A novel mutation in the PRPF31 in a North Indian adRP family with incomplete penetrance

Bhatia, Sofia; Goyal, Shiwali; Singh, Indu; Singh, Dilbag; Vanita, Vanita

doi:10.1007/s10633-018-9654-x

Cited by 15 publications

(9 citation statements)

References 38 publications

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“…Segregation analysis confirmed maternal inheritance of the SV. However, the proband's mother was phenotypically unaffected, due to incomplete penetrance associated with variants in PRPF31, noted in other studies [38][39][40] . TFPT is a molecular partner of TCF3 and is associated with childhood acute lymphoblastic leukemia (OMIM: 613065) 41 .…”

Section: Discussionmentioning

confidence: 78%

Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases

et al. 2021

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Inherited retinal diseases (IRDs) are a major cause of visual impairment. These clinically heterogeneous disorders are caused by pathogenic variants in more than 270 genes. As 30–40% of cases remain genetically unexplained following conventional genetic testing, we aimed to obtain a genetic diagnosis in an IRD cohort in which the genetic cause was not found using whole-exome sequencing or targeted capture sequencing. We performed whole-genome sequencing (WGS) to identify causative variants in 100 unresolved cases. After initial prioritization, we performed an in-depth interrogation of all noncoding and structural variants in genes when one candidate variant was detected. In addition, functional analysis of putative splice-altering variants was performed using in vitro splice assays. We identified the genetic cause of the disease in 24 patients. Causative coding variants were observed in genes such as ATXN7, CEP78, EYS, FAM161A, and HGSNAT. Gene disrupting structural variants were also detected in ATXN7, PRPF31, and RPGRIP1. In 14 monoallelic cases, we prioritized candidate noncanonical splice sites or deep-intronic variants that were predicted to disrupt the splicing process based on in silico analyses. Of these, seven cases were resolved as they carried pathogenic splice defects. WGS is a powerful tool to identify causative variants residing outside coding regions or heterozygous structural variants. This approach was most efficient in cases with a distinct clinical diagnosis. In addition, in vitro splice assays provide important evidence of the pathogenicity of rare variants.

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Section: Discussionmentioning

confidence: 78%

Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases

et al. 2021

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“…Designated RP11 (OMIM: #600138), this rod-cone dystrophy (RCD) usually presents in the teenage years but the age of onset may vary widely between and within families [8,9]. In addition, non-penetrance has been reported in many RP11 families [10][11][12]. It is widely accepted that haploinsufficiency is the underlying mechanism of retinal degeneration caused by the PRPF31 mutation where expressivity of the normal allele determines the phenotype [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Clinical Evidence for the Importance of the Wild-Type PRPF31 Allele in the Phenotypic Expression of RP11

Roshandel

Thompson

Jeffery

et al. 2021

Genes

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PRPF31-associated retinopathy (RP11) is a common form of autosomal dominant retinitis pigmentosa (adRP) that exhibits wide variation in phenotype ranging from non-penetrance to early-onset RP. Herein, we report inter-familial and intra-familial variation in the natural history of RP11 using multimodal imaging and microperimetry. Patients were recruited prospectively. The age of symptom onset, best-corrected visual acuity, microperimetry mean sensitivity (MS), residual ellipsoid zone span and hyperautofluorescent ring area were recorded. Genotyping was performed using targeted next-generation and Sanger sequencing and copy number variant analysis. PRPF31 mutations were found in 14 individuals from seven unrelated families. Four disease patterns were observed: (A) childhood onset with rapid progression (N = 4), (B) adult-onset with rapid progression (N = 4), (C) adult-onset with slow progression (N = 4) and (D) non-penetrance (N = 2). Four different patterns were observed in a family harbouring c.267del; patterns B, C and D were observed in a family with c.772_773delins16 and patterns A, B and C were observed in 3 unrelated individuals with large deletions. Our findings suggest that the RP11 phenotype may be related to the wild-type PRPF31 allele rather than the type of mutation. Further studies that correlate in vitro wild-type PRPF31 allele expression level with the disease patterns are required to investigate this association.

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“…encode proteins with yet-unknown function [5]. In addition, genetic abnormalities expressed in various organs other than the eyes cause syndromic RP such as Usher syndrome [6].…”

Section: Patientsmentioning

confidence: 99%

“…More than 80 genes have been identified as being responsible for RP [ 1 , 4 ]. Diverse functions of RP causative genes involve various pathways, i.e., phototransduction, vitamin A metabolism, signaling, cell–cell interaction, and protein synthesis, i.e., structural or cytoskeletal proteins, synaptic interaction proteins, mRNA intron-splicing factors, trafficking of intracellular proteins, maintenance of cilia/ciliated cells, phagocytosis, pH regulator and a few encode proteins with yet-unknown function [ 5 ]. In addition, genetic abnormalities expressed in various organs other than the eyes cause syndromic RP such as Usher syndrome [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort

Kim

Yoon

et al. 2021

Genes

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We conducted targeted next-generation sequencing (TGS) and/or whole exome sequencing (WES) to assess the genetic profiles of clinically suspected retinitis pigmentosa (RP) in the Korean population. A cohort of 279 unrelated Korean patients with clinically diagnosed RP and available family members underwent molecular analyses using TGS consisting of 88 RP-causing genes and/or WES with clinical variant interpretation. The combined genetic tests (TGS and/or WES) found a mutation in the 44 RP-causing genes and seven inherited retinal disease (IRD)-causing genes, and the total mutation detection rate was 57%. The mutation detection rate was higher in patients who experienced visual deterioration at a younger age (75.4%, age of symptom onset under 10 years) and who had a family history of RP (70.7%). The most common causative genes were EYS (8.2%), USH2A (6.8%), and PDE6B (4.7%), but mutations were dispersed among the 51 RP/IRD genes generally. Meanwhile, the PDE6B mutation was the most common in patients experiencing initial symptoms in their first decade, EYS in their second to third decades, and USH2A in their fifth decades and older. Of note, WES revealed some unexpected genotypes: ABCC6, CHM, CYP4V2, RS1, TGFBI, VPS13B, and WDR19, which were verified by ophthalmological re-phenotyping.

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A novel mutation in the PRPF31 in a North Indian adRP family with incomplete penetrance

Cited by 15 publications

References 38 publications

Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases

Whole genome sequencing and in vitro splice assays reveal genetic causes for inherited retinal diseases

Clinical Evidence for the Importance of the Wild-Type PRPF31 Allele in the Phenotypic Expression of RP11

Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort

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