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Cancers Aug 2023Embryonic tumors share few recurrent mutations, suggesting that other mechanisms, such as aberrant DNA methylation, play a prominent role in their development. The loss...
Embryonic tumors share few recurrent mutations, suggesting that other mechanisms, such as aberrant DNA methylation, play a prominent role in their development. The loss of imprinting (LOI) at the chromosome region 11p15 is the germline alteration behind Beckwith-Wiedemann syndrome that results in an increased risk of developing several embryonic tumors. This study analyzed the methylome, using EPIC Beadchip arrays from 99 sporadic embryonic tumors. Among these tumors, 46.5% and 14.6% presented alterations at imprinted control regions (ICRs) 1 and 2, respectively. Based on the methylation levels of ICR1 and ICR2, four clusters formed with distinct methylation patterns, mostly for medulloblastomas (ICR1 loss of methylation (LOM)), Wilms tumors, and hepatoblastomas (ICR1 gain of methylation (GOM), with or without ICR2 LOM). To validate the results, the methylation status of 29 cases was assessed with MS-MLPA, and a high level of agreement was found between both methodologies: 93% for ICR1 and 79% for ICR2. The MS-MLPA results indicate that 15 (51.7%) had ICR1 GOM and 11 (37.9%) had ICR2 LOM. To further validate our findings, the ICR1 methylation status was characterized via digital PCR (dPCR) in cell-free DNA (cfDNA) extracted from peripheral blood. At diagnosis, we detected alterations in the methylation levels of ICR1 in 62% of the cases, with an agreement of 76% between the tumor tissue (MS-MLPA) and cfDNA methods. Among the disagreements, the dPCR was able to detect ICR1 methylation level changes presented at heterogeneous levels in the tumor tissue, which were detected only in the methylome analysis. This study highlights the prevalence of 11p15 methylation status in sporadic embryonic tumors, with differences relating to methylation levels (gain or loss), location (ICR1 or ICR2), and tumor types (medulloblastomas, Wilms tumors, and hepatoblastomas).
PubMed: 37686532
DOI: 10.3390/cancers15174256 -
Cureus Dec 2023The deletion of the DIS3L2 gene causes the extremely uncommon congenital overgrowth syndrome, known as Perlman syndrome, which is autosomal recessive. Polyhydramnios,...
The deletion of the DIS3L2 gene causes the extremely uncommon congenital overgrowth syndrome, known as Perlman syndrome, which is autosomal recessive. Polyhydramnios, macrosomia, facial dysmorphism, renal dysplasia, and several congenital abnormalities with Wilms tumor propensity are its defining features. Beckwith-Wiedemann syndrome (BWS), prune belly syndrome (PBS), and Simpson-Golabi-Behmel syndrome (SGBS1) have certain similar clinical characteristics with Perlman syndrome. The syndrome is often associated with a high neonatal mortality rate and there are few reports of long-term survivors. Here, we present a case with the classic clinical features of Perlman syndrome and a DIS3L2 gene deletion that was discovered prenatally.
PubMed: 38161545
DOI: 10.7759/cureus.49777 -
Molecular Genetics & Genomic Medicine Dec 2023Beckwith-Wiedemann syndrome and Silver-Russel syndrome are two imprinting disorders caused by opposite molecular alterations in 11p15.5. With the current diagnostic...
BACKGROUND
Beckwith-Wiedemann syndrome and Silver-Russel syndrome are two imprinting disorders caused by opposite molecular alterations in 11p15.5. With the current diagnostic tests, their molecular diagnosis is challenging due to molecular heterogeneity and mosaic occurrence of the most frequent alterations. As the determination of precise (epi)genotype of patients is relevant as the basis for a personalized treatment, different approaches are needed to increase the sensitivity of diagnostic testing of imprinting disorders.
METHODS
We established methylation-specific droplet digital PCR approaches (MS-ddPCR) for the two imprinting centers in 11p15.5, and analyzed patients with paternal uniparental disomy of chromosome 11p15.5 (upd(11)pat) and other imprinting defects in the region. The results were compared to those from MS-MLPA (multiplex ligation-dependent probe amplification) and MS-pyrosequencing.
RESULTS
MS-ddPCR confirmed the molecular alterations in all patients and the results matched well with MS-MLPA. The results of MS-pyrosequencing varied between different runs, whereas MS-ddPCR results were reproducible.
