RESUMEN
BACKGROUND: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro. METHODS: DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients. RESULTS: We detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation. CONCLUSION: We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.
Asunto(s)
Anomalías Múltiples/genética , Desarrollo Fetal/genética , Retardo del Crecimiento Fetal/genética , Trastornos del Crecimiento/genética , Receptor IGF Tipo 1/genética , Anomalías Múltiples/epidemiología , Anomalías Múltiples/fisiopatología , Adolescente , Niño , Enanismo/genética , Enanismo/fisiopatología , Femenino , Retardo del Crecimiento Fetal/epidemiología , Retardo del Crecimiento Fetal/fisiopatología , Trastornos del Crecimiento/epidemiología , Trastornos del Crecimiento/fisiopatología , Heterocigoto , Homocigoto , Humanos , Recién Nacido Pequeño para la Edad Gestacional/crecimiento & desarrollo , Factor I del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Microcefalia/genética , Microcefalia/fisiopatología , Mutación Missense/genética , Linaje , Polimorfismo de Nucleótido Simple/genética , Receptores de Somatomedina/genéticaRESUMEN
Imprinting disorders (IDs) often affect growth in humans, leading to diseases with overlapping features, regardless of the genomic region affected. IDs related to hypomethylation of the human 14q32.2 region and its DLK1/MEG3 domain are associated with Temple syndrome (TS14). TS14 is a rare type of growth retardation, the clinical signs of which overlap considerably with those of Silver-Russell syndrome (SRS), another ID related to IGF2 down-regulation at 11p15.5 region. We show that 14q32.2 hypomethylation affects expression, not only for genes at this locus but also for other imprinted genes, and especially lowers IGF2 levels at 11p15.5. Furthermore, expression of nonimprinted genes is also affected, some of which are also deregulated in SRS patients. These findings highlight the epigenetic regulation of gene expression at the DLK1/MEG3 domain. Expression profiling of TS14 and SRS patients highlights common signatures, which may account for the clinical overlap observed between TS14 and SRS.
Asunto(s)
Proteínas de Unión al Calcio , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 14 , Metilación de ADN , Epigénesis Genética , Impresión Genómica , Proteínas de la Membrana , Síndrome de Silver-Russell , Proteínas de Unión al Calcio/biosíntesis , Proteínas de Unión al Calcio/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 11/metabolismo , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 14/metabolismo , Femenino , Humanos , Masculino , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/metabolismoRESUMEN
Context: Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap. Objective: To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS. Patients: We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis. Results: Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation. Conclusions: Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.
Asunto(s)
Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 14/genética , Síndrome de Silver-Russell/genética , Adolescente , Adulto , Proteínas de Unión al Calcio , Niño , Preescolar , Deleción Cromosómica , Trastornos de los Cromosomas/diagnóstico , Metilación de ADN/genética , Diagnóstico Diferencial , Femenino , Impresión Genómica/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Proteínas de la Membrana/genética , Fenotipo , Pubertad Precoz/genética , ARN Largo no Codificante/genética , Estudios Retrospectivos , Síndrome de Silver-Russell/diagnóstico , Síndrome , Disomía Uniparental , Adulto JovenRESUMEN
PurposeFetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver-Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2.MethodsWhole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway.ResultsWe report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.ConclusionGenetic defects of the HMGA2-PLAG1-IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.
Asunto(s)
Proteínas de Unión al ADN/genética , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/metabolismo , Predisposición Genética a la Enfermedad , Variación Genética , Proteína HMGA2/genética , Factor II del Crecimiento Similar a la Insulina/genética , Línea Celular , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , Facies , Femenino , Retardo del Crecimiento Fetal/diagnóstico , Regulación del Desarrollo de la Expresión Génica , Estudios de Asociación Genética , Genotipo , Gráficos de Crecimiento , Proteína HMGA2/metabolismo , Humanos , Factor II del Crecimiento Similar a la Insulina/metabolismo , Modelos Biológicos , Mutación , Linaje , Transducción de Señal , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/metabolismo , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: The 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex. OBJECTIVES: To report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations. METHODS: From a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain. RESULTS: Large duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C. CONCLUSIONS: The phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.
Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Duplicación de Gen/genética , Impresión Molecular , Síndrome de Silver-Russell/genética , Adulto , Síndrome de Beckwith-Wiedemann/patología , Centrómero/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 11/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Análisis Citogenético , Femenino , Humanos , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Mutación , Fenotipo , Síndrome de Silver-Russell/patología , Telómero/genéticaRESUMEN
The 11p15 region harbors the IGF2/H19 imprinted domain, implicated in fetal and postnatal growth. Silver-Russell syndrome (SRS) is characterized by fetal and postnatal growth failure, and is caused principally by hypomethylation of the 11p15 imprinting control region 1 (ICR1). However, the mechanisms leading to ICR1 hypomethylation remain unknown. Maternally inherited genetic defects affecting the ICR1 domain have been associated with ICR1 hypermethylation and Beckwith-Wiedemann syndrome (an overgrowth syndrome, the clinical and molecular mirror of SRS), and paternal deletions of IGF2 enhancers have been detected in four SRS patients. However, no paternal deletions of ICR1 have ever been associated with hypomethylation of the IGF2/H19 domain in SRS. We screened for new genetic defects within the ICR1 in a cohort of 234 SRS patients with hypomethylated IGF2/H19 domain. We report deletions close to the boundaries of ICR1 on the paternal allele in one familial and two sporadic cases of SRS with ICR1 hypomethylation. These deletions are associated with hypomethylation of the remaining CBS, and decreased IGF2 expression. These results suggest that these regions are most likely required to maintain methylation after fertilization. We estimate these anomalies to occur in about 1% of SRS cases with ICR1 hypomethylation.
Asunto(s)
Cromosomas Humanos Par 11 , Metilación de ADN , Impresión Genómica , Factor II del Crecimiento Similar a la Insulina/genética , ARN Largo no Codificante/genética , Eliminación de Secuencia , Síndrome de Silver-Russell/genética , Preescolar , Femenino , Fibroblastos , Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , LinajeRESUMEN
BACKGROUND: Multiple clinical scoring systems have been proposed for Silver-Russell syndrome (SRS). Here we aimed to test a clinical scoring system for SRS and to analyse the correlation between (epi)genotype and phenotype. SUBJECTS AND METHODS: Sixty-nine patients were examined by two physicians. Clinical scores were generated for all patients, with a new, six-item scoring system: (1) small for gestational age, birth length and/or weight ≤-2SDS, (2) postnatal growth retardation (height ≤-2SDS), (3) relative macrocephaly at birth, (4) body asymmetry, (5) feeding difficulties and/or body mass index (BMI) ≤-2SDS in toddlers; (6) protruding forehead at the age of 1-3â years. Subjects were considered to have likely SRS if they met at least four of these six criteria. Molecular investigations were performed blind to the clinical data. RESULTS: The 69 patients were classified into two groups (Likely-SRS (n=60), Unlikely-SRS (n=9)). Forty-six Likely-SRS patients (76.7%) displayed either 11p15 ICR1 hypomethylation (n=35; 58.3%) or maternal UPD of chromosome 7 (mUPD7) (n=11; 18.3%). Eight Unlikely-SRS patients had neither ICR1 hypomethylation nor mUPD7, whereas one patient had mUPD7. The clinical score and molecular results yielded four groups that differed significantly overall and for individual scoring system factors. Further molecular screening led identifying chromosomal abnormalities in Likely-SRS-double-negative and Unlikely-SRS groups. Four Likely-SRS-double negative patients carried a DLK1/GTL2 IG-DMR hypomethylation, a mUPD16; a mUPD20 and a de novo 1q21 microdeletion. CONCLUSIONS: This new scoring system is very sensitive (98%) for the detection of patients with SRS with demonstrated molecular abnormalities. Given its clinical and molecular heterogeneity, SRS could be considered as a spectrum.
