<i>C21orf2</i>is mutated in recessive early-onset retinal dystrophy with macular staphyloma and encodes a protein that localises to the photoreceptor primary cilium

Khan, Arif O.; Eisenberger, Tobias; Nagel-Wolfrum, Kerstin; Wolfrum, Uwe; Bolz, Hanno J.

doi:10.1136/bjophthalmol-2015-307277

Cited by 33 publications

(27 citation statements)

References 22 publications

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“…In recent reports, C21orf2 has been reported as a causal gene for JATD, 20 a syndromic ciliopathy with retinal degeneration, and for retinal dystrophy with macular staphyloma. 21 Those reports suggest that mutations in C21orf2 could cause several types of retinal ciliopathy in a syndromic and nonsyndromic manner, which was also supported by this study showing that mutations in C21orf2 were associated with RP with skeletal defects and also with nonsyndromic CRD. Thus far, C21orf2 mutations have been primarily associated with photoreceptor degenerations, and they also cause skeletal anormality in some cases, diagnosed as JATD.…”

Section: Discussionsupporting

confidence: 82%

“…C21orf2 has very recently been reported as a causal gene for JATD 20 and retinal dystrophy with macular staphyloma. 21 The previously reported mutations are located in the LRRs and in the C-terminal region ( Fig. 2A, lower panel, blue arrowheads).…”

Section: Identification Of Candidate Disease-causative Mutations In Fmentioning

confidence: 76%

“…For example, compound heterozygous mutations (p.L224P, p.R73P) have been associated with two JATD patients with CRD and also with a nonsyndromic CRD patient. 20,26 In addition, another group 21 has described that only one of two patients carrying the same mutation exhibits short stature. In our study, the phenotypic variation could be due to the different impacts of compound heterozygous mutations and homozygous mutations, and also due to the individual genetic background.…”

Section: Discussionmentioning

confidence: 99%

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Identification of Novel Mutations in the LRR-Cap Domain ofC21orf2in Japanese Patients With Retinitis Pigmentosa and Cone–Rod Dystrophy

Suga

Mizota

Kato

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Section: Discussionsupporting

confidence: 82%

Section: Identification Of Candidate Disease-causative Mutations In Fmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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Identification of Novel Mutations in the LRR-Cap Domain ofC21orf2in Japanese Patients With Retinitis Pigmentosa and Cone–Rod Dystrophy

Suga

Mizota

Kato

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Although many childhood retinal dystrophy phenotypes are non‐specific, there is increasing recognition of distinct phenotypes that are highly suggestive or even pathognomonic for certain gene mutations . In many instances, phenotype‐genotype correlations for recessive retinal dystrophies have been uncovered in consanguineous and/or endogamous families …”

Section: Introductionmentioning

confidence: 99%

“…Although many childhood retinal dystrophy phenotypes are non-specific, there is increasing recognition of distinct phenotypes that are highly suggestive or even pathognomonic for certain gene mutations. [1][2][3][4] In many instances, phenotype-genotype correlations for recessive retinal dystrophies have been uncovered in consanguineous and/or endogamous families. [5][6][7][8][9][10] We report results of extensive genetic analysis for a cone-rod dystrophy phenotype with central nummular macular atrophy in 2 siblings from an endogamous family.…”

Section: Introductionmentioning

confidence: 99%

Genome‐wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1‐related fundus phenotype

