Confirmation of spondylo‐epi‐metaphyseal dysplasia with joint laxity, <i>EXOC6B</i> type

Campos‐Xavier, Belinda; Rogers, R. Curtis; Niel-Bütschi, Florence; Ferreira, Catarina; Unger, Sheila; Spranger, Jürgen W.; Superti-Furga, Andrea

doi:10.1002/ajmg.a.40631

Cited by 6 publications

(10 citation statements)

References 6 publications

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“…Two of these genes ( CYP26B1 and EXOC6B ) are associated with the same trait (lamb metacarpal length) and are located within 0.5 Mb of the same top SNP on chromosome 3. CYP26B1 is associated with skeletal abnormalities in humans and zebrafish (Laue et al, 2011 ) and CYP26B1 knockouts produced reduced limbs in mice (Yashiro et al, 2004 ), while EXOC6B is associated with spondyloepimetaphyseal dysplasia in humans which symptoms include skeletal malformations affecting the long bones of the limbs and short stature (Campos‐Xavier et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

“…Cytochrome P450 26B1 ENSOARG00000011582 3 Lamb metacarpal length Associated with skeletal abnormalities in humans and zebrafish (Laue et al, 2011), knockouts produce reduced limbs in mice (Yashiro et al, 2004). EXOC6B ENSOARG00000011607 3 Lamb metacarpal length Associated with spondyloepimetaphyseal dysplasia (resulting in short stature) in humans (Campos-Xavier et al, 2018).…”

Section: Gene Name Ensembl Gene Id Chr Associated Trait Effects In Ot...mentioning

confidence: 99%

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The impact of SNP density on quantitative genetic analyses of body size traits in a wild population of Soay sheep

James

Pemberton

Navarro

et al. 2022

Ecology and Evolution

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Understanding the genetic architecture underpinning quantitative traits in wild populations is pivotal to understanding the processes behind trait evolution. The ‘animal model’ is a popular method for estimating quantitative genetic parameters such as heritability and genetic correlation and involves fitting an estimate of relatedness between individuals in the study population. Genotypes at genome‐wide markers can be used to estimate relatedness; however, relatedness estimates vary with marker density, potentially affecting results. Increasing density of markers is also expected to increase the power to detect quantitative trait loci (QTL). In order to understand how the density of genetic markers affects the results of quantitative genetic analyses, we estimated heritability and performed genome‐wide association studies (GWAS) on five body size traits in an unmanaged population of Soay sheep using two different SNP densities: a dataset of 37,037 genotyped SNPs and an imputed dataset of 417,373 SNPs. Heritability estimates did not differ between the two SNP densities, but the high‐density imputed SNP dataset revealed four new SNP‐trait associations that were not found with the lower density dataset, as well as confirming all previously‐found QTL. We also demonstrated that fitting fixed and random effects in the same step as performing GWAS is a more powerful approach than pre‐correcting for covariates in a separate model.

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Section: Resultsmentioning

confidence: 99%

Section: Gene Name Ensembl Gene Id Chr Associated Trait Effects In Ot...mentioning

confidence: 99%

The impact of SNP density on quantitative genetic analyses of body size traits in a wild population of Soay sheep

James

Pemberton

Navarro

et al. 2022

Ecology and Evolution

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“…EXOC6B variants have previously been suggested in the genetic etiology of developmental delay (Evers et al, 2014;Girisha et al, 2016). In addition, low-normal intelligence was reported in one of the two sisters originally described by Spranger et al (2006) who was later found to have biallelic EXOC6B deletion (Campos-Xavier et al, 2018). However, the developmental delay has not been considered among one of the clinical features of SEMDJL3 so far.…”

Section: Discussionmentioning

confidence: 99%

“…Two siblings of Indian origin were first reported with a homozygous truncating variant in EXOC6B (Girisha et al, 2016). Subsequently, two additional affected individuals, reported earlier, were molecularly diagnosed with an approximately 220 kb biallelic deletion spanning exons 9–20 of EXOC6B (Campos‐Xavier et al, 2018; Spranger et al, 2006). These reports helped in defining a new clinical entity of SEMD in the Nosology and Classification of Genetic Skeletal Disorders under Group 20 “Dysplasias with multiple joint dislocations” (Mortier et al, 2019).…”

