A founder mutation in <i><scp>CERKL</scp></i> is a major cause of retinal dystrophy in Finland

Avela, Kristiina; Sankila, Eeva‐Marja; Seitsonen, Sanna; Kuuluvainen, Liina; Barton, Stephanie; Gillies, Stuart; Aittomäki, Kristiina

doi:10.1111/aos.13551

Cited by 28 publications

(29 citation statements)

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“…), and 2.8 kb deletion in CLN3 (), and most recently, c.1155T>A (p.Cys385Ter) in EYS (Avela et al. ), whereas c.148delG in TULP1 , c.2314C>T (p.Gln772Ter) in RPGRIP1 , and c.533G>A (p.Trp178Ter) in TYR were novel findings.…”

Section: Resultsmentioning

confidence: 91%

“…, and Avela et al. ). EYS mutations have been reported in arRP in several European countries, and in Japan and China with variable phenotypes (Littink et al.…”

Section: Discussionmentioning

confidence: 93%

“…Recently, c.375C>G p.(Cys125Trp) in CERKL and c.1155T>A (p.Cys385Ter) in EYS were reported to be founder mutations in a Finnish cohort of adult RD patients (Avela et al. ). The total absence of CERKL patients and the relatively small number of EYS patients in this paediatric cohort most likely reflects the typical adolescence or adult onset of those diseases (Pierrottet et al.…”

Section: Discussionmentioning

confidence: 99%

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The genetic aetiology of retinal degeneration in children in Finland – new founder mutations identified

Avela

Salonen‐Kajander

Laitinen

et al. 2019

Acta Ophthalmologica

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Purpose: To study the genetic aetiology and phenotypes of retinal degeneration (RD) in Finnish children born during 1993-2009. Methods: Children with retinal degeneration (N = 68) were investigated during 2012-2014 with a targeted gene analysis or a next-generation sequencing (NGS) based gene panel. Also, a full clinical ophthalmological examination was performed. Results: The cohort covered 44% (68/153) of the Finnish children with inherited RD born 1993-2009. X-linked retinoschisis, retinitis pigmentosa, Leber congenital amaurosis and cone-rod dystrophy were the most common clinical diagnoses in the study group. Pathogenic mutations were found in 17 retinal genes. The molecular genetic aetiology was identified in 77% of the patients (in 77% of the families) analysed by NGS method. Several founder mutations were detected including three novel founder mutations c.148delG in TULP1, c.2314C>R (p.Gln772Ter) in RPGRIP1 and c.533G>A (Trp178Ter) in TYR. We also confirmed the previous tentative finding of c.2944 + 1delG in GYCU2D being the most frequent cause of Leber congenital amaurosis (LCA) in Finland. Conclusions: Globally, RD is genetically heterogeneous with over 260 disease genes reported so far. This was shown not to be the case in Finland, where the genetic aetiology of RD is caused by a small group of genes, due to several founder mutations that are enriched in the population. We found that Xchromosomal retinoschisis constitutes the major group in Finnish paediatric RD population and is almost exclusively caused by two founder mutations. Several other founder mutations were detected including three novel founder mutations. All in all, the genetic aetiology of 77% of families was identified which is higher than previously reported from other populations, likely due to the specific genomic constitution of the Finns.

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Section: Resultsmentioning

confidence: 91%

“…, and Avela et al. ). EYS mutations have been reported in arRP in several European countries, and in Japan and China with variable phenotypes (Littink et al.…”

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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The genetic aetiology of retinal degeneration in children in Finland – new founder mutations identified

Avela

Salonen‐Kajander

Laitinen

et al. 2019

Acta Ophthalmologica

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“…The IFT140 gene proposed for patient O was a good fit for the patient's phenotype of retinal dysfunction. However, the variant has a relatively high MAF (1.57% in the Finnish gnomAD cohort) yet is not a major cause of retinal disease in the Finns (Avela et al, ). It was classified therefore as benign.…”

Section: Resultsmentioning

confidence: 99%

CAGI SickKids challenges: Assessment of phenotype and variant predictions derived from clinical and genomic data of children with undiagnosed diseases

et al. 2019

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Whole‐genome sequencing (WGS) holds great potential as a diagnostic test. However, the majority of patients currently undergoing WGS lack a molecular diagnosis, largely due to the vast number of undiscovered disease genes and our inability to assess the pathogenicity of most genomic variants. The CAGI SickKids challenges attempted to address this knowledge gap by assessing state‐of‐the‐art methods for clinical phenotype prediction from genomes. CAGI4 and CAGI5 participants were provided with WGS data and clinical descriptions of 25 and 24 undiagnosed patients from the SickKids Genome Clinic Project, respectively. Predictors were asked to identify primary and secondary causal variants. In addition, for CAGI5, groups had to match each genome to one of three disorder categories (neurologic, ophthalmologic, and connective), and separately to each patient. The performance of matching genomes to categories was no better than random but two groups performed significantly better than chance in matching genomes to patients. Two of the ten variants proposed by two groups in CAGI4 were deemed to be diagnostic, and several proposed pathogenic variants in CAGI5 are good candidates for phenotype expansion. We discuss implications for improving in silico assessment of genomic variants and identifying new disease genes.

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“…To date, only one pathogenic mutation in CERKL, c.316C > A (p.Arg106Ser) has been documented in the Pakistani population 7 . Several studies of Yemenite Jewish, Finnish, and Spanish populations have identified mutations in CERKL as a cause of RD 6,[8][9][10] . Importantly, the affected individuals in family PKRP373 and affected individuals described in previously published reports of CERKL-related RD suffer from early and severe involvement of the central retina in addition to peripheral retinal degeneration 6,[8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Mutations in CERKL and RP1 cause retinitis pigmentosa in Pakistani families

Nadeem

Kabir

et al. 2020

Hum Genome Var

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This study was conducted to identify the genetic basis of retinal dystrophies in consanguineous Pakistani families. We recruited two families with retinitis pigmentosa (RP) displaying visual difficulties, including nyctalopia and constricted visual fields. Linkage analysis and Sanger sequencing resulted in the identification of a previously reported nonsense mutation, c.847C > T, in exon 5 of CERKL in one family and a novel four-base pair deletion in exon 4 of RP1, c.delAGAA4218_4221, leading to premature protein termination in the second family. Here, we report two RP-causing mutations extending the genetic heterogeneity of the disease.

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A founder mutation in CERKL is a major cause of retinal dystrophy in Finland

Cited by 28 publications

References 28 publications

The genetic aetiology of retinal degeneration in children in Finland – new founder mutations identified

The genetic aetiology of retinal degeneration in children in Finland – new founder mutations identified

CAGI SickKids challenges: Assessment of phenotype and variant predictions derived from clinical and genomic data of children with undiagnosed diseases

Mutations in CERKL and RP1 cause retinitis pigmentosa in Pakistani families

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