Asunto(s)
Genotipo , Fenotipo , Proyectos de Investigación/normas , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/patología , Peso al Nacer/fisiología , Índice de Masa Corporal , Frente/anomalías , Crecimiento/fisiología , Humanos , Megalencefalia/patología , Estudios ProspectivosRESUMEN
BACKGROUND: The structural organisation of the human IGF2/ICR1/H19 11p15 domain is very complex, and the mechanisms underlying its regulation are poorly understood. The Imprinted Center Region 1 (ICR1) contains seven binding sites for the zinc-finger protein CTCF (CBS: CTCF Binding Sites); three additional differentially methylated regions (DMR) are located at the H19 promoter (H19DMR) and two in the IGF2 gene (DMR0 and DMR2), respectively. Loss of imprinting at the IGF2/ICR1/H19 domain results in two growth disorders with opposite phenotypes: Beckwith-Wiedemann syndrome and Russell Silver syndrome (RSS). Despite the IGF2/ICR1/H19 locus being widely studied, the extent of hypomethylation across the domain remains not yet addressed in patients with RSS. METHODS: We assessed a detailed investigation of the methylation status of the 11p15 ICR1 CBS1-7, IGF2DMR0 and H19DMR (H19 promoter) in a population of controls (n=50) and RSS carrying (n=104) or not (n=65) carrying a hypomethylation at the 11p15 ICR1 region. RESULTS: The methylation indexes (MI) were balanced at all regions in the control population and patients with RSS without any as yet identified molecular anomaly. Interestingly, patients with RSS with ICR1 hypomethylation showed uneven profiles of methylation among the CBSs and DMRs. Furthermore, normal MIs at CBS1 and CBS7 were identified in 9% of patients. CONCLUSIONS: The hypomethylation does not spread equally throughout the IGF2/ICR1/H19 locus, and some loci could have normal MI, which may lead to underdiagnosis of patients with RSS with ICR1 hypomethylation. The uneven pattern of methylation suggests that some CBSs may play different roles in the tridimensional chromosomal looping regulation of this locus.
Asunto(s)
Cromosomas Humanos Par 11/genética , Metilación de ADN/genética , Regulación de la Expresión Génica/genética , Factor II del Crecimiento Similar a la Insulina/genética , ARN Largo no Codificante/genética , Síndrome de Silver-Russell/genética , Secuencia de Bases , Humanos , Factor II del Crecimiento Similar a la Insulina/metabolismo , Datos de Secuencia Molecular , Paris , Análisis de Componente Principal , ARN Largo no Codificante/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ADN , SulfitosRESUMEN
Russell-Silver Syndrome (RSS) is a prenatal and postnatal growth retardation syndrome caused mainly by 11p15 ICR1 hypomethylation. Clinical presentation is heterogeneous in RSS patients with 11p15 ICR1 hypomethylation. We previously identified a subset of RSS patients with 11p15 ICR1 and multilocus hypomethylation. Here, we examine the relationships between IGF2 expression, 11p15 ICR1 methylation, and multilocus imprinting defects in various cell types from 39 RSS patients with 11p15 ICR1 hypomethylation in leukocyte DNA. 11p15 ICR1 hypomethylation was more pronounced in leukocytes than in buccal mucosa cells. Skin fibroblast IGF2 expression was correlated with the degree of ICR1 hypomethylation. Different tissue-specific multilocus methylation defects coexisted in 38% of cases, with some loci hypomethylated and others hypermethylated within the same cell type in some cases. Our new results suggest that tissue-specific epigenotypes may lead to clinical heterogeneity in RSS.
Asunto(s)
Cromosomas Humanos Par 11/genética , Metilación de ADN , Impresión Genómica , Factor II del Crecimiento Similar a la Insulina/genética , Síndrome de Silver-Russell/genética , Adulto , Niño , Preescolar , Epitelio/metabolismo , Fibroblastos/metabolismo , Expresión Génica , Humanos , Recién Nacido , Leucocitos/metabolismo , Mucosa Bucal/metabolismo , Especificidad de Órganos , Piel/metabolismoRESUMEN
BACKGROUND: Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS; MIM 130650) and the Silver-Russell (SRS; MIM 180860) syndromes. DNA methylation defects account for 60% of BWS and SRS cases and, in most cases, occur without any identified mutation in a cis-acting regulatory sequence or a trans-acting factor. METHODS: We investigated whether 11p15 cis-acting sequence variants account for primary DNA methylation defects in patients with SRS and BWS with loss of DNA methylation at ICR1 and ICR2, respectively. RESULTS: We identified a 4.5â kb haplotype that, upon maternal transmission, is associated with a risk of ICR2 loss of DNA methylation in patients with BWS. This novel region is located within the second intron of the KCNQ1 gene, 170â kb upstream of the ICR2 imprinting centre and encompasses two CTCF binding sites. We showed that, within the 4.5â kb region, two SNPs (rs11823023 and rs179436) affect CTCF occupancy at DNA motifs flanking the CTCF 20â bp core motif. CONCLUSIONS: This study shows that genetic variants confer a risk of DNA methylation defect with a parent-of-origin effect and highlights the crucial role of CTCF for the regulation of genomic imprinting of the CDKN1C/KCNQ1 domain.
Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Canal de Potasio KCNQ1/genética , Sitios de Unión/genética , Factor de Unión a CCCTC , Metilación de ADN/genética , Femenino , Haplotipos/genética , Humanos , Intrones/genética , Canal de Potasio KCNQ1/metabolismo , Masculino , Mutación/genética , Proteínas Represoras/metabolismoRESUMEN
Isolated gain of methylation (GOM) at the IGF2/H19 imprinting control region 1 (ICR1) accounts for about 10% of patients with BWS. A subset of these patients have genetic defects within ICR1, but the frequency of these defects has not yet been established in a large cohort of BWS patients with isolated ICR1 GOM. Here, we carried out a genetic analysis in a large cohort of 57 BWS patients with isolated ICR1 GOM and analyzed the methylation status of the entire domain. We found a new point mutation in two unrelated families and a 21 bp deletion in another unrelated child, both of which were maternally inherited and affected the OCT4/SOX2 binding site in the A2 repeat of ICR1. Based on data from this and previous studies, we estimate that cis genetic defects account for about 20% of BWS patients with isolated ICR1 GOM. Methylation analysis at eight loci of the IGF2/H19 domain revealed that sites surrounding OCT4/SOX2 binding site mutations were fully methylated and methylation indexes declined as a function of distance from these sites. This was not the case in BWS patients without genetic defects identified. Thus, GOM does not spread uniformly across the IGF2/H19 domain, suggesting that OCT4/SOX2 protects against methylation at local sites. These findings add new insights to the mechanism of the regulation of the ICR1 domain. Our data show that mutations and deletions within ICR1 are relatively common. Systematic identification is therefore necessary to establish appropriate genetic counseling for BWS patients with isolated ICR1 GOM.
Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/metabolismo , Metilación de ADN , Impresión Genómica , Factor II del Crecimiento Similar a la Insulina/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , ARN Largo no Codificante/genética , Factores de Transcripción SOXB1/metabolismo , Secuencia de Bases , Síndrome de Beckwith-Wiedemann/diagnóstico , Sitios de Unión , Estudios de Casos y Controles , Cromosomas Humanos Par 11 , Femenino , Frecuencia de los Genes , Heterocigoto , Humanos , Masculino , Mutación , Motivos de Nucleótidos , Linaje , Fenotipo , Eliminación de SecuenciaRESUMEN
Genomic imprinting is among the most important epigenetic mechanisms whereby expression of a subset of genes is restricted to a single parental allele. Loss of imprinting (LOI) through hypo or hyper methylation is involved in various human syndromes. These LOI occur early during development and usually impair growth. Some imprinting syndromes are the consequences of genetic anomalies, such as uniparental disomies (UPD) or copy number variations (deletion or duplications) involving the imprinted domains; others are due to LOI at the imprinting control regions (ICR) regulating each domain. Imprinting disorders are phenotypically heterogeneous, although some share various common clinical features such that diagnosis may be difficult. Multilocus imprinting defects associated with several syndromes have been increasingly reported in recent years, although there are no obvious clinical differences between monolocus and multilocus LOI patients. Subsequently, some rare mutations of transacting factors have been identified in patients with multilocus imprinting defects but they do not explain the majority of the cases; this therefore implies that other factors are involved. By contrast, no mutation of a transacting factor has yet been identified in monolocus LOI. The effect of the environment on the regulation of imprinting is clearly illustrated by studies of assisted reproductive technology (ART). The regulation of imprinting is complex and involves a huge range of genetic and environmental factors; the identification of these factors will undoubtedly help to elucidate the regulation of imprinting and contribute to the understanding of imprinting disorders. This would be beneficial for diagnostics, clinical follow up and the development of treatment guidelines.
