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Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm

Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm
Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm
CBL is a tumour suppressor gene on chromosome 11 encoding a multivalent adaptor protein with E3 ubiquitin ligase activity. Germline CBL mutations are dominant, with pathogenic de novo mutations reported that can phenotypically overlap Noonan syndrome.1 Some patients with CBL mutations go on to develop juvenile myelomonocytic leukaemia (JMML), an aggressive malignancy that usually necessitates bone marrow transplantation. Using whole exome sequencing methods, we identified a known mutation in CBL in a 4-year-old Caucasian boy with atypical haemolytic uraemic syndrome (aHUS), moyamoya phenomenon and dysmorphology consistent with a mild Noonan-like phenotype. Exome data revealed loss of heterozygosity across chromosome 11q consistent with JMML but in the absence of clinical leukaemia. Our finding challenges conventional clinical diagnostics since we have identified a pathogenic variant in the CBL gene previously only ascertained in children presenting with leukaemia. The increasing affordability of expansive sequencing is likely to increase the scope of clinical profiles observed for previously identified pathogenic variants and calls into question the interpretability and indications for clinical management.
2296-2360
Seaby, Eleanor G.
ec948f42-007c-4bd8-9dff-bb86278bf03f
Gilbert, Rodney D.
a60642f2-761a-4a29-acad-2720db1d8ce9
Andreoletti, Gaia
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Pengelly, Reuben J
af97c0c1-b568-415c-9f59-1823b65be76d
Mercer, Catherine
0c67d6a4-c49b-42b1-a688-3f8cc5807ea7
Hunt, David
5867549e-0e44-4f07-9a42-93aaf092fd4d
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Seaby, Eleanor G.
ec948f42-007c-4bd8-9dff-bb86278bf03f
Gilbert, Rodney D.
a60642f2-761a-4a29-acad-2720db1d8ce9
Andreoletti, Gaia
75cfc74e-f938-48c8-b3d5-5b377297d008
Pengelly, Reuben J
af97c0c1-b568-415c-9f59-1823b65be76d
Mercer, Catherine
0c67d6a4-c49b-42b1-a688-3f8cc5807ea7
Hunt, David
5867549e-0e44-4f07-9a42-93aaf092fd4d
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9

Seaby, Eleanor G., Gilbert, Rodney D., Andreoletti, Gaia, Pengelly, Reuben J, Mercer, Catherine, Hunt, David and Ennis, Sarah (2017) Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm. Frontiers in Pediatrics, 5, [113]. (doi:10.3389/fped.2017.00113).

Record type: Article

Abstract

CBL is a tumour suppressor gene on chromosome 11 encoding a multivalent adaptor protein with E3 ubiquitin ligase activity. Germline CBL mutations are dominant, with pathogenic de novo mutations reported that can phenotypically overlap Noonan syndrome.1 Some patients with CBL mutations go on to develop juvenile myelomonocytic leukaemia (JMML), an aggressive malignancy that usually necessitates bone marrow transplantation. Using whole exome sequencing methods, we identified a known mutation in CBL in a 4-year-old Caucasian boy with atypical haemolytic uraemic syndrome (aHUS), moyamoya phenomenon and dysmorphology consistent with a mild Noonan-like phenotype. Exome data revealed loss of heterozygosity across chromosome 11q consistent with JMML but in the absence of clinical leukaemia. Our finding challenges conventional clinical diagnostics since we have identified a pathogenic variant in the CBL gene previously only ascertained in children presenting with leukaemia. The increasing affordability of expansive sequencing is likely to increase the scope of clinical profiles observed for previously identified pathogenic variants and calls into question the interpretability and indications for clinical management.

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Accepted/In Press date: 1 May 2017
e-pub ahead of print date: 22 May 2017
Published date: 22 May 2017
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 407950
URI: http://eprints.soton.ac.uk/id/eprint/407950
ISSN: 2296-2360
PURE UUID: 3aad7ce9-2fc1-43e4-88ea-08c40be5219f
ORCID for Eleanor G. Seaby: ORCID iD orcid.org/0000-0002-6814-8648
ORCID for Reuben J Pengelly: ORCID iD orcid.org/0000-0001-7022-645X
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869

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Date deposited: 05 May 2017 01:03
Last modified: 16 Mar 2024 04:45

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Contributors

Author: Eleanor G. Seaby ORCID iD
Author: Rodney D. Gilbert
Author: Gaia Andreoletti
Author: Catherine Mercer
Author: David Hunt
Author: Sarah Ennis ORCID iD

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