Walne, AJ;
Collopy, L;
Cardoso, S;
Ellison, A;
Plagnol, V;
Albayrak, C;
Albayrak, D;
... Dokal, I; + view all
(2016)
Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis.
Haematologica
, 101
(10)
pp. 1180-1189.
10.3324/haematol.2016.147769.
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Abstract
Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically, these were homozygous variants in USB1 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements.
| Type: | Article |
|---|---|
| Title: | Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3324/haematol.2016.147769 |
| Publisher version: | http://dx.doi.org/10.3324/haematol.2016.147769 |
| Language: | English |
| Additional information: | ©2016 Ferrata Storti Foundation. Material published in Haematologica is covered by copyright. All rights reserved to Ferrata Storti Foundation. Copies of articles are allowed for personal or internal use. A permission in writing by the publisher is required for any other use. |
| Keywords: | Text Case Converter Text case converter - Change the case of any text easily Text case converter is a handy web application that allows you to change text case of any text easily to upper case, lower case, title case or sentence case. Simply paste the text you want to convert into the text area below, click on one of the buttons and let the tool to do the work for you. Don't know what the different text cases are? No problem! Just hover over the buttons to see examples. Share! del.icio.us Facebook Digg Technocrati Blinklist Furl Reddit Science & Technology, Life Sciences & Biomedicine, Hematology, Bone-Marrow Failure, Poly(A)-Specific Ribonuclease Parn, Dna-Damage Response, Ligase Iv Syndrome, Telomere Biology, Poikiloderma, Neutropenia, Mutations, C16Orf57, Length |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1535964 |
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