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Low frequency of imprinting defects in ICSI children born small for gestational age.

ABSTRACT: Although there is an increased frequency of low birth weight after assisted reproduction, the mechanisms underlying this association are unclear. We have proposed that some of the children conceived by intracytoplasmic sperm injection (ICSI) with low birth weight might have an epimutation (faulty methylation pattern) in one of the imprinted genes involved in fetal growth control, eg, KCNQ1OT1, PEG1, PEG3, GTL2, IGF2/H19 and PLAGL1. Using bisulfite DNA sequencing and sequence-based quantitative methylation analysis (SeQMA), we determined the methylation pattern of these genes in buccal smears from 19 ICSI children born small for gestational age (SGA, birth weight <3rd percentile) and from 29 term-born normal weight children after spontaneous conception. We detected clear hypermethylation of KCNQ1OT1 and borderline hypermethylation of PEG1 in one and the same ICSI child. The other children and the parents of the affected child have normal methylation patterns. Imprinting defects appear to be a rare finding in ICSI children born SGA. Methylation of the paternal KCNQ1OT1 and PEG1 alleles may be a previously unrecognized cause of SGA. The epimutations found in the SGA child, whose father had oligozoospermia, probably result from an imprint erasure defect in the paternal germ line and therefore appear to be linked to the fertility problem of the father and not to in vitro fertilization/ICSI.

SUBMITTER: Kanber D

PROVIDER: S-EPMC2985955 | biostudies-literature |

REPOSITORIES: biostudies-literature

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New Horizons in Short Children Born Small for Gestational Age.

Project description:Children born small for gestational age (SGA) comprise a heterogeneous group due to the varied nature of the cause. Approximately 85-90% have catch-up growth within the first 4 postnatal years, while the remainder remain short. In later life, children born SGA have an increased risk to develop metabolic abnormalities, including visceral adiposity, insulin resistance, and cardiovascular problems, and may have impaired pubertal onset and growth. The third "360° European Meeting on Growth and Endocrine Disorders" in Rome, Italy, in February 2018, funded by Merck KGaA, Germany, included a session that examined aspects of short children born SGA, with three presentations followed by a discussion period, on which this report is based. Children born SGA who remain short are eligible for GH treatment, which is an approved indication. GH treatment increases linear growth and can also improve some metabolic abnormalities. After stopping GH at near-adult height, metabolic parameters normalize, but pharmacological effects on lean body mass and fat mass are lost; continued monitoring of body composition and metabolic changes may be necessary. Guidelines have been published on diagnosis and management of children with Silver-Russell syndrome, who comprise a specific group of those born SGA; these children rarely have catch-up growth and GH treatment initiation as early as possible is recommended. Early and moderate pubertal growth spurt can occur in children born SGA, including those with Silver-Russell syndrome, and reduce adult height. Treatments that delay puberty, specifically metformin and gonadotropin releasing hormone analogs in combination with GH, have been proposed, but are used off-label, currently lack replication of data, and require further studies of efficacy and safety.

| S-EPMC8155308 | biostudies-literature

Array-based determination of DNA methylation in children born small for gestational age

Project description:Genome wide DNA methylation profiling of peripheral blood samples obtained from normal controls and children born SGA. Illumina's HumanMethylation450 BeadChip was used to obtain DNA methylation profiles across approximately 450.000 CpGs. Bisulphite converted DNA from the 110 samples were hybridised to the Illumina HumanMethylation450 Beadchip.

2016-07-03 | E-GEOD-47880 | biostudies-arrayexpress

Copy number variants in short children born small for gestational age.

Project description:Background/aimsIn addition to genome-wide association studies (GWAS), height-associated genes may be uncovered by studying individuals with extreme short or tall stature.MethodsGenome-wide analysis for copy number variants (CNVs), using single nucleotide polymorphism (SNP) arrays, was performed in 49 index cases born small for gestational age with persistent short stature. Segregation analysis was performed, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates, and published information.ResultsCNVs were detected in 13 cases. In 5 children a known cause of short stature was found: UPD7, UPD14, a duplication of the SHOX enhancer region, an IGF1R deletion, and a 22q11.21 deletion. In the remaining 8 cases, potential pathogenic CNVs were detected, either de novo (n = 1), segregating (n = 2), or not segregating with short stature (n = 5). Bioinformatic analysis of the de novo and segregating CNVs suggested that HOXD4, AGPS, PDE11A, OSBPL6, PRKRA and PLEKHA3, and possibly DGKB and TNFRSF11B are potential candidate genes. A SERPINA7 or NRK defect may be associated with an X-linked form of short stature.ConclusionSNP arrays detected 5 known causes of short stature with prenatal onset and suggested several potential candidate genes.

| S-EPMC4236248 | biostudies-literature

Array-based determination of DNA methylation in children born small for gestational age

2016-01-01 | GSE47880 | GEO

No evidence for copy number and methylation variation in H19 and KCNQ10T1 imprinting control regions in children born small for gestational age.

