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First report of vertical transmission of a somatic NLRP3 mutation in cryopyrin-associated periodic syndromes
  1. Santiago Jiménez-Treviño1,
  2. Eva González-Roca2,
  3. Estibaliz Ruiz-Ortiz2,
  4. Jordi Yagüe2,
  5. Eduardo Ramos1,
  6. Juan Ignacio Aróstegui2
  1. 1 Pediatrics Department, Hospital Central de Asturias, Oviedo, Asturias, Spain
  2. 2 Immunology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain
  1. Correspondence to Dr Juan Ignacio Aróstegui, Immunology Department (esc 4-pl 0), Hospital Clinic, IDIBAPS, Villarroel, 170, Barcelona 08036, Spain; jiaroste{at}

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Cryopyrin-associated periodic syndromes (CAPS) are rare autoinflammatory diseases caused by dominantly inherited or de novo gain-of-function NLRP3 mutations. They include familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological, cutaneous and articular syndrome.1 The NLRP3 gene encodes cryopyrin, a key component of the cytosolic complex termed inflammasome, which generates the active form of interleukin (IL)-1ß. Previous studies showed an uncontrolled IL-1ß overproduction in CAPS, representing the basis from which to treat these patients with IL-1 blockade.1–3

The important role of somatic NLRP3 mutations in CAPS has been recently shown.4 However, as occurs in most Mendelian diseases, no data are available concerning the presence of low-level somatic NLRP3 mosaicism in parents of CAPS patients. To address this issue we performed massively parallel DNA sequencing using a GS Junior 454 platform in selected families from our unit. The inclusion criteria were: (1) the family's index patient may be affected by any CAPS phenotype, (2) previous analyses should have detected an apparent de novo germline NLRP3 mutation in index patients, (3) no familial history of the disease in previous generations and (4) availability of biological samples from patient and patient's parents (trio).

Four families fulfilling all these criteria were enrolled. Massively parallel sequencing was performed in the four trios using genomic DNA extracted from peripheral blood. We only detected the presence of somatic NLRP3 mosaicism in the healthy mother of one family. The index patient of this family is a previously reported patient with Muckle-Wells syndrome carrying the germline p.Thr348Met mutation.5 ,6 This mutation was detected at low frequency in different tissues of the patient's mother, including haematopoietic and epithelial cells, and also must be present in her gonadal tissues. Moreover, the frequency of the mutated allele remained identical in blood samples obtained over a 9-year period (table 1).

Table 1

NLRP3 genotyping in the family of the patient with Muckle-Wells syndrome harbouring the germline p.Thr348Met NLRP3 mutation

To our knowledge this case represents the first known CAPS patient consequence of the vertical transmission of a somatic NLRP3 mutation. Moreover, the presence of this somatic mutation in the mother's cells from different embryonal origins, which remains stable over years, suggests that the mutational event probably occurred early in embryogenesis. However, the low-level somatic NLRP3 mosaicism detected in an otherwise completely healthy woman is a question that must be addressed. The combination of the precise NLRP3 mutation, its functional consequences and the frequency and tissue distribution of the mutated allele could probably explain the differences observed between the patient's healthy mother described here and some CAPS patients carrying low-level somatic NLRP3 mosaicism recently described.4

The evidence shown here could have serious implications for genetic counselling. Based on our results we would recommend a systematic search for somatic mosaicism in all patients with an apparent de novo mutation. However, the necessary genetic technologies are not widely available. As somatic mosaicism is considered a rare genetic phenomenon in Mendelian diseases, with an unknown frequency, the message to the families is that the risk of having another affected child is not zero but remains very low.


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  • Contributors SJ-T and ER contributed to collection of biological samples, acquisition of data, revising the article and approval of the version of the article submitted for publication. EG-R, ER and JY contributed to acquisition of data, analysis and interpretation of data, revising the article and approval of the version of the article submitted for publication. JIA contributed to study design, acquisition of data, analysis and interpretation of data, drafting the article, writing the manuscript and approval of the version of the article submitted for publication.

  • Funding Supported by Ministerio de Sanidad y Consumo grant FIS PS09/01182.

  • Competing interests None.

  • Ethics approval Ethics Committee of the Hospital Clinic.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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