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Research question <p>Can preimplantation genetic testing for monogenic disorders (PGT-M) be effectively implemented to prevent recurrence of X-linked severe combined immunodeficiency (X-SCID) caused by a novel <i>IL2RG</i> variant when conventional parental carrier testing initially yields a negative result?</p> Design:&#xa0;Case report <p>A Thai couple with a prior affected child (deceased; T⁻B⁺NK⁻ immunophenotype; <i>IL2RG</i> c.676C &gt; G, p.(Arg226Gly)) underwent whole exome sequencing (WES), which was initially negative in both parents. Subsequent WES reanalysis identified a low-level heterozygous signal (~ 12% allele frequency) in the mother's blood, below the standard 30% calling threshold, consistent with low-level maternal mosaicism. Direct sequencing and PCR–RFLP from buccal swab tissue showed a concordant low-level signal in a second tissue compartment. Six blastocysts obtained via ICSI underwent trophectoderm biopsy for combined PGT-M (targeted to the proband's confirmed variant) and comprehensive chromosomal screening (PGT-A). </p> Results <p>Four blastocysts were euploid and two aneuploids. Of the euploid embryos, three were mutation-free (wild-type) and one carried the <i>IL2RG</i> c.676C &gt; G variant. A single frozen-thawed embryo transfer of a mutation-free euploid embryo resulted in a confirmed intrauterine pregnancy. Non-invasive prenatal testing (NIPT) at 12&#xa0;weeks demonstrated low risk for Trisomy 21, 18, and 13, with fetal sex concordant with PGT-A findings.</p> Conclusions <p>The novel <i>IL2RG</i> c.676C &gt; G (p.(Arg226Gly)) variant identified at a known mutational hotspot (codon 226) and absent from global variant databases is classified as Likely Pathogenic per ACMG criteria. Low-level maternal mosaicism was subsequently identified in blood and supported by concordant low-level findings in buccal mucosa, clarifying recurrence-risk counselling for this family. PGT-M anchored to the proband's confirmed IL2RG variant successfully identified three transferable, euploid, mutation-free embryos, and transfer of one embryo resulted in an ongoing pregnancy. This case demonstrates that ICSI with PGT-M can prevent X-SCID recurrence even when standard parental carrier testing is initially non-informative, establishing a reproductive workflow applicable to families in whom the proband's variant is confirmed.</p>

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Prevention of recurrence of severe combined immunodeficiency through preimplantation genetic testing: a case study of a novel IL2RG variant and confirmed maternal somatic mosaicism in Thailand

  • 期刊论文

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  • 发表日期：

    2026年7月28日

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  • Rattanamon Koonthaweelab,
  • Napadon Yaibuates,
  • Pongpet Benjaponwattana,
  • Busarin Boonyacheeva,
  • Jitti Saksantisuk

摘要

Research question

Can preimplantation genetic testing for monogenic disorders (PGT-M) be effectively implemented to prevent recurrence of X-linked severe combined immunodeficiency (X-SCID) caused by a novel IL2RG variant when conventional parental carrier testing initially yields a negative result?

Design: Case report

A Thai couple with a prior affected child (deceased; T⁻B⁺NK⁻ immunophenotype; IL2RG c.676C > G, p.(Arg226Gly)) underwent whole exome sequencing (WES), which was initially negative in both parents. Subsequent WES reanalysis identified a low-level heterozygous signal (~ 12% allele frequency) in the mother's blood, below the standard 30% calling threshold, consistent with low-level maternal mosaicism. Direct sequencing and PCR–RFLP from buccal swab tissue showed a concordant low-level signal in a second tissue compartment. Six blastocysts obtained via ICSI underwent trophectoderm biopsy for combined PGT-M (targeted to the proband's confirmed variant) and comprehensive chromosomal screening (PGT-A).

Results

Four blastocysts were euploid and two aneuploids. Of the euploid embryos, three were mutation-free (wild-type) and one carried the IL2RG c.676C > G variant. A single frozen-thawed embryo transfer of a mutation-free euploid embryo resulted in a confirmed intrauterine pregnancy. Non-invasive prenatal testing (NIPT) at 12 weeks demonstrated low risk for Trisomy 21, 18, and 13, with fetal sex concordant with PGT-A findings.

Conclusions

The novel IL2RG c.676C > G (p.(Arg226Gly)) variant identified at a known mutational hotspot (codon 226) and absent from global variant databases is classified as Likely Pathogenic per ACMG criteria. Low-level maternal mosaicism was subsequently identified in blood and supported by concordant low-level findings in buccal mucosa, clarifying recurrence-risk counselling for this family. PGT-M anchored to the proband's confirmed IL2RG variant successfully identified three transferable, euploid, mutation-free embryos, and transfer of one embryo resulted in an ongoing pregnancy. This case demonstrates that ICSI with PGT-M can prevent X-SCID recurrence even when standard parental carrier testing is initially non-informative, establishing a reproductive workflow applicable to families in whom the proband's variant is confirmed.