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Precision molecular diagnosis defines specific therapy in combined immunodeficiency with megaloblastic anaemia secondary to MTHFD1 deficiency

Precision molecular diagnosis defines specific therapy in combined immunodeficiency with megaloblastic anaemia secondary to MTHFD1 deficiency
Precision molecular diagnosis defines specific therapy in combined immunodeficiency with megaloblastic anaemia secondary to MTHFD1 deficiency
Background
Methylenetetrahydrofolate dehydrogenase (MTHFD1) deficiency has recently been reported to cause a folate-responsive syndrome displaying a phenotype that includes megaloblastic anemia and severe combined immunodeficiency.

Objective
To describe our investigative approach to the molecular diagnosis and evaluation of immune dysfunction in a family with MTHFD1 deficiency.

Methods
The methods used were exome sequencing and analysis of variants in genes involved in the folate metabolic pathway in a family with 2 affected siblings. Routine laboratory and research data were analyzed to gain an in-depth understanding of innate, humoral, and cell-mediated immune function before and after folinic acid supplementation.

Results
Interrogation of exome data for concordant variants between the siblings in the genes involved in folate metabolic pathway identified a heterozygous mutation in exon 3 of the MTHFD1 gene that was shared with their mother. In view of highly suggestive phenotype, we extended our bioinformatics interrogation for structural variants in the MTHFD1 gene by manual evaluation of the exome data for sequence depth coverage of all the exons. A deletion involving exon 13 that was shared with their father was identified. Routine laboratory data showed lymphopenia involving all subsets and poor response to vaccines. In vitro analysis of dendritic cell and lymphocyte function was comparable to that in healthy volunteers. Treatment with folinic acid led to immune reconstitution, enabling discontinuation of all prophylactic therapies.

Conclusions
Exome sequencing demonstrated MTHFD1 deficiency as a novel cause of a combined immunodeficiency. Folinic acid was established as precision therapy to reverse the clinical and laboratory phenotype of this primary immunodeficiency.
2213-2198
1160-1166.e10
Ramakrishnan, Kesava
c7c565f4-69a5-4c57-a277-1497c01aff1d
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Gao, Yifang
eea234ba-f566-4f21-a65e-234b84cba285
Morgan, Mary
ee43f2e9-c61d-4b13-9fbf-8637c76ac850
Patel, Sanjay
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Davies, E.Graham
25b72164-1bcb-4a6a-baf6-0b29ee4a840e
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Faust, Saul
f97df780-9f9b-418e-b349-7adf63e150c1
Williams, Tony
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Ramakrishnan, Kesava
c7c565f4-69a5-4c57-a277-1497c01aff1d
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Gao, Yifang
eea234ba-f566-4f21-a65e-234b84cba285
Morgan, Mary
ee43f2e9-c61d-4b13-9fbf-8637c76ac850
Patel, Sanjay
4ea4db7c-bf45-41af-8d57-4e925f24474c
Davies, E.Graham
25b72164-1bcb-4a6a-baf6-0b29ee4a840e
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Faust, Saul
f97df780-9f9b-418e-b349-7adf63e150c1
Williams, Tony
973ff46f-46f1-4d7c-b27d-0f53221e4c44

Ramakrishnan, Kesava, Pengelly, Reuben, Gao, Yifang, Morgan, Mary, Patel, Sanjay, Davies, E.Graham, Ennis, Sarah, Faust, Saul and Williams, Tony (2016) Precision molecular diagnosis defines specific therapy in combined immunodeficiency with megaloblastic anaemia secondary to MTHFD1 deficiency. The Journal of Allergy and Clinical immunology: In Practice, 4 (6), 1160-1166.e10. (doi:10.1016/j.jaip.2016.07.014). (PMID:27707659)

Record type: Article

Abstract

Background
Methylenetetrahydrofolate dehydrogenase (MTHFD1) deficiency has recently been reported to cause a folate-responsive syndrome displaying a phenotype that includes megaloblastic anemia and severe combined immunodeficiency.

Objective
To describe our investigative approach to the molecular diagnosis and evaluation of immune dysfunction in a family with MTHFD1 deficiency.

Methods
The methods used were exome sequencing and analysis of variants in genes involved in the folate metabolic pathway in a family with 2 affected siblings. Routine laboratory and research data were analyzed to gain an in-depth understanding of innate, humoral, and cell-mediated immune function before and after folinic acid supplementation.

Results
Interrogation of exome data for concordant variants between the siblings in the genes involved in folate metabolic pathway identified a heterozygous mutation in exon 3 of the MTHFD1 gene that was shared with their mother. In view of highly suggestive phenotype, we extended our bioinformatics interrogation for structural variants in the MTHFD1 gene by manual evaluation of the exome data for sequence depth coverage of all the exons. A deletion involving exon 13 that was shared with their father was identified. Routine laboratory data showed lymphopenia involving all subsets and poor response to vaccines. In vitro analysis of dendritic cell and lymphocyte function was comparable to that in healthy volunteers. Treatment with folinic acid led to immune reconstitution, enabling discontinuation of all prophylactic therapies.

Conclusions
Exome sequencing demonstrated MTHFD1 deficiency as a novel cause of a combined immunodeficiency. Folinic acid was established as precision therapy to reverse the clinical and laboratory phenotype of this primary immunodeficiency.

Text
INPRACTICE-D-16-00040R2.pdf - Accepted Manuscript
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More information

Accepted/In Press date: 8 July 2016
e-pub ahead of print date: 1 October 2016
Published date: 1 November 2016
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 401946
URI: http://eprints.soton.ac.uk/id/eprint/401946
ISSN: 2213-2198
PURE UUID: de677af3-62a3-4fda-9840-0dfd9b9812fd
ORCID for Reuben Pengelly: ORCID iD orcid.org/0000-0001-7022-645X
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869
ORCID for Saul Faust: ORCID iD orcid.org/0000-0003-3410-7642

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Date deposited: 24 Oct 2016 14:11
Last modified: 18 Feb 2021 17:22

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Contributors

Author: Kesava Ramakrishnan
Author: Reuben Pengelly ORCID iD
Author: Yifang Gao
Author: Mary Morgan
Author: Sanjay Patel
Author: E.Graham Davies
Author: Sarah Ennis ORCID iD
Author: Saul Faust ORCID iD
Author: Tony Williams

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