The University of Southampton
University of Southampton Institutional Repository

Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement

Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement
Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement
Background: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis.

Aims and methods: to determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing.

Results and conclusions: we detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype–phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes
0022-2593
309-323
Schmidts, M.
fa4e63c0-3093-4b31-8e32-5365b4ee6511
Arts, H.H.
5446d0b6-d44c-438b-b09b-ee4d82849f0e
Bongers, E.M.H.F.
ac970543-f82f-49a1-80ea-c8ff88b3c993
Yap, Z.
1f8093da-696e-4347-a4fa-1db08f5ef846
Oud, M.M.
7e4ae11e-6947-4aa1-82da-80b996e12669
Antony, D.
75a958ef-aacc-4a85-a8df-f6e92dad9095
Duijkers, L.
914e3798-ae64-494f-bd78-8b5290b13e65
Emes, R.D.
80422933-0d31-4119-b9f6-0e47a7a3630f
Stalker, J.
1fcb7fc5-fdd0-4a0d-8880-4a70d904714e
Yntema, J.-B.L.
112b9d40-f0d1-40c8-801d-d0a43120afac
Plagnol, V.
6ab82c04-3048-49d4-8072-a60ac20e7ea5
Hoischen, A.
d8d38e96-d65d-4c0b-b8fb-fdf337f9d90c
Gilissen, C.
ae5f9b7a-05d1-4360-adcb-9e8c53ddf69c
Forsythe, E.
a9635576-31ff-497d-8a07-b6be01409536
Lausch, E.
97c8c359-5c0b-4440-af78-1f0a73c1734d
Veltman, J.A.
91d53f1a-2e02-48fb-ab7d-8a9cfddd9fd9
Roeleveld, N.
73163608-0090-4d10-b324-78a637982edd
Superti-Furga, A.
0cc6f7e2-9acd-4f9a-98ba-fa089a615115
Kutkowska-Kazmierczak, A.
44d1a0a3-cb94-4b7d-8dd4-af463b0582e8
Kamsteeg, E.-J.
3838f7f3-1c28-41ff-98b7-14f091490871
Elcioglu, N.
e52846c5-6666-42db-89a7-d487dc0d776d
van Maarle, M.C.
e0be8a28-035a-452b-98cf-5ccfe029ded6
Graul-Neumann, L.M.
bd215137-a557-43da-8702-f20e23407581
Devriendt, K.
6ecee932-4437-4b9f-8b5d-abde26ad3daa
Smithson, S.F.
3a4cd2f8-ce0e-4083-aa35-43215fc1877c
Wellesley, D.
17cbd6c1-0efb-4df1-ae05-64a44987c9c0
Verbeek, N.E.
c268adaa-ce91-45e7-bf97-05a945580d05
Hennekam, R.C.M.
d3e620b5-33e4-473c-961b-18bb5e8da8a0
Kayserili, H.
270f285b-d7ce-496c-b7ce-1c5ab18f6790
Scambler, P.J.
1294940b-d050-4ab3-b5cf-66c0c206ec05
Beales, P.L.
07d1597b-0f72-47cc-a58d-29590099b742
Knoers, N.V.
9846bf53-bd05-47da-b578-09dfc7534513
Roepman, R.
2f37bff2-ff8d-472b-9e1d-98c43e34b96b
Mitchison, H.M.
e54a2b6a-aa40-49e7-9c83-dfcc18cf9e40
Schmidts, M.
fa4e63c0-3093-4b31-8e32-5365b4ee6511
Arts, H.H.
5446d0b6-d44c-438b-b09b-ee4d82849f0e
Bongers, E.M.H.F.
ac970543-f82f-49a1-80ea-c8ff88b3c993
Yap, Z.
1f8093da-696e-4347-a4fa-1db08f5ef846
Oud, M.M.
7e4ae11e-6947-4aa1-82da-80b996e12669
Antony, D.
75a958ef-aacc-4a85-a8df-f6e92dad9095
Duijkers, L.
914e3798-ae64-494f-bd78-8b5290b13e65
Emes, R.D.
80422933-0d31-4119-b9f6-0e47a7a3630f
Stalker, J.
1fcb7fc5-fdd0-4a0d-8880-4a70d904714e
Yntema, J.-B.L.
112b9d40-f0d1-40c8-801d-d0a43120afac
Plagnol, V.
6ab82c04-3048-49d4-8072-a60ac20e7ea5
Hoischen, A.
d8d38e96-d65d-4c0b-b8fb-fdf337f9d90c
Gilissen, C.
ae5f9b7a-05d1-4360-adcb-9e8c53ddf69c
Forsythe, E.
a9635576-31ff-497d-8a07-b6be01409536
Lausch, E.
97c8c359-5c0b-4440-af78-1f0a73c1734d
Veltman, J.A.
91d53f1a-2e02-48fb-ab7d-8a9cfddd9fd9
Roeleveld, N.
73163608-0090-4d10-b324-78a637982edd
Superti-Furga, A.
0cc6f7e2-9acd-4f9a-98ba-fa089a615115
Kutkowska-Kazmierczak, A.
44d1a0a3-cb94-4b7d-8dd4-af463b0582e8
Kamsteeg, E.-J.
3838f7f3-1c28-41ff-98b7-14f091490871
Elcioglu, N.
e52846c5-6666-42db-89a7-d487dc0d776d
van Maarle, M.C.
e0be8a28-035a-452b-98cf-5ccfe029ded6
Graul-Neumann, L.M.
bd215137-a557-43da-8702-f20e23407581
Devriendt, K.
6ecee932-4437-4b9f-8b5d-abde26ad3daa
Smithson, S.F.
3a4cd2f8-ce0e-4083-aa35-43215fc1877c
Wellesley, D.
17cbd6c1-0efb-4df1-ae05-64a44987c9c0
Verbeek, N.E.
c268adaa-ce91-45e7-bf97-05a945580d05
Hennekam, R.C.M.
d3e620b5-33e4-473c-961b-18bb5e8da8a0
Kayserili, H.
270f285b-d7ce-496c-b7ce-1c5ab18f6790
Scambler, P.J.
1294940b-d050-4ab3-b5cf-66c0c206ec05
Beales, P.L.
07d1597b-0f72-47cc-a58d-29590099b742
Knoers, N.V.
9846bf53-bd05-47da-b578-09dfc7534513
Roepman, R.
2f37bff2-ff8d-472b-9e1d-98c43e34b96b
Mitchison, H.M.
e54a2b6a-aa40-49e7-9c83-dfcc18cf9e40