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Retardo del Crecimiento Fetal/genética , Impresión Genómica/genética , Trastornos del Crecimiento/genética , Alelos , Animales , Variaciones en el Número de Copia de ADN , Epigénesis Genética , Retardo del Crecimiento Fetal/diagnóstico , Trastornos del Crecimiento/diagnóstico , Humanos , Mutación , Guías de Práctica Clínica como Asunto , Técnicas Reproductivas Asistidas , SíndromeRESUMEN
The ZAC1 gene, mapped to the 6q24 region, is part of a network of co-regulated imprinted genes involved in the control of embryonic growth. Loss of methylation at the ZAC1 differentially methylated region (DMR) is associated with transient neonatal diabetes mellitus, a developmental disorder involving growth retardation and diabetes in the first weeks of post-natal life. We assessed whether the degree of methylation of the ZAC1 DMR in leukocytes DNA extracted from cord blood is associated with fetal, birth and post-natal anthropometric measures or with C-peptide concentrations in cord serum. We also searched for an influence of dietary intake and maternal parameters on ZAC1 DMR methylation. We found positive correlations between the ZAC1 DMR methylation index (MI) and estimated fetal weight (EFW) at 32 weeks of gestation, weight at birth and weight at one year of age (respectively, r = 0.15, 0.09, 0.14; P values = 0.01, 0.15, 0.03). However, there were no significant correlations between the ZAC1 DMR MI and cord blood C-peptide levels. Maternal intakes of alcohol and of vitamins B2 were positively correlated with ZAC1 DMR methylation (respectively, r = 0.2 and 0.14; P = 0.004 and 0.04). The influence of ZAC1 seems to start in the second half of pregnancy and continue at least until the first year of life. The maternal environment also appears to contribute to the regulation of DNA methylation.
Asunto(s)
Peso Corporal/genética , Proteínas de Ciclo Celular/metabolismo , Metilación de ADN , Desarrollo Fetal/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto , Factores de Edad , Consumo de Bebidas Alcohólicas , Antropometría , Péptido C/metabolismo , Proteínas de Ciclo Celular/sangre , Estudios de Cohortes , Dieta , Femenino , Sangre Fetal , Impresión Genómica , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Fumar , Factores de Transcripción/sangre , Proteínas Supresoras de Tumor/sangre , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The imprinted human 11p15.5 region encompasses two imprinted domains important for the control of fetal growth: the H19/IGF2 domain in the telomeric region and the KCNQ1OT1/CDKN1C domain in the centromeric region. These two domains are differentially methylated and each is regulated by its own imprinting control region (ICR): ICR1 in the telomeric region and ICR2 in the centromeric region. Aberrant methylation of the 11p15.5 imprinted region, through genetic or epigenetic mechanisms, leads to two clinical syndromes, with opposite growth phenotypes: Russell-Silver Syndrome (RSS; with severe fetal and postnatal growth retardation) and Beckwith-Wiedemann Syndrome (BWS; an overgrowth syndrome). RECENT FINDINGS: In this review, we discuss the recently identified molecular abnormalities at 11p15.5 involved in RSS and BWS, which have led to the identification of cis-acting elements and trans-acting regulatory factors involved in the regulation of imprinting in this region. We also discuss the multilocus imprinting disorders identified in various human syndromes, their clinical outcomes and their impact on commonly identified metabolism disorders. SUMMARY: These new findings and progress in this field will have direct consequence for diagnostic and predictive tools, risk assessment and genetic counseling for these syndromes.
Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Pruebas Genéticas/métodos , Impresión Genómica , Síndrome de Silver-Russell/genética , Síndrome de Beckwith-Wiedemann/diagnóstico , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Metilación de ADN , Epigénesis Genética , Femenino , Asesoramiento Genético , Pruebas Genéticas/tendencias , Humanos , Recién Nacido , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Canales de Potasio con Entrada de Voltaje/genética , Guías de Práctica Clínica como Asunto , Embarazo , Medición de Riesgo , Síndrome de Silver-Russell/diagnósticoRESUMEN
Beckwith-Wiedemann syndrome is an overgrowth disorder with an increased risk of childhood tumors that results from a dysregulation of imprinted gene expression in the 11p15 region. Since epigenetic defects are the most frequent anomalies, first-line diagnostic methods involve methylation analysis. When paternal isodisomy is suspected, it should be confirmed by a second technique capable of distinguishing true 11p15 paternal disomy (patUPD) from paternal 11p15 duplication or 11p15 trisomy. We sought to evaluate the interest of using SNP arrays in the Beckwith-Wiedemann syndrome diagnostic strategy. We analyzed the SNP profiles of 25 Beckwith Wiedemann patients with previously determined methylation indexes. Among them, 3 had 11p15 trisomies, 13 had patUPD, 8 had an inconclusive methylation index and 1 had a normal result. All known trisomies and known patUPDs were detected. Moreover we found 7 low-rate mosaicisms 11p15 patUPDs among the 8 patients with an inconclusive methylation index. We were able to precisely characterize the sizes and mosaicism rates of the anomalies. We demonstrate that SNP arrays are of real diagnostic interest in Beckwith-Wiedemann syndrome: 1) they help to distinguish patUPDs from trisomies more precisely than karyotyping and FISH, 2) they help determine the size and mosaicism rate of patUPDs, 3) they provide complementary information in inconclusive cases, helping to distinguish low-rate patUPD mosaicism from other BWS-related molecular defects.
Asunto(s)
Síndrome de Beckwith-Wiedemann/diagnóstico , Polimorfismo de Nucleótido Simple , Síndrome de Beckwith-Wiedemann/genética , Puntos de Rotura del Cromosoma , Metilación de ADN , Impresión Genómica , Humanos , Técnicas de Diagnóstico Molecular , Mosaicismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Trisomía/diagnóstico , Disomía Uniparental/diagnósticoRESUMEN
Most patients with pseudohypoparathyroidism type 1b (PHP-1b) display a loss of imprinting (LOI) encompassing the GNAS locus resulting in PTH resistance. In other imprinting disorders, such as Russell-Silver or Beckwith-Wiedemann syndrome, we and others have shown that the LOI is not restricted to one imprinted locus but may affect other imprinted loci for some patients. Therefore, we hypothesized that patients with PHP-1b might present multilocus imprinting defects. We investigated, in 63 patients with PHP-1b, the methylation pattern of eight imprinted loci: GNAS, ZAC1, PEG1/MEST, ICR1, and ICR2 on chromosome 11p15, SNRPN, DLK1/GTL2 IG-DMR, and L3MBTL1. We found multilocus imprinting defects in four PHP-1b patients carrying broad LOI at the GNAS locus (1) simultaneous hypermethylation at L3MBTL1 differentially methylated region 3 (DMR3), and hypomethylation at PEG1/MEST DMR (n = 1), (2) hypermethylation at the L3MBTL1 (DMR3) (n = 1) and at the DLK1/GTL2 IG-DMR (n = 1), and (3) hypomethylation at the L3MBTL1 DMR3 (n = 1). We suggest that mechanisms underlying multilocus imprinting defects in PHP-1b differ from those of other imprinting disorders having only multilocus loss of methylation. Furthermore, our results favor the hypothesis of "epidominance", that is, the phenotype is controlled by the most severely affected imprinted locus.
Asunto(s)
Metilación de ADN , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Impresión Genómica , Polimorfismo de Nucleótido Simple , Seudohipoparatiroidismo/genética , Cromograninas , Estudios de Cohortes , Subunidades alfa de la Proteína de Unión al GTP Gs/química , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Humanos , Seudohipoparatiroidismo/metabolismoRESUMEN
Fetal growth is a complex process involving environmental, epigenetic and genetic factors. Fetal growth restriction is associated with morbidity among small for gestational age (SGA) neonates as well as in children and adults who were former SGA. Imprinted genes (whose expression is restricted to a single parental allele) have a critical role in controlling mammalian fetal growth. The human chromosome 11p15 encompasses two imprinted domains regulated by their own differentially methylated imprinted control region (ICR1 at the H19/IGF2 domain, and ICR2 at the KCNQ1/CDKN1C domain). Loss of imprinting at these two domains is implicated in two clinically opposite growth disorders. Indeed, our group has identified a loss of DNA methylation (LOM) at ICR1 in over 50% of patients with Russell-Silver syndrome (RSS) characterized by intrauterine and postnatal growth retardation with spared cranial growth, dysmorphic features, frequent body asymmetry and severe feeding difficulties. By contrast, gain of methylation at ICR1 is found in 10% of patients with Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome with an enhanced childhood tumor risk. We have now identified over 130 RSS patients with 11p15 LOM. This 11p15 epimutation is a frequent and specific cause of RSS as it has not been identified in non syndromic SGA patients. These new findings in the pathophysiology of RSS allow long-term follow-up studies to be performed based on molecular diagnosis. This will help to define appropriate clinical guidelines regarding growth, rapid bone age advance during puberty and feeding difficulties. Remarkably, we have also recently found that â¼10% of RSS patients and â¼25% of BWS patients showed multilocus LOM at imprinted regions other than ICR1 or ICR2 11p15, respectively. Several clinical studies demonstrated that assisted reproductive technology significantly increased the risk of human imprinting diseases including BWS and RSS, suggesting that the environment may favor imprinting disorders.
