAP31 messenger RNA (mRNA) but the presence of two novel BCAP31 mRNAs. The major alternatively spliced mRNA is due to Exon 2 skipping and the utilization of a new initiation site in Exon 3 that leads to a frameshift and truncated transcript while the minor novel mRNA has a 110 nucleotide insertion to Exon 2. Phasing studies showed that the de novo variant arose in the paternal X chromosome. X chromosome inactivation assay was done and confirmed that the patient's maternal X chromosome was preferentially inactivated, providing evidence that the mutated BCAP31 gene was the one predominantly expressed. According to the American College of Medical Genetics and Genomics guideline, this variant is deemed “pathogenic” (PS2, PS3, PM2, PP3, and PP4) and deleterious. This is the first reported female patient in BCAP31‐related syndrome resulted from skewed X‐inactivation and a de novo mutation in the active X chromosome.

show abstract

X-Chromosome Inactivation Is a Biomarker of Clinical Severity in Female Carriers of RPGR-Associated X-Linked Retinitis Pigmentosa

Cited by 39 publications

References 60 publications

Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

Next-Generation Sequencing Applications for Inherited Retinal Diseases

De novo mutation and skewed X‐inactivation in girl with BCAP31 ‐related syndrome

Contact Info

Product

Resources

About