High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome

Kock, Leanne de; Wang, Yu Chang; Revil, Timothée; Badescu, Dunarel; Rivera, Bárbara; Sabbaghian, Nelly; Wu, Mona; Weber, Evan; Sandoval, Claudio; Hopman, Saskia; Merks, Johannes H. M.; Hagen, Johanna M. van; Bouts, Antonia H.; Plager, David A.; Ramasubramanian, Aparna; Forsmark, Linus; Doyle, Kristine L.; Toler, Tonja; Callahan, Janine; Engelenberg, Charlotte; Soglio, Dorothée Bouron Dal; Priest, John R.; Ragoussis, Jiannis; Foulkes, William D.

doi:10.1136/jmedgenet-2015-103428

Cited by 69 publications

(67 citation statements)

References 47 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since the DICER1 syndrome was relatively recently recognized, systematic evaluations of growth have not been reported, although there have been accounts of developmental delay, macrocephaly and overgrowth in 10 patients with mosaic DICER1 “hotspot” RNase IIIb mutations. Other accounts have not reported overgrowth or developmental delay in these patients 11 . In our natural history study of the DICER1 syndrome, we comprehensively evaluated individuals with germline DICER1 mutations and family controls.…”

Section: Introductionmentioning

confidence: 59%

“…They hypothesize that an imbalance in specific 3p microRNAs arising from the DICER1 RNase IIIb mutations lead to excessive cell and tissue growth and tumor predisposition. Mosaic DICER1 RNase IIIb domain mutations are associated with a more severe neoplastic phenotype 11,18 . Many of the “GLOW” phenotype features, including macrocephaly and overgrowth, were not observed in a set of four patients with mosaic DICER1 RNase IIIb mutations 11 .…”

Section: Discussionmentioning

confidence: 99%

“…Mosaic DICER1 RNase IIIb domain mutations are associated with a more severe neoplastic phenotype 11,18 . Many of the “GLOW” phenotype features, including macrocephaly and overgrowth, were not observed in a set of four patients with mosaic DICER1 RNase IIIb mutations 11 . The differences in these studies may be attributable to the pleiotropy and phenotypic variability inherent in mosaicism and highlight the need for a systematic, statistically-grounded approach to syndrome delineation.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Macrocephaly associated with the DICER1 syndrome

Khan

Bauer

Doros

et al. 2017

Genetics in Medicine

View full text Add to dashboard Cite

Background Germline mutations in DICER1 increase the risk of various tumors, including pleuropulmonary blastoma. Macrocephaly and symmetric overgrowth has been reported in some, but not all, patients with mosaic DICER1 RNase IIIb mutations; the prevalence of these features in individuals with constitutional germline DICER1 mutations is unknown. Methods We analyzed prospectively collected auxology data from 67 DICER1 mutation carriers and 43 family controls. We assessed differences between groups using an exact test for proportions and generalized estimating equations for continuous dependent variables. Results Twenty-eight DICER1 mutation carriers (42%) were macrocephalic, and none had an occipital-frontal circumference (OFC) below the 3rd centile, which significantly differed from family controls, of whom five were macrocephalic (12%) and two had OFC below the 3rd centile (5%) (P<0.001). DICER1 mutation carriers were taller than familial controls after controlling for gender (P=0.048), but similar proportions of both groups were above the 97th centile of population norms. Head circumference remained increased after adjusting for differences in height. Conclusions For the first time, we establish macrocephaly as a common finding in the DICER1 syndrome. Like some of the other tumor-predisposition disorders, macrocephaly may be a useful, albeit a subtle, clinical clue to the DICER1 syndrome diagnosis.

show abstract

Section: Introductionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Macrocephaly associated with the DICER1 syndrome

Khan

Bauer

Doros

et al. 2017

Genetics in Medicine

View full text Add to dashboard Cite

show abstract

“…However, considering the time and cost of generating iPSCs together with the new mutations generated by reprogramming events, iPSCs are not always practical for the screening purposes. On the other hand, recently, mosaic mutations were reported to be an important cause of the DICER syndrome by using HaloPlex HS technology, which was also employed in our study 20. This technology containing the molecular barcode provides the sensitivity and general applicability required for the detection of low-level mosaic mutations.…”

Section: Discussionmentioning

confidence: 98%

Somatic mosaicism containing double mutations inPTCH1revealed by generation of induced pluripotent stem cells from nevoid basal cell carcinoma syndrome

et al. 2017

View full text Add to dashboard Cite

This is the first case of mosaicism unequivocally demonstrated in NBCCS. Furthermore, the mosaicism is unique in that the patient carries one normal and two mutant alleles. Because these mutations are located in close proximity, reversion error is likely to be involved in this event rather than a spontaneous mutation. In addition, this study indicates that gene analysis of iPSC clones can contribute to the detection of mosaicism containing a minor population carrying a second mutation.

show abstract

“…Most neoplasms in the syndrome have been shown to harbor biallelic pathogenic variants in DICER1, usually a germline loss-of-function pathogenic variant in one allele that can occur in any domain and a tumorspecific pathogenic somatic variant in exons encoding the RNase IIIb domain of the second allele. Rarely, an individual will have mosaicism for an RNAse IIIb pathogenic variant, and the tumorspecific "second hit" will be a loss of function pathogenic variant (24)(25)(26). These individuals may display earlier diagnosis of DICER1-related conditions, have a higher number of sites of disease, and warrant more intensive surveillance.…”

Section: Dicer1 Syndromementioning

confidence: 99%

PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

Schultz

Rednam

Kamihara

et al. 2017

Clinical Cancer Research

136

View full text Add to dashboard Cite

PTEN hamartoma tumor syndrome (PHTS), DICER1 syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years. DICER1 syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord-stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended.

show abstract

High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome

Cited by 69 publications

References 47 publications

Macrocephaly associated with the DICER1 syndrome

Macrocephaly associated with the DICER1 syndrome

Somatic mosaicism containing double mutations inPTCH1revealed by generation of induced pluripotent stem cells from nevoid basal cell carcinoma syndrome

PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

Contact Info

Product

Resources

About