CONCLUSION
We show for the first time that MS-ddPCR is a reliable and easy applicable method for determination of MS-associated changes in imprinting disorders. It is therefore an additional tool for multimethod diagnostics of imprinting disorders suitable to improve the diagnostic yield.
Topics: Humans; DNA Methylation; Genomic Imprinting; Beckwith-Wiedemann Syndrome; Silver-Russell Syndrome; Multiplex Polymerase Chain Reaction; Imprinting Disorders
PubMed: 37519217
DOI: 10.1002/mgg3.2264 -
Frontiers in Genetics 2023The amount of Insulin Growth Factor 2 (IGF2) controls the rate of embryonal and postnatal growth. The and adjacent are the imprinted genes of the telomeric cluster in...
The amount of Insulin Growth Factor 2 (IGF2) controls the rate of embryonal and postnatal growth. The and adjacent are the imprinted genes of the telomeric cluster in the 11p15 chromosomal region regulated by differentially methylated regions (DMRs) or imprinting centers (ICs): H19/IGF2:IG-DMR (IC1). Dysregulation due to IC1 Loss-of-Methylation (LoM) or Gain-of-Methyaltion (GoM) causes Silver-Russell syndrome (SRS) or Beckwith-Wiedemann syndrome (BWS) disorders associated with growth retardation or overgrowth, respectively. Specific features define each of the two syndromes, but isolated asymmetry is a common cardinal feature, which is considered sufficient for a diagnosis in the BWS spectrum. Here, we report the case of a girl with right body asymmetry, which suggested BWS spectrum. Later, BWS/SRS molecular analysis identified IC1_LoM revealing the discrepant diagnosis of SRS. A clinical re-evaluation identified a relative macrocephaly and previously unidentified growth rate at lower limits of normal at birth, feeding difficulties, and asymmetry. Interestingly, and never previously described in IC1_LoM SRS patients, since the age of 16, she has developed hand-writer's cramps, depression, and bipolar disorder. Trio-WES identified a heterozygous variant [NM_022575.4:c.2185C>G:p.Leu729Val] inherited from her healthy mother. VPS16 is involved in the endolysosomal system, and its dysregulation is linked to autosomal dominant dystonia with incomplete penetrance and variable expressivity. IGF2 involvement in the lysosomal pathway led us to speculate that the neurological phenotype of the proband might be triggered by the concurrent IGF2 deficit and alteration.
PubMed: 37529781
DOI: 10.3389/fgene.2023.1198821 -
ArXiv Apr 2024Individuals with suspected rare genetic disorders often undergo multiple clinical evaluations, imaging studies, laboratory tests and genetic tests, to find a possible...
Individuals with suspected rare genetic disorders often undergo multiple clinical evaluations, imaging studies, laboratory tests and genetic tests, to find a possible answer over a prolonged period of time. Addressing this "diagnostic odyssey" thus has substantial clinical, psychosocial, and economic benefits. Many rare genetic diseases have distinctive facial features, which can be used by artificial intelligence algorithms to facilitate clinical diagnosis, in prioritizing candidate diseases to be further examined by lab tests or genetic assays, or in helping the phenotype-driven reinterpretation of genome/exome sequencing data. Existing methods using frontal facial photos were built on conventional Convolutional Neural Networks (CNNs), rely exclusively on facial images, and cannot capture non-facial phenotypic traits and demographic information essential for guiding accurate diagnoses. Here we introduce GestaltMML, a multimodal machine learning (MML) approach solely based on the Transformer architecture. It integrates facial images, demographic information (age, sex, ethnicity), and clinical notes (optionally, a list of Human Phenotype Ontology terms) to improve prediction accuracy. Furthermore, we also evaluated GestaltMML on a diverse range of datasets, including 528 diseases from the GestaltMatcher Database, several in-house datasets of Beckwith-Wiedemann syndrome (BWS, over-growth syndrome with distinct facial features), Sotos syndrome (overgrowth syndrome with overlapping features with BWS), NAA10-related neurodevelopmental syndrome, Cornelia de Lange syndrome (multiple malformation syndrome), and KBG syndrome (multiple malformation syndrome). Our results suggest that GestaltMML effectively incorporates multiple modalities of data, greatly narrowing candidate genetic diagnoses of rare diseases and may facilitate the reinterpretation of genome/exome sequencing data.