Khan¹,

Budde

Nürnberg

et al. 2017

Clinical Genetics

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Funding informationStiftung Auge (Deutsche Ophthalmologische Gesellschaft, DOG.To uncover the genotype underlying early-onset cone-rod dystrophy and central nummular macular atrophic lesion in 2 siblings from an endogamous Arab family, we performed targeted next-generation sequencing (NGS) of 44 retinal dystrophy genes, whole-exome sequencing (WES) and genome-wide linkage analysis. Targeted NGS and WES in the index patient highlighted 2 homozygous variants, a CCDC66 frameshift deletion and a novel missense NMNAT1 variant, c.500G>A (p.Asn167Ser). Linkage and segregation analysis excluded the CCDC66 variant and confirmed the NMNAT1 mutation. Biallelic NMNAT1 mutations cause Leber congenital amaurosis with a central nummular macular atrophic lesion (LCA9). The NMNAT1 mutation reported here underlied cone-rod dystrophy rather than LCA but the fundus lesion was compatible with that of LCA9 patients, highlighting that such a fundus appearance should raise suspicion for biallelic mutations in NMNAT1 when in the context of any retinal dystrophy.Although Ccdc66 mutations have been proposed to cause retinal disease in dogs, our results and public databases challenge CCDC66 as a candidate gene for human retinal dystrophy. | METHODS Institutional board approval (Ethics Committee of the University ofCologne) and signed informed consent were obtained for this report.Methodology of NGS of known retinal dystrophy genes, genome-wide linkage analysis, and whole-exome sequencing (WES) are provided in Appendix S1, Methodology.3 | RESULTS | Clinical investigationsA 13-year-old index patient (Figure 1A,B; II:1, Figure 2B), the first of 4 siblings, had worsening visual acuity since early childhood.Her parents were from the same tribe, and a younger brother, the third sibling (Figure 1C,D; II:3, Figure 2B), was similarly affected. Development was considered normal until II:1 was 3 years old, when the parents noted difficulty with navigating stairs. Soon thereafter, poor vision, particularly in daylight, and eye shaking were noted. When seen at 13 years of age, she had 4/200 vision in either eye, eccentric fixation, moderate exotropia, and pendular nystagmus with small amplitude and high frequency.

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Homozygous variant in C21orf2 in a case of Jeune syndrome with severe thoracic involvement: Extending the phenotypic spectrum

McInerney-Leo

Wheeler

Marshall

et al. 2017

American J of Med Genetics Pt A

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We previously reported exome sequencing in a short-rib thoracic dystrophy (SRTD) cohort, in whom recessive mutations were identified in SRTD-associated genes in 10 of 11 cases. A heterozygous stop mutation in the known SRTD gene WDR60 was identified in the remaining case; no novel candidate gene/s were suggested by homozygous/compound heterozygous analysis. This case was thus considered unsolved. Re-analysis following an analysis pipeline update identified a homozygous mutation in C21orf2 (c.218G > C; p.Arg73Pro). This homozygous variant was previously removed at the quality control stage by the default GATK parameter "in-breeding co-efficient." C21orf2 was recently associated with both Jeune asphyxiating thoracic dystrophy (JATD) and axial spondylometaphyseal dysplasia (axial SMD); this particular mutation was reported in homozygous and compound heterozygous state in both conditions. Our case has phenotypic features of both JATD and axial SMD; and the extent of thoracic involvement appears more severe than in other C21orf2-positive cases. Identification of a homozygous C21orf2 mutation in this case emphasizes the value of exome sequencing for simultaneously screening known genes and identifying novel genes. Additionally, it highlights the importance of re-interrogating data both as novel gene associations are identified and as analysis pipelines are refined. Finally, the severity of thoracic restriction in this case adds to the phenotypic spectrum attributable to C21orf2 mutations.

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C21orf2is mutated in recessive early-onset retinal dystrophy with macular staphyloma and encodes a protein that localises to the photoreceptor primary cilium

Cited by 33 publications

References 22 publications

Identification of Novel Mutations in the LRR-Cap Domain ofC21orf2in Japanese Patients With Retinitis Pigmentosa and Cone–Rod Dystrophy

Identification of Novel Mutations in the LRR-Cap Domain ofC21orf2in Japanese Patients With Retinitis Pigmentosa and Cone–Rod Dystrophy

Genome‐wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1‐related fundus phenotype

Homozygous variant in C21orf2 in a case of Jeune syndrome with severe thoracic involvement: Extending the phenotypic spectrum

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