Clin Genet 2014: 85: 500–501
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© 2013 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd
Letter to the Editor
Severe combined immunodeficiency: first
report of a de novo mutation in the IL2RG
gene in a boy conceived by in vitro
To the Editor:
Severe combined immunodeficiencies (SCID) are a
group of rare inherited disorders with profound defects
in T-cell and B-cell immunity, characterized by severe
and persistent infections starting in the first months of
life typically accompanied by diarrhea and failure to
thrive (1). The overall incidence of SCID is estimated to
be 1 in 75,000–100,000 live births (2). Most cases are
X linked and caused by mutations in the IL2RG gene
(MIM 308380) encoding the common gamma chain of
the interleukin-2 (IL-2) receptor (3).
We report on a 2month-old boy, the first child of non-
consanguineous Spanish parents conceived by in vitro
fertilization (IVF) using the parents’ own gametes, who
was referred to our hospital presenting a febrile syn-
drome of 10days’ duration and diarrhea. The mother’s
first pregnancy had been lost by spontaneous abortion,
but there was no family history of immunodeficiency.
Rotavirus and adenovirus were detected in the patient’s
stool samples. Immunological evaluation revealed low
serum immunoglobulin levels: IgG (118mg/dl), IgA
(3mg/dl) and IgM (15mg/dl). In addition, flow cyto-
metric immunophenotyping of lymphocyte subsets in
peripheral blood showed significantly decreased lev-
els of CD3+T (30c/μl) and natural killer (NK) cells
(2c/μl) with normal levels of CD19+B lymphocytes
(1578c/μl). Furthermore, there was no expression of
CD132 on lymphocytes. These results were indicative
Fig. 1. Electropherograms of exon 1 of the IL2RG gene: (a) patient with the c.2T>C (p.M1T) mutation, (b) normal subject, and (c) mother of the
patient. The position of the mutation is indicated by an arrow. Sequencing numbering corresponds to accession number NM_000206.2.
of X-linked T−B+NK−SCID and prompted us to
select IL2RG gene for sequence analysis. The patient
received a maternal haploidentical hematopoietic stem
cell transplant at the age of 4months, but despite the
evidence of T cell reconstitution, he died 5months after
transplant from severe cytomegalovirus infection.
The eight coding exons and intron–exon boundaries
of the IL2RG gene were amplified using previously
published primers (4). The PCR products were
sequenced using the Big Bye Terminator Cycle
Sequencing kit (Applied Biosystems, Foster City,
CA) on an ABI 3500 Genetic Analyser (Applied
Biosystems). Sequence variations were numbered
considering adenine of the ATG initiation codon
as the first nucleotide (GenBank accession number
NM_000206.2). Approval from the local medical ethics
committee and informed consent were obtained prior
to the study.
Sequence analysis of the IL2RG gene in the patient
revealed a hemizygous mutation in exon 1, the muta-
tion c.2T>C (Fig. 1). This previously reported mutation
leads to a methionine to threonine replacement at amino
acid position 1 (p.M1T) (5). This mutation was not
identified in the whole blood DNA of the patient’s
mother suggesting a de novo mutation, although a possi-
ble maternal germline mosaicism could not be ruled out.
To our knowledge, this is the first report on a de
novo mutation in the IL2RG gene in a patient born after
Letter to the Editor Download full-text
IVF. There has always been a concern that the infants
conceived by assisted reproductive technologies (ART)
are at an increased risk of birth defects (6). To date, the
influence of ART on point mutations has been largely
ignored, as it is impractical to study the occurrence of
de novo mutations in human offspring (7). Recently,
Caperton et al. (8) used a transgenic mouse model
and found no alteration in frequency of de novo point
mutations consequent to in vitro culture conditions
or after several different ART procedures. However,
the authors observed differences in the proportion of
transferred embryos that developed to midgestation
among the various methods of ART. Therefore, it is
possible that embryos exhibiting an increase in point
mutations, some possibly lethal, do not implant (7).
Our results highlight the importance of reporting
de novo mutations in patients conceived by ART.
Further investigations should focus on whether these
procedures increase the rate of point mutations involved
in decisive development checkpoints that could result
in implantation failure or pregnancy losses.
This work was supported by the Project 04087/GERM/06 (Fun-
daci´ on Seneca, Consejeria de Empresas y Universidades, Murcia).
We are grateful to the patient and his family for their collaboration
in this study. We would like to thank A Mrowiec for manuscript
edition and proofreading.
bPediatric Infectious Disease Unit, and
cPediatric Oncology Unit,
University Hospital Virgen Arrixaca
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chain mutation results in X-linked severe combined immunodeficiency
in humans. Cell 1993: 73 (1): 147–157.
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Dr Maria Rosa Moya-Quiles
University Hospital Virgen Arrixaca