PubMed: 38711434
DOI: No ID Found -
Cureus Oct 2023Beckwith-Wiedemann syndrome (BWS) is a rare genetic disorder, distinguished by the following characteristics: macrosomia, macroglossia, abdominal wall...
Beckwith-Wiedemann syndrome (BWS) is a rare genetic disorder, distinguished by the following characteristics: macrosomia, macroglossia, abdominal wall deformities such as omphalocele, visceromegaly, hemihypertrophy and elevated risk of developing tumors such as nephroblastoma or hepatoblastoma. A 2.5-year-old female patient came to the Department of Pediatric and Preventive Dentistry with a complaint of abnormally large tongue along with difficulty in swallowing and slurred speech. On clinical examination, the built of the patient was greater than normal. Intraoral examination revealed an enlarged tongue that led to the inability to close her mouth. Preliminary tests like blood tests, ECG, etc., were done before proceeding further to correct the enlarged tongue surgically under general anesthesia. The patient was intubated nasally, and a keyhole incision pattern was marked on the dorsum of the tongue at the central part. Reduction glossectomy was performed using electrocautery and the two parts were thereafter sutured with 5-0 vicryl sutures. The patient was kept under observation for one week and then discharged. Satisfactory healing was observed. Early diagnosis, close monitoring by healthcare specialists, and a thorough treatment plan that includes speech therapy, food support, and dental care can help manage the issues associated with BWS macroglossia.
PubMed: 37933371
DOI: 10.7759/cureus.46579 -
Journal of Pediatric Genetics Jun 2024The genetic influences on human growth are being increasingly deciphered. Silver-Russell and Beckwith-Wiedemann syndromes (SRS; BWS) are two relatively common genetic...
The genetic influences on human growth are being increasingly deciphered. Silver-Russell and Beckwith-Wiedemann syndromes (SRS; BWS) are two relatively common genetic syndromes with under- and overgrowth-related issues being the reason for referral. Aberration in genomic imprinting is the underlying genetic pathomechanism behind these syndromes. Herein, we described a series of children with these two growth disorders and give an orientation to the reader of the concept of imprinting as well as the genetic testing strategy and counseling to be offered in these syndromes.
PubMed: 38721577
DOI: 10.1055/s-0041-1739388 -
Journal of Medical Case Reports Feb 2024We present two genetic causes of polyhydramnios that were challenging to diagnose due to their rarity and complexity. In view of the severe implications, we wish to...
BACKGROUND
We present two genetic causes of polyhydramnios that were challenging to diagnose due to their rarity and complexity. In view of the severe implications, we wish to highlight these rare genetic conditions when obstetricians consider differential diagnoses of polyhydramnios in the third trimester.
CASE PRESENTATION
Patient 1 is a 34-year-old Asian woman who was diagnosed with polyhydramnios at 28 weeks' gestation. First trimester testing, fetal anomaly scan, and intrauterine infection screen were normal. Subsequent antenatal ultrasound scans revealed macroglossia, raising the suspicion for Beckwith-Wiedemann syndrome. Chromosomal microarray analysis revealed a female profile with no pathological copy number variants. The patient underwent amnioreduction twice in the pregnancy. The patient presented in preterm labor at 34 weeks' gestation but elected for an emergency caesarean section. Postnatally, the baby was noted to have a bell-shaped thorax, coat hanger ribs, hypotonia, abdominal distension, and facial dysmorphisms suggestive of Kagami-Ogata syndrome. Patient 2 is a 30-year-old Asian woman who was diagnosed with polyhydramnios at 30 weeks' gestation. She had a high-risk first trimester screen but declined invasive testing; non-invasive prenatal testing was low risk. Ultrasound examination revealed a macrosomic fetus with grade 1 echogenic bowels but no other abnormalities. Intrauterine infection screen was negative, and there was no sonographic evidence of fetal anemia. She had spontaneous rupture of membranes at 37 + 3 weeks but subsequently delivered by caesarean section in view of pathological cardiotocography. The baby was noted to have inspiratory stridor, hypotonia, low-set ears, and bilateral toe polysyndactyly. Further genetic testing revealed a female profile with a pathogenic variant of the GLI3 gene, confirming a diagnosis of Greig cephalopolysyndactyly syndrome.