Project description:BACKGROUND: There is a substantial genetic component for birthweight variation, and although there are known associations between fetal genotype and birthweight, the role of common epigenetic variation in influencing the risk for small for gestational age (SGA) is unknown. The two imprinting control regions (ICRs) located on chromosome 11p15.5, involved in the overgrowth disorder Beckwith-Wiedemann syndrome (BWS) and the growth restriction disorder Silver-Russell syndrome (SRS), are prime epigenetic candidates for regulating fetal growth. We investigated whether common variation in copy number in the BWS/SRS 11p15 region or altered methylation levels at IGF2/H19 ICR or KCNQ10T1 ICR was associated with SGA. METHODS: We used a methylation-specific multiplex-ligation-dependent probe amplification assay to analyse copy number variation in the 11p15 region and methylation of IGF2/H19 and KCNQ10T1 ICRs in blood samples from 153 children (including 80 SGA), as well as bisulfite pyrosequencing to measure methylation at IGF2 differentially methylated region (DMR)0 and H19 DMR. RESULTS: No copy number variants were detected in the analyzed cohort. Children born SGA had 2.7% lower methylation at the IGF2 DMR0. No methylation differences were detected at the H19 or KCNQ10T1 DMRs. CONCLUSIONS: We confirm that a small hypomethylation of the IGF2 DMR0 is detected in peripheral blood leucocytes of children born SGA at term. Copy number variation within the 11p15 BWS/SRS region is not an important cause of non-syndromic SGA at term.

| S-EPMC4089969 | biostudies-literature

Antecedents of epilepsy and seizures among children born at extremely low gestational age.

Project description:OBJECTIVE:To identify specific risk factors for epilepsy for individuals born extremely preterm. STUDY DESIGN:In a prospective cohort study, at 10-year follow-up, children were classified as having epilepsy or seizures not associated with epilepsy. We evaluated for association of perinatal factors using time-oriented, multinomial logistic regression models. RESULTS:Of the 888 children included in the study, 66 had epilepsy and 39 had seizures not associated with epilepsy. Epilepsy was associated with an indicator of low socioeconomic status, maternal gestational fever, early physiologic instability, postnatal exposure to hydrocortisone, cerebral white matter disease and severe bronchopulmonary dysplasia. Seizure without epilepsy was associated with indicators of placental infection and inflammation, and hypoxemia during the first 24 postnatal hours. CONCLUSIONS:In children born extremely preterm, epilepsy and seizures not associated with epilepsy have different risk profiles. Though both profiles included indicators of infection and inflammation, the profile of risk factors for epilepsy included multiple indicators of endogenous vulnerability.

| S-EPMC7216413 | biostudies-literature

Global and regional differences in brain anatomy of young children born small for gestational age.

Project description:In children who are born small for gestational age (SGA), an adverse intrauterine environment has led to underdevelopment of both the body and the brain. The delay in body growth is (partially) restored during the first two years in a majority of these children. In addition to a negative influence on these physical parameters, decreased levels of intelligence and cognitive impairments have been described in children born SGA. In this study, we used magnetic resonance imaging to examine brain anatomy in 4- to 7-year-old SGA children with and without complete bodily catch-up growth and compared them to healthy children born appropriate for gestational age. Our findings demonstrate that these children strongly differ on brain organisation when compared with healthy controls relating to both global and regional anatomical differences. Children born SGA displayed reduced cerebral and cerebellar grey and white matter volumes, smaller volumes of subcortical structures and reduced cortical surface area. Regional differences in prefrontal cortical thickness suggest a different development of the cerebral cortex. SGA children with bodily catch-up growth constitute an intermediate between those children without catch-up growth and healthy controls. Therefore, bodily catch-up growth in children born SGA does not implicate full catch-up growth of the brain.

| S-EPMC3172224 | biostudies-other

Beckwith Wiedemann imprinting defect found in leucocyte but not buccal DNA in a child born small for gestational age.

