Homozygous mutation in<i>CEP19,</i>a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly

Bölükbaşı, Esra Yıldız; Mumtaz, Sara; Afzal, Muhammad Sohail; Woehlbier, Ute; Malik, Sajid; Tolun, Aslıhan

doi:10.1136/jmedgenet-2017-104758

Cited by 28 publications

(17 citation statements)

References 47 publications

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“…IMPG2 has previously been associated with autosomal recessive RP and vitelliform macular dystrophy (VMD) in humans [ 61 , 62 ] and is therefore a strong candidate gene for canine PRA. CEP97 plays a role in centrosome function and ciliary formation [ 63 ] and although CEP97 has not directly been implicated with human retinal degenerations, mutations in other centrosomal protein coding genes have been associated with both syndromic and non-syndromic retinal degenerations ( CEP19 , CEP78 , CEP164 , CEP250 and CEP290 ) [ 64 – 75 ].…”

Section: Resultsmentioning

confidence: 99%

A LINE-1 insertion situated in the promoter of IMPG2 is associated with autosomal recessive progressive retinal atrophy in Lhasa Apso dogs

et al. 2020

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Background Canine progressive retinal atrophies are a group of hereditary retinal degenerations in dogs characterised by depletion of photoreceptor cells in the retina, which ultimately leads to blindness. PRA in the Lhasa Apso (LA) dog has not previously been clinically characterised or described in the literature, but owners in the UK are advised to have their dog examined through the British Veterinary Association/ Kennel Club/ International Sheep Dog Society (BVA/KC/ISDS) eye scheme annually, and similar schemes that are in operation in other countries. After the exclusion of 25 previously reported canine retinal mutations in LA PRA-affected dogs, we sought to identify the genetic cause of PRA in this breed. Results Analysis of whole-exome sequencing data of three PRA-affected LA and three LA without signs of PRA did not identify any exonic or splice site variants, suggesting the causal variant was non-exonic. We subsequently undertook a genome-wide association study (GWAS), which identified a 1.3 Mb disease-associated region on canine chromosome 33, followed by whole-genome sequencing analysis that revealed a long interspersed element-1 (LINE-1) insertion upstream of the IMPG2 gene. IMPG2 has previously been implicated in human retinal disease; however, until now no canine PRAs have been associated with this gene. The identification of this PRA-associated variant has enabled the development of a DNA test for this form of PRA in the breed, here termed PRA4 to distinguish it from other forms of PRA described in other breeds. This test has been used to determine the genotypes of over 900 LA dogs. A large cohort of genotyped dogs was used to estimate the allele frequency as between 0.07–0.1 in the UK LA population. Conclusions Through the use of GWAS and subsequent sequencing of a PRA case, we have identified a LINE-1 insertion in the retinal candidate gene IMPG2 that is associated with a form of PRA in the LA dog. Validation of this variant in 447 dogs of 123 breeds determined it was private to LA dogs. We envisage that, over time, the developed DNA test will offer breeders the opportunity to avoid producing dogs affected with this form of PRA.

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Section: Resultsmentioning

confidence: 99%

A LINE-1 insertion situated in the promoter of IMPG2 is associated with autosomal recessive progressive retinal atrophy in Lhasa Apso dogs

et al. 2020

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“…; Ylldlz Bölükbasi et al. ). Our affected subject presented with fatty liver and elevated transaminases which may be related to the AGBL5 mutation, but additional analysis is needed to clarify the gene function and explain the extraocular pathologies related to this gene.…”

Section: Discussionmentioning

confidence: 99%

The combination of whole‐exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies

Diab

AlTalbishi

Rosin

et al. 2019

Acta Ophthalmologica

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“…With an effect on expressivity we mention variants in TMEM67, MKKS, CCDC28B, C8orf37, BBS1 genes [55,[57][58][59]…”

Section: Modifiersmentioning

confidence: 99%

“…With an effect on expressivity we mention variants in TMEM67 , MKKS , CCDC28B , C8orf37 , BBS1 genes [ 55 , 57 , 58 , 59 ]. For example, Bölükbaşı et al found that most severe phenotype of BBS was allowed by following changes: C8orf37: c.533C>T (p.Ala178Val), CCDC28B: c.330C>T (p.Phe110Phe), MKKS: c.1015A>G (p.Ile339Val), and TMEM67: p.Asp799Asp [ 57 ].…”

Section: Determinants Of Clinical Effectsmentioning

confidence: 99%

Bardet–Biedl Syndrome—Multiple Kaleidoscope Images: Insight into Mechanisms of Genotype–Phenotype Correlations

Florea

Caba

Gorduza

2021

Genes

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Bardet–Biedl Syndrome is a rare non-motile primary ciliopathy with multisystem involvement and autosomal recessive inheritance. The clinical picture is extremely polymorphic. The main clinical features are retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, hypogonadism and genitourinary abnormalities, and kidney disease. It is caused by various types of mutations, mainly in genes encoding BBSome proteins, chaperonins, and IFT complex. Variable expressivity and pleiotropy are correlated with the existence of multiple genes and variants modifiers. This review is focused on the phenomena of heterogeneity (locus, allelic, mutational, and clinical) in Bardet–Biedl Syndrome, its mechanisms, and importance in early diagnosis and proper management.

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Homozygous mutation inCEP19,a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly

Cited by 28 publications

References 47 publications

A LINE-1 insertion situated in the promoter of IMPG2 is associated with autosomal recessive progressive retinal atrophy in Lhasa Apso dogs

A LINE-1 insertion situated in the promoter of IMPG2 is associated with autosomal recessive progressive retinal atrophy in Lhasa Apso dogs

The combination of whole‐exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies

Bardet–Biedl Syndrome—Multiple Kaleidoscope Images: Insight into Mechanisms of Genotype–Phenotype Correlations

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