CONCLUSION
These cases illustrate the importance of considering rare genetic causes of polyhydramnios in the differential diagnosis, particularly when fetal anomalies are not apparent at the 20-week structural scan. We would like to raise awareness for these rare conditions, as a high index of suspicion enables appropriate counseling, prenatal testing, and timely referral to pediatricians and geneticists. Early identification and diagnosis allow planning of perinatal care and birth in a tertiary center managed by a multidisciplinary team.
Topics: Adult; Female; Humans; Pregnancy; Cesarean Section; Fetal Diseases; Muscle Hypotonia; Polyhydramnios; Pregnancy Trimester, Third; Ultrasonography, Prenatal
PubMed: 38369506
DOI: 10.1186/s13256-024-04435-0 -
Plastic and Reconstructive Surgery.... Mar 2024Beckwith-Wiedemann syndrome (BWS) is a complex congenital overgrowth disorder necessitating a multidisciplinary approach for effective management. A 5-year-old Saudi...
Beckwith-Wiedemann syndrome (BWS) is a complex congenital overgrowth disorder necessitating a multidisciplinary approach for effective management. A 5-year-old Saudi girl with BWS received comprehensive care involving various specialists, including a plastic surgeon who performed a keyhole technique tongue reduction to address macroglossia. The intervention resulted in significant improvements in speech and quality of life, with no postoperative complications. Intensive speech therapy further enhanced speech development. This case report emphasizes the importance of a multidisciplinary approach and the critical role of the plastic surgeon in managing BWS patients with macroglossia to achieve optimal outcomes.
PubMed: 38463705
DOI: 10.1097/GOX.0000000000005635 -
The British Journal of Ophthalmology Aug 2023Retinopathy of prematurity (ROP) is currently diagnosed through repeated eye examinations to find the low percentage of infants that fulfil treatment criteria to reduce...
BACKGROUND/AIMS
Retinopathy of prematurity (ROP) is currently diagnosed through repeated eye examinations to find the low percentage of infants that fulfil treatment criteria to reduce vision loss. A prediction model for severe ROP requiring treatment that might sensitively and specifically identify infants that develop severe ROP, DIGIROP-Birth, was developed using birth characteristics. DIGIROP-Screen additionally incorporates first signs of ROP in different models over time. The aim was to validate DIGIROP-Birth, DIGIROP-Screen and their decision support tool on a contemporary Swedish cohort.
METHODS
Data were retrieved from the Swedish national registry for ROP (2018-2019) and two Swedish regions (2020), including 1082 infants born at gestational age (GA) 24 to <31 weeks. The predictors were GA at birth, sex, standardised birth weight and age at the first sign of ROP. The outcome was ROP treatment. Sensitivity, specificity and area under the receiver operating characteristic curve (AUC) with 95% CI were described.
RESULTS
For DIGIROP-Birth, the AUC was 0.93 (95% CI 0.90 to 0.95); for DIGIROP-Screen, it ranged between 0.93 and 0.97. The specificity was 49.9% (95% CI 46.7 to 53.0) and the sensitivity was 96.5% (95% CI 87.9 to 99.6) for the tool applied at birth. For DIGIROP-Screen, the cumulative specificity ranged between 50.0% and 78.7%. One infant with Beckwith-Wiedemann syndrome who fulfilled criteria for ROP treatment and had no missed/incomplete examinations was incorrectly flagged as not needing screening.
CONCLUSIONS
DIGIROP-Birth and DIGIROP-Screen showed high predictive ability in a contemporary Swedish cohort. At birth, 50% of the infants born at 24 to <31 weeks of gestation were predicted to have low risk of severe ROP and could potentially be released from ROP screening examinations. All routinely screened treated infants, excluding those screened for clinical indications of severe illness, were correctly flagged as needing ROP screening.
Topics: Infant, Newborn; Infant; Humans; Retinopathy of Prematurity; Sweden; Risk Factors; Infant, Premature; Birth Weight; Gestational Age; Neonatal Screening; Retrospective Studies
PubMed: 35277395
DOI: 10.1136/bjophthalmol-2021-320738