Section: Introductionsmentioning

confidence: 99%

Biallelic loss‐of‐function variants in EXOC6B are associated with impaired primary ciliogenesis and cause spondylo‐epi‐metaphyseal dysplasia with joint laxity type 3

et al. 2022

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Spondylo-epi-metaphyseal dysplasias with joint laxity, type 3 (SEMDJL3) is a genetic skeletal disorder characterized by multiple joint dislocations, caused by biallelic pathogenic variants in the EXOC6B gene. Only four individuals from two families have been reported to have this condition to date. The molecular pathogenesis related to primary ciliogenesis has not been enumerated in subjects with SEMDJL3.In this study, we report two additional affected individuals from unrelated families with biallelic pathogenic variants, c.2122+15447_2197-59588del and c.401T>G in EXOC6B identified by exome sequencing. One of the affected individuals had an intellectual disability and central nervous system anomalies, including hydrocephalus, hypoplastic mesencephalon, and thin corpus callosum. Using the fibroblast cell lines, we demonstrate the primary evidence for the abrogation of exocytosis in an individual with SEMDLJ3 leading to impaired primary ciliogenesis. Osteogenesis differentiation and pathways related to the extracellular matrix were also found to be reduced. Additionally, we provide a review of the clinical and molecular profile of all the mutation-proven patients reported hitherto, thereby further characterizing SEMDJL3. SEMDJL3 with biallelic pathogenic variants in EXOC6B might represent yet another ciliopathy with central nervous system involvement and joint dislocations.

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“…Two of these genes ( CYP26B1 and EXOC6B ) are associated with the same trait (lamb metacarpal length) and are located within 0.5Mb of the same top SNP on chromosome 3. CYP26B1 is associated with skeletal abnormalities in humans and zebrafish (Laue et al 2011) and CYP26B1 knockouts produced reduced limbs in mice (Yashiro et al 2004), whilst EXOC6B is associated with spondyloepimetaphyseal dysplasia in humans which symptoms include skeletal malformations affecting the long bones of the limbs and short stature (Campos-Xavier et al 2018).…”

Section: Gwasmentioning

confidence: 99%

The impact of SNP density on quantitative genetic analyses of body size traits in a wild population of Soay sheep

James

Pemberton

Navarro

et al. 2022

Preprint

View full text Add to dashboard Cite

Understanding the genetic architecture underpinning quantitative traits in wild populations is pivotal to understanding the processes behind trait evolution. The ‘animal model’ is a popular method for estimating quantitative genetic parameters such as heritability and genetic correlation and involves fitting an estimate of relatedness between individuals in the study population. Genotypes at genome-wide markers can be used to estimate relatedness; however, relatedness estimates vary with marker density, potentially affecting results. Increasing density of markers is also expected to increase the power to detect quantitative trait loci (QTL). We estimated heritability and performed genome-wide association studies (GWAS) on five body size traits in an unmanaged population of Soay sheep using two different SNP densities: a dataset of 37,037 genotyped SNPs, and an imputed dataset of 417,373 SNPs. Heritability estimates did not differ between the two SNP densities, but the high-density imputed SNP dataset revealed five new SNP-trait associations that were not found with the lower density dataset. Conditional GWAS analyses after fitting the most significant SNPs revealed two more novel SNP-trait associations.

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Confirmation of spondylo‐epi‐metaphyseal dysplasia with joint laxity, EXOC6B type

Cited by 6 publications

References 6 publications

The impact of SNP density on quantitative genetic analyses of body size traits in a wild population of Soay sheep

The impact of SNP density on quantitative genetic analyses of body size traits in a wild population of Soay sheep

Biallelic loss‐of‐function variants in EXOC6B are associated with impaired primary ciliogenesis and cause spondylo‐epi‐metaphyseal dysplasia with joint laxity type 3

The impact of SNP density on quantitative genetic analyses of body size traits in a wild population of Soay sheep

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