Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

Fuke, Tomoko; Nakamura, Akie; Inoue, Takeshi; Kawashima, Sayaka; Hara, Kazushi; Matsubara, Kazuo; Shinzaki, Shinichiro; Yamazawa, Kazuki; Fukami, Maki; Ogata, Tsutomu; Kagami, Masayo

doi:10.1210/clinem/dgaa856

Cited by 22 publications

(14 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We identified two rare cases with severe prenatal and postnatal growth failure together with some SRS features caused by microdeletions involving the KCNQ1OT1 :TSS-DMR on the paternal allele which leads to CDKN1C hyperexpression, and conducted detailed clinical and genetic analyses in the patients and their family members. Clinical manifestations of patients 1 and 2 were similar to those of patients with H19 LOM, UPD(7)mat17 or CDKN1C GOF variant4–7 (table 1). Notably, both patients showed poor responses to GH treatment.…”

Section: Discussionsupporting

confidence: 55%

CDKN1Chyperexpression in two patients with severe growth failure and microdeletions affecting the paternally inheritedKCNQ1OT1:TSS-DMR

et al. 2022

Self Cite

View full text Add to dashboard Cite

BackgroundTwo imprinting control centres, H19/IGF2:IG-differentialy methylated region (DMR) and KCNQ1OT1:TSS-DMR, reside on chromosome 11p15.5. Paternal deletions involving the KCNQ1OT1:TSS-DMR result in variable phenotypes, namely, normal phenotype, Silver-Russel syndrome (SRS) and fetal demise. However, expression analyses for CDKN1C in these patients are very limited.CasesPatient 1 (adult woman) and patient 2 (boy in early childhood) showed prenatal and postnatal growth failure and clinical suspicion of SRS.Molecular analysesBoth patients showed hypermethylation of the KCNQ1OT1:TSS-DMR caused by the paternal heterozygous de novo deletions involving the KCNQ1OT1:TSS-DMR, but not including CDKN1C enhancers. The deletion sizes were 5 kb and 12 kb for patients 1 and 2, respectively. CDKN1C gene expressions in immortalised leucocytes of both patients were increased compared with those of controls.ConclusionPaternal deletions involving the KCNQ1OT1:TSS-DMR, but not including CDKN1C enhancers, disrupt KCNQ1OT1 expression, strongly activate CDKN1C expression and consequently cause severe growth failure.

show abstract

Section: Discussionsupporting

confidence: 55%

CDKN1Chyperexpression in two patients with severe growth failure and microdeletions affecting the paternally inheritedKCNQ1OT1:TSS-DMR

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…The diagnostic yield of NGS in SGA in the present study was 21 (24.1%) of 87, among whom 13 (14.9%) and 8 (9.2%) had P/LP variants in genes and CNVs which was below that of the total cohort (361/814; 44.3%) ( P < .05). Imprinted genes in the placenta are important for the control of fetal growth ( 34 , 35 ). A recent study of 269 patients with SGA with short stature reported a diagnostic yield of 107 (39.78%) of the 269 patients by comparative genomic hybridization combined with methylation analysis, and 32.34% (87/269) patients were diagnosed with imprinting disorders and 7.44% (20/269) were CNVs ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

“…Imprinted genes in the placenta are important for the control of fetal growth ( 34 , 35 ). A recent study of 269 patients with SGA with short stature reported a diagnostic yield of 107 (39.78%) of the 269 patients by comparative genomic hybridization combined with methylation analysis, and 32.34% (87/269) patients were diagnosed with imprinting disorders and 7.44% (20/269) were CNVs ( 35 ). The diagnostic power of exome sequencing in SGA is limited; further methylation analysis can be an effective approach to diagnose SGA, and environmental causes for SGA should be considered.…”