Schmidts, M., Arts, H.H., Bongers, E.M.H.F., Yap, Z., Oud, M.M., Antony, D., Duijkers, L., Emes, R.D., Stalker, J., Yntema, J.-B.L., Plagnol, V., Hoischen, A., Gilissen, C., Forsythe, E., Lausch, E., Veltman, J.A., Roeleveld, N., Superti-Furga, A., Kutkowska-Kazmierczak, A., Kamsteeg, E.-J., Elcioglu, N., van Maarle, M.C., Graul-Neumann, L.M., Devriendt, K., Smithson, S.F., Wellesley, D., Verbeek, N.E., Hennekam, R.C.M., Kayserili, H., Scambler, P.J., Beales, P.L., Knoers, N.V., Roepman, R. and Mitchison, H.M. (2013) Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. Journal of Medical Genetics, 50 (5), 309-323. (doi:10.1136/jmedgenet-2012-101284).

Record type: Article

Abstract

Background: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis.

Aims and methods: to determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing.

Results and conclusions: we detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype–phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes

This record has no associated files available for download.

More information

e-pub ahead of print date: 1 March 2013
Published date: March 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 349502
URI: http://eprints.soton.ac.uk/id/eprint/349502
ISSN: 0022-2593
PURE UUID: 59227b6f-ac67-495e-ab04-547545df8f6d

Catalogue record

Date deposited: 06 Mar 2013 12:28
Last modified: 22 Jul 2022 18:24

Export record

Altmetrics

Contributors

Author: M. Schmidts
Author: H.H. Arts
Author: E.M.H.F. Bongers
Author: Z. Yap
Author: M.M. Oud
Author: D. Antony
Author: L. Duijkers
Author: R.D. Emes
Author: J. Stalker
Author: J.-B.L. Yntema
Author: V. Plagnol
Author: A. Hoischen
Author: C. Gilissen
Author: E. Forsythe
Author: E. Lausch
Author: J.A. Veltman
Author: N. Roeleveld
Author: A. Superti-Furga
Author: A. Kutkowska-Kazmierczak
Author: E.-J. Kamsteeg
Author: N. Elcioglu
Author: M.C. van Maarle
Author: L.M. Graul-Neumann
Author: K. Devriendt
Author: S.F. Smithson
Author: D. Wellesley
Author: N.E. Verbeek
Author: R.C.M. Hennekam
Author: H. Kayserili
Author: P.J. Scambler
Author: P.L. Beales
Author: N.V. Knoers
Author: R. Roepman
Author: H.M. Mitchison

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×