Asunto(s)
Epigénesis Genética , Retardo del Crecimiento Fetal/genética , Trastornos del Crecimiento/genética , Alelos , Síndrome de Beckwith-Wiedemann/genética , Niño , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 11/metabolismo , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Metilación de ADN/genética , Estudios de Asociación Genética , Sitios Genéticos , Humanos , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Factor II del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/metabolismo , Canal de Potasio KCNQ1/genética , Canal de Potasio KCNQ1/metabolismo , Mutación , Técnicas Reproductivas Asistidas , Síndrome de Silver-RussellRESUMEN
Fetal growth is a complex process. Its restriction is associated with morbidity and long term metabolic consequences. Imprinted genes have a critical role in mammalian fetal growth. The human chromosome 11p15 encompasses two imprinted domains regulated by their own differentially methylated region (DMR), also called Imprinted Control Region (ICR1 at the H19/IGF-2 domain, paternally methylated), and ICR2 at the KCNQ1/CDKN1C domain (maternally methylated). Loss of imprinting at these two domains is implicated in two growth disorders clinically opposite. A loss of DNA methylation (LOM) at ICR1 is identified in over 50% of patients with Russell-Silver syndrome (RSS), characterized by intrauterine and postnatal growth retardation, spared cranial growth, frequent body asymmetry and severe feeding difficulties. Inversely, a gain of methylation at ICR1 is found in 10% of patients with Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome with an enhanced childhood tumor risk. We have identified over 150 RSS patients with 11p15 LOM allowing long-term follow-up studies and proposal of clinical guidelines. We also found that â¼10% of RSS patients and â¼25% of BWS patients have multilocus LOM at imprinted regions other than ICR1 or ICR2 11p15, respectively. Recent studies have identified cis-acting regulatory elements and trans-acting factors involved in the regulation of 11p15 imprinting, establishing new potential mechanisms of RSS and BWS.
Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Enfermedades Fetales/genética , Impresión Genómica/fisiología , Trastornos del Crecimiento/genética , Síndrome de Silver-Russell/genética , Edad de Inicio , Niño , Femenino , Trastornos del Crecimiento/congénito , Trastornos del Crecimiento/epidemiología , Humanos , Recién Nacido , Modelos Biológicos , EmbarazoRESUMEN
The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS.
Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Cromosomas Humanos Par 11 , Variaciones en el Número de Copia de ADN , Impresión Genómica , Síndrome de Silver-Russell/genética , Adulto , Secuencia de Bases , Hibridación Genómica Comparativa , Metilación de ADN , Femenino , Humanos , Masculino , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
The phenotype caused by human genetic insulin-like growth factor-I (IGF-I) defects is characterised by the association of intrauterine and postnatal growth retardation with sensorineural deafness and intellectual deficit. This syndrome is extremely rare and only four cases have been reported. Addition clinical features may include microcephaly and later in life adiposity and insulin resistance. Partial gonadal dysfunction and osteoporosis may also be present. A case of partial IGF-I deficiency has recently been described and was associated with pre- and postnatal growth retardation and microcephaly but the developmental delay was mild and hearing tests were normal. IGF-I deficiency is transmitted as an autosomal recessive trait and is caused by homozygous mutations in the IGF1 gene. Currently these patients can benefit from recombinant IGF-I which is now available for treatment. These observations demonstrate that the integrity of IGF-I signalling is important for normal growth and brain development.