Section: Discussionmentioning

confidence: 99%

Clinical Profiles and Genetic Spectra of 814 Chinese Children With Short Stature

Yao

Chang

et al. 2021

The Journal of Clinical Endocrinology &Amp; Metabolism

View full text Add to dashboard Cite

Context Data of and studies based on exome sequencing for the genetic evaluation of short stature are limited, and more large-scale studies are warranted. Some factors increase the likelihood of a monogenic cause of short stature, including skeletal dysplasia, severe short stature, and small for gestational age (SGA) without catch-up growth. However, whether these factors can serve as predictors of molecular diagnosis remains unknown. Objectives We aimed to explore the diagnostic efficiency of the associated risk factors and their exome sequences for screening. Design, Settings, and Patients We defined and applied factors that increased the likelihood of monogenic causes of short stature in diagnostic genetic tests based on next-generation sequencing (NGS) in 814 patients with short stature and at least one other factor. Results Pathogenic/likely pathogenic (P/LP) variants in genes, copy number variations (CNVs), and chromosomal abnormalities were identified in 361 patients. We found P/LP variants among 111 genes, and RASopathies comprised the most important etiology. Short stature combined with other phenotypes significantly increased the likelihood of monogenic cause, including skeletal dysplasia, facial dysmorphism, and intellectual disability, compared with simple severe short stature (<–3 standard deviation scores). We report novel candidate pathogenic genes, KMT2C for unequivocal growth hormone insensitivity and GATA6 for SGA. Conclusions Our study identified the diagnostic characteristics of NGS in short stature with different risk factor. Our study provides novel insights into the current understanding of the etiology of short stature in patients with different phenotypes.

show abstract

“…We enrolled 130 patients with aneuploid UPD-IDs con rmed by molecular studies, including 77 previously reported patients (UPDmat of chromosome 7 (n = 9) [20], UPD( 14)pat (n = 19) [21], UPD( 14)mat (n = 17) [22], UPD( 15)mat (n = 27) [17], and UPDmat of chromosome 20 (n = 5) [23]). We classi ed these 130 patients into UPD-IDs caused by aneuploid oocytes or sperms based on the UPD subtypes con rmed by microsatellite analysis and SNP array analysis.…”

Section: Patientsmentioning

confidence: 99%

Risk assessment of assisted reproductive technology and parental ages at childbirth for the development of uniparental disomy-mediated imprinting disorders caused by aneuploid gametes

Hara-Isono¹,

Matsubara²,

Nakamura³

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Our previous study suggested that assisted reproductive technology (ART) may be a possible risk factor for the development of epimutation-mediated imprinting disorders (epi-IDs) for mothers aged ≥ 30 years. However, whether ART or advanced parental age facilitates the development of uniparental disomy-mediated IDs (UPD-IDs) has not yet been investigated. Results: We enrolled 130 patients with aneuploid UPD-IDs including various IDs confirmed by molecular studies and obtained ART data of the general population and patients with epi-IDs from a robust nationwide database and our previous report, respectively. We compared the proportion of ART-conceived livebirths and maternal childbearing ages between patients with UPD-IDs and the general population or patients with epi-IDs. The proportion of ART-conceived livebirths in patients with aneuploid UPD-IDs was consistent with that in the general population of maternal age ≥ 30 years and was lower than that in the patients with epi-IDs, although there was no significant difference. The maternal childbearing ages of patients with aneuploid UPD-IDs were skewed to the increased ages with several cases exceeding the 97.5th percentile of maternal childbearing ages of the general population, and significantly higher than that of patients with epi-IDs (P < 0.001). In addition, we compared the proportion of ART-conceived livebirths and parental ages at childbirth between patients with UPD-IDs caused by aneuploid oocytes (oUPD-IDs) and that by aneuploid sperms (sUPD-IDs). Almost all ART-conceived livebirths were identified in patients with oUPD-IDs, and both maternal and paternal ages at childbirth were significantly higher in patients with oUPD-IDs than in patients with sUPD-IDs. Because maternal and paternal ages were strongly correlated (r = 0.637, P < 0.001), higher paternal ages in oUPD-IDs were due to the higher maternal ages in this group. Conclusions: Different from the case of epi-IDs, ART itself is not likely to facilitate the development of aneuploid UPD-IDs. We demonstrated that advanced maternal age can be a risk factor for the development of aneuploid UPD-IDs, particularly oUPD-IDs. (318/350words)

show abstract

Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

Cited by 22 publications

References 41 publications

CDKN1Chyperexpression in two patients with severe growth failure and microdeletions affecting the paternally inheritedKCNQ1OT1:TSS-DMR

CDKN1Chyperexpression in two patients with severe growth failure and microdeletions affecting the paternally inheritedKCNQ1OT1:TSS-DMR

Clinical Profiles and Genetic Spectra of 814 Chinese Children With Short Stature

Risk assessment of assisted reproductive technology and parental ages at childbirth for the development of uniparental disomy-mediated imprinting disorders caused by aneuploid gametes

Contact Info

Product

Resources

About