Syndromic ciliopathies: From single gene to multi gene analysis by SNP arrays and next generation sequencing

Knopp, Cordula; Rudnik‐Schöneborn, Sabine; Eggermann, Thomas; Bergmann, Carsten; Begemann, Matthias; Schoner, Katharina; Zerres, Klaus; Brüchle, Nadina Ortiz

doi:10.1016/j.mcp.2015.05.008

Cited by 26 publications

(26 citation statements)

References 75 publications

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“…Besides gene discovery, next‐generation sequencing technologies have also revolutionized genetic diagnosis, allowing us to simultaneously, rapidly, and cost‐effectively sequence hundreds of ciliary genes in large cohorts of patients . This has resulted in a more accurate estimate of the mutation frequency, as well as in an unexpected expansion of the phenotypic spectrum of ciliary genes (Figure ).…”

Section: Genetic Basis Of Non‐motile Ciliopathiesmentioning

confidence: 99%

Motile and non‐motile cilia in human pathology: from function to phenotypes

Mitchison

Valente

2016

The Journal of Pathology

367

401

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Ciliopathies are inherited human disorders caused by both motile and non-motile cilia dysfunction that form an important and rapidly expanding disease category. Ciliopathies are complex conditions to diagnose, being multisystem disorders characterized by extensive genetic heterogeneity and clinical variability with high levels of lethality. There is marked phenotypic overlap among distinct ciliopathy syndromes that presents a major challenge for their recognition, diagnosis, and clinical management, in addition to posing an on-going task to develop the most appropriate family counselling. The impact of next-generation sequencing and high-throughput technologies in the last decade has significantly improved our understanding of the biological basis of ciliopathy disorders, enhancing our ability to determine the possible reasons for the extensive overlap in their symptoms and genetic aetiologies. Here, we review the diverse functions of cilia in human health and disease and discuss a growing shift away from the classical clinical definitions of ciliopathy syndromes to a more functional categorization. This approach arises from our improved understanding of this unique organelle, revealed through new genetic and cell biological insights into the discrete functioning of subcompartments of the cilium (basal body, transition zone, intraflagellar transport, motility). Mutations affecting these distinct ciliary protein modules can confer different genetic diseases and new clinical classifications are possible to define, according to the nature and extent of organ involvement.

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Section: Genetic Basis Of Non‐motile Ciliopathiesmentioning

confidence: 99%

Motile and non‐motile cilia in human pathology: from function to phenotypes

Mitchison

Valente

2016

The Journal of Pathology

367

401

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“…Hepatic involvement was rare (1 case 37,44,45 We report here the largest cohort of fetuses with pathogenic variants in BBS genes with US and/or autopsy data in order to delineate the antenatal presentation of BBS.…”

Section: Phenotype-genotype Correlationsmentioning

confidence: 99%

Bardet‐Biedl syndrome: Antenatal presentation of forty‐five fetuses with biallelic pathogenic variants in known Bardet‐Biedl syndrome genes

et al. 2019

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Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses. K E Y W O R D Santenatal presentation, Bardet-Biedl syndrome, BBS, diagnostic strategy

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“…Annotating the morbid genome of ciliopathies can greatly expand our knowledge about the non-redundant components of the “ciliome,” and the annotation has progressed dramatically with the advent of massive parallel sequencing [11]. However, the annotation of the morbid genome remains incomplete, and the suggestion that its missing part lies in non-Mendelian forms of inheritance remains controversial [12].…”

Section: Introductionmentioning

confidence: 99%

Characterizing the morbid genome of ciliopathies

et al. 2016

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BackgroundCiliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete.ResultsWe applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their “mutation load” beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population.ConclusionsOur study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1099-5) contains supplementary material, which is available to authorized users.

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Syndromic ciliopathies: From single gene to multi gene analysis by SNP arrays and next generation sequencing

Cited by 26 publications

References 75 publications

Motile and non‐motile cilia in human pathology: from function to phenotypes

Motile and non‐motile cilia in human pathology: from function to phenotypes

Bardet‐Biedl syndrome: Antenatal presentation of forty‐five fetuses with biallelic pathogenic variants in known Bardet‐Biedl syndrome genes

Characterizing the morbid genome of ciliopathies

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