Targeted next-generation sequencing identifies novel compound heterozygous mutations of DYNC2H1 in a fetus with short rib-polydactyly syndrome, type III

Mei, Lingyun; Huang, Yanru; Pan, Qian; Su, Wei; Quan, Yi; Wu, Lingqian

doi:10.1016/j.cca.2015.05.005

Cited by 23 publications

(15 citation statements)

References 25 publications

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“…Dagoneau et al (2009) Okamoto et al (2015) identified compound heterozygosity for mutations c.5682_5683delAA and c.9070C > T in exons 37 and 57, respectively, of the DYNC2H1 gene in a fetus with SRPS3. Mei et al (2015) identified compound heterozygosity for mutations c.1151C > T and c.4351C > T in exons 8 and 28, respectively, of the DYNC2H1 gene in a fetus with SRPS3. All cases showed similar radiographic findings, such as shortened long bones and a narrow thorax.…”

Section: Discussionmentioning

confidence: 96%

Identification of novel DYNC2H1 mutations associated with short rib-polydactyly syndrome type III using next-generation panel sequencing

Chen¹,

Shi²,

Zou³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Short rib-polydactyly syndrome type III (SRPS3) is a perinatal lethal skeletal disorder with polydactyly and multisystem organ abnormalities. While ultrasound of the fetus can detect skeletal abnormalities characteristic of SRPS3, the syndrome is often difficult to diagnose before birth. As SRPS3 is an autosomal recessive disorder, identification of the gene mutations involved could lead to the development of prenatal genetic testing as an accurate method of diagnosis. In this study, we describe genetic screening approaches to identify potential abnormalities associated with SRPS3. Karyotype analysis, array comparative genomic hybridization (aCGH), and nextgeneration panel sequencing were each performed on a fetus showing signs of the disorder, as well as on the mother and father. Karyotype and aCGH results revealed no abnormalities. However, next-generation panel sequencing identified novel mutations in the DYNC2H1 gene. The fetus was compound heterozygous for both a missense mutation c.8313A > T and a frameshift mutation c.10711_10714delTTTA in the DYNC2H1 gene, which were inherited from the mother and father, respectively. These variants were further confirmed using Sanger sequencing and have not been previously reported. Our study indicates the utility of using next-generation panel sequencing in screening for novel disease-associated mutations.

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Section: Discussionmentioning

confidence: 96%

Identification of novel DYNC2H1 mutations associated with short rib-polydactyly syndrome type III using next-generation panel sequencing

Chen¹,

Shi²,

Zou³

et al. 2016

Genet. Mol. Res.

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“…These are recessively inherited developmental disorders characterized by short ribs, shortened tubular bones, polydactyly and multisystem organ defects ( Huber and Cormier-Daire, 2012 ). In recent years, whole exome-sequencing technology has enabled the identification of new mutations involved in skeletal ciliopathies, notably a range of mutations affecting DYNC2H1 (DHC2, [ Chen et al, 2016 ; Cossu et al, 2016 ; Dagoneau et al, 2009 ; El Hokayem et al, 2012 ; Mei et al, 2015 ; Merrill et al, 2009 ; Okamoto et al, 2015 ; Schmidts et al, 2013a ]). Additionally, mutations in WDR34 ( Huber et al, 2013 ; Schmidts et al, 2013b ), WDR60 ( Cossu et al, 2016 ; McInerney-Leo et al, 2013 ), LIC3/DYNC2LI1 ( Kessler et al, 2015 ; Taylor et al, 2015 ) and TCTEX1D2 ( Schmidts et al, 2015 ) have also been reported.…”

Section: Introductionmentioning

confidence: 99%

Dynein-2 intermediate chains play crucial but distinct roles in primary cilia formation and function

Vuolo

Stevenson

Heesom

et al. 2018

eLife

112

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The dynein-2 microtubule motor is the retrograde motor for intraflagellar transport. Mutations in dynein-2 components cause skeletal ciliopathies, notably Jeune syndrome. Dynein-2 contains a heterodimer of two non-identical intermediate chains, WDR34 and WDR60. Here, we use knockout cell lines to demonstrate that each intermediate chain has a distinct role in cilium function. Using quantitative proteomics, we show that WDR34 KO cells can assemble a dynein-2 motor complex that binds IFT proteins yet fails to extend an axoneme, indicating complex function is stalled. In contrast, WDR60 KO cells do extend axonemes but show reduced assembly of dynein-2 and binding to IFT proteins. Both proteins are required to maintain a functional transition zone and for efficient bidirectional intraflagellar transport. Our results indicate that the subunit asymmetry within the dynein-2 complex is matched with a functional asymmetry between the dynein-2 intermediate chains. Furthermore, this work reveals that loss of function of dynein-2 leads to defects in transition zone architecture, as well as intraflagellar transport.

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“…Other potential benefits include a definitive diagnosis, even for a fetus or infant that dies in the perinatal period . The identification of a new autosomal recessive disorder in a family will allow accurate recurrence risk counseling and an exploration of various options in future pregnancies, including pre‐implantation genetic diagnosis.…”

Section: Clinical Benefits Of Prenatal Whole Genome Sequencingmentioning

confidence: 99%

Prenatal DNA Sequencing: Clinical, Counseling, and Diagnostic Laboratory Considerations

et al. 2017

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Clinical diagnostic laboratories are producing next-generation sequencing-based test results that are becoming increasingly incorporated into patient care. Whole genome and exome sequencing on fetal material derived from amniocytes, chorionic villi, or products of conception is starting to be offered clinically in specialized centers, but it has not yet become routine practice. The technical, interpretation, and ethical challenges are greatest in the area of prenatal medicine because the fetus has a limited health history, and the physical examination is only indirectly available via prenatal sonography. Here, we provide an overview of these challenges and highlight the clinical utility, reporting, and counseling issues associated with prenatal DNA sequencing. Future considerations are also discussed. © 2017 John Wiley & Sons, Ltd.

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Targeted next-generation sequencing identifies novel compound heterozygous mutations of DYNC2H1 in a fetus with short rib-polydactyly syndrome, type III

Cited by 23 publications

References 25 publications

Identification of novel DYNC2H1 mutations associated with short rib-polydactyly syndrome type III using next-generation panel sequencing

Identification of novel DYNC2H1 mutations associated with short rib-polydactyly syndrome type III using next-generation panel sequencing

Dynein-2 intermediate chains play crucial but distinct roles in primary cilia formation and function

Prenatal DNA Sequencing: Clinical, Counseling, and Diagnostic Laboratory Considerations

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