Project description:BACKGROUND: Loss of methylation (LOM) at imprinting control region (ICR) 1 or LOM at ICR 2 on chromosome 11p15 in leucocyte DNA is commonly used to diagnose the imprinting disorders Silver Russell syndrome (SRS) characterized by growth restriction or Beckwith Wiedemann syndrome (BWS) characterized by overgrowth, respectively. CASE PRESENTATION: A child was normally conceived and born by caesarian section to a healthy 19 year old smoking mother (G2P1) at 38 weeks gestation, with SGA (birthweight SDS -2.44), placenta weight 250g (normal histology), with an umbilical hernia and transient neonatal hypoglycemia but no other features of BWS.The methylation status at 11p15 region was initially investigated by multiplex ligation dependent probe amplification (MLPA). Subsequently, methylation-specific (ms) PCR was performed to screen for this and other imprinted loci abnormalities at PLAG1 (6q24), IGF2R (6q27), GRB10 (7p12), PEG1/MEST (7q32), DLK1 (14q32), SNRPN (15q11); PEG3 (19q32), NESPAS/GNAS (20q13).Leucocyte DNA methylation was normal at ICR1 but markedly reduced at ICR2 using both MLPA and ms-PCR, and no other anomalies of imprinting were detected. Buccal DNA methylation was normal at all imprinted sites tested. CONCLUSION: This is the first report of an isolated LOM at ICR2 in leucocyte but not buccal DNA in a normally conceived singleton SGA child without overt SRS or BWS.

| S-EPMC3514203 | biostudies-literature

Neurocognitive Correlates of Attention-Deficit Hyperactivity Disorder Symptoms in Children Born at Extremely Low Gestational Age.

Project description:ObjectiveCompared with children born near term, those born extremely preterm (EP) are at much higher risk for attention-deficit hyperactivity disorder (ADHD). Little information is available about differences in neuropsychological outcomes among EP children with and without ADHD. Our analyses aimed to evaluate the neuropsychological correlates of ADHD symptoms in extremely low gestational age newborns (ELGANs).MethodsWe obtained Child Symptom Inventory-4 reports from parents (n = 871) and teachers (n = 634) of 10-year-old children born before the 28th week of gestation. Participants completed standardized assessments of neurocognitive and academic functioning.ResultsIn the total sample, children who screened positive for ADHD symptoms were at increased risk for neurocognitive limitations. These associations were weaker when the sample was limited to those with intelligence quotient (IQ) ≥70 or ≥85. Even those with IQ ≥85 who screened positive for ADHD symptoms were more likely than their peers to have deficits on the DAS-II Working Memory Cluster and the NEPSY-II Auditory Response subtest. The risks for impaired academic performance (Z ≤ -1) on components of the WIAT-III were 2-to-3 times higher in this group than among ELGANs not classified as having ADHD symptoms.ConclusionAmong children born EP, those with ADHD symptoms are more likely to have global neurocognitive impairment. When IQ is within normal limits, ADHD symptoms are associated with deficits in executive functioning skills. These findings highlight a group at risk for executive functioning deficits and related academic difficulties, even in the absence of intellectual disability.

| S-EPMC5746049 | biostudies-literature

Cardiometabolic sex differences in adults born small for gestational age.

Project description:AimThis study aimed to assess the cardiometabolic sex similarities and differences in adults born small for gestational age.MethodsThis study was an ambispective cohort study from a birth registry in Barcelona, Spain, including 523 adult participants (20-40 years-old) subdivided as born small for gestational age (SGA, if birth weight <10th centile) or adequate fetal growth for gestational age (AGA). Cardiometabolic health was assessed by echocardiography, electrocardiogram, blood pressure measurement, vascular ultrasound, anthropometric measurements, and serum glycemia and lipid profile. Stratified analyses by sex were performed by estimation of adjusted absolute difference (AAD) using inverse probability weighting.ResultsCompared with AGA, the stratified analyses by sex showed a more pronounced reduction in ejection fraction [AAD: female -1.73 (95% CI -3.2 to -0.28) vs. male -1.33 (-3.19 to 0.52)] and increment in heart rate [female 3.04 (0.29-5.8) vs. male 2.25 (-0.82 to 5.31)] in SGA females compared with SGA males. In contrast, a more pronounced reduction in PR interval [female -1.36 (-6.15 to 3.42) vs. male -6.61 (-11.67 to -1.54)] and an increase in systolic blood pressure [female 0.06 (-2.7 to 2.81) vs. male 2.71 (-0.48 to 5.9)] and central-to-peripheral fat ratio [female 0.05 (-0.03 to 0.12) vs. male 0.40 (0.17-0.62)] were mainly observed in SGA male compared with SGA female.ConclusionsSex differences were observed in the effect of SGA on cardiometabolic endpoints with female being more prone to cardiac dysfunction and male to electrocardiographic, vascular, and metabolic changes. Future research including sex-stratification data is warranted.

| S-EPMC10634502 | biostudies-literature

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