Uniparental Disomy Research Articles

RF17 | PMON27 Genetic Subtype Differences in Relation to Health Problems Among Adults With Prader-Willi Syndrome

Abstract Background Prader-Willi syndrome (PWS) is a complex rare genetic disorder associated with hypothalamic dysfunction, pituitary hormone deficiencies, hyperphagia and (morbid) obesity. PWS is caused by loss of expression of paternally expressed genes on chromosome 15q11.2-q13. The most common genetic mechanisms leading to PWS are paternal deletion (DEL) and maternal uniparental disomy (mUPD). DELs can be subdivided in type 1 and (smaller) type 2 deletions (DEL-1, DEL-2). Most research has focused on behavioral, cognitive and psychological differences between patients with a DEL-1, DEL-2 or mUPD. However, little is known about the genetic subtype differences in relation to physical health problems. Methods We reviewed the medical files of all adults with genetically confirmed PWS who visited the outpatient clinic of the Center for Adults with Complex Rare Genetic Syndromes at the Erasmus University Medical Center, Rotterdam, the Netherlands, between January 2015 and June 2021. All patients underwent a systematic health screening, including a structured interview, a medical questionnaire, a complete physical examination, biochemical measurements, and a review of the medical records. Health problems, physical complaints, symptoms of disease and behavioral challenges were compared between adults with an mUPD and DEL and between adults with a DEL-1 and DEL-2. Results Twenty-eight adults had an mUPD and 65 a DEL (13 DEL-1, 27 DEL-2, 25 unspecified). Gender, age and BMI did not differ between the genetic subgroups. Although psychiatric problems (psychotic episodes) were significantly more often present in adults with an mUPD (P < 0.001) and scoliosis was more prevalent among patients with DEL (P = 0.04), there was only a slight difference in prevalence of other medical problems like hypertension, cold intolerance, edema, hyperphagia, skin picking, abdominal pain and fatigue. There were no significant differences between DEL-1 and DEL-2. However, fatigue, cold intolerance, edema and hyperphagia were slightly more prevalent among adults with a DEL-1, whereas osteopenia, constipation and skin picking were more prevalent among adults with a DEL-2. Conclusion The differences in health problems between PWS adults with DEL-1, DEL-2 and mUPD are mostly present in the psychological domain. Especially psychotic episodes were more frequent in adults with an mUPD. Apart from scoliosis, there were no significant differences in physical health outcomes between the genetic subtypes. Presentation: Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

OR27-5 Malignancies in Prader-Willi Syndrome: Practical Recommendations Based on a Large International Cohort

Abstract Introduction Prader-Willi syndrome (PWS) is a complex disorder combining hypothalamic dysfunction, pituitary hormone deficiencies, neurodevelopmental delay, high pain threshold, hypotonia and hyperphagia with risk of obesity and its complications. PWS is caused by the loss of expression of a cluster of paternally expressed genes on chromosome 15q11.2-q13 called the PWS critical region, mostly due to paternal deletion (DEL) or maternal uniparental disomy. As life expectancy of patients with PWS increases, age-related diseases like malignancies might pose a new threat to health. Multiple genes in the PWS critical region have been associated with the development of malignancies and obesity is a risk factor for many types of malignancies. The aim of this study was to investigate the prevalence and pathogenesis of malignancies and to provide clinical recommendations for screening in patients with PWS. Methods We collected information on a (for rare disorders) exceptionally large cohort of 706 patients with PWS (160 children, 546 adults). All patients had visited the seven participating centers in Europe and Australia. Data was collected retrospectively from medical records on past or current malignancies, the type of malignancy and risk factors for malignancies. Genotype, age, gender, body mass index (BMI), tobacco use, presence of type 2 diabetes mellitus, growth hormone treatment and sex hormone replacement therapy were assessed in relation to the occurrence of malignancies. Additionally, we systematically searched the literature for information about the relationship between genes in the PWS critical region and malignancies. Results Seven adults (age range 18-55 years old) had been diagnosed with malignancies (acute lymphoblastic leukemia, intracranial hemangiopericytoma, melanoma, adenocarcinoma of the stomach, cholangiocarcinoma, parotid adenocarcinoma and colorectal carcinoma). Genetic subtype was DEL for 100% of the patients with malignancies, compared to 58% in patients without a malignancy (p=0.045). Age, gender, BMI, tobacco use, type 2 diabetes mellitus, growth hormone treatment and sex hormone replacement were not significantly related to the presence of malignancies. Conclusion In conclusion, malignancies are rare in patients with PWS. Remarkably, patients with the DEL genetic subtype have a significantly higher risk of developing malignancies compared to patients with other genotypes. Although malignancies are rare in PWS, participation in regular national screening programs for cervical, breast and colon cancer is important as the high pain threshold and intellectual disability make presentation of physical complaints less reliable. We recommend to perform additional diagnostic testing in case of symptoms suggestive of paraneoplastic syndrome, localizing symptoms, loss of appetite or unexplained weight loss. Presentation: Tuesday, June 14, 2022 10:45 a.m. - 11:00 a.m.

Deciphering Epigenetic Backgrounds in a Korean Cohort with Beckwith-Wiedemann Syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder caused by genetic or epigenetic alterations at two imprinting centers (ICs) in the 11p15.5 region. Delineation of the molecular defects is important for prognosis and predicting familial recurrence. We evaluated epigenetic alterations and potential epigenotype-phenotype correlations in Korean children with BWS. Forty children with BWS with proven genetic or epigenetic defects in the 11p15.5 region were included. The phenotype was scored using the BWS consensus scoring system. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), bisulfite pyrosequencing, a single-nucleotide polymorphism microarray, and CDKN1C sequencing were used for confirmative diagnosis. Patients met the criteria for genetic testing, with a mean clinical score of 5.4±2.0. Methylation alterations were consistent between MS-MLPA and bisulfite pyrosequencing in all patients. Twenty-six patients (65.0%) had IC2 loss of methylation (IC2-LoM), 11 (27.5%) had paternal uniparental disomy (patUPD), and one (2.5%) had IC1 gain of methylation. Macroglossia and external ear anomalies were more common in IC2-LoM than in patUPD, and lateralized overgrowth was more common in patUPD than in IC2-LoM (all P<0.05). Methylation levels at IC2 were inversely correlated with birth weight standard deviation score (r=-0.476, P=0.014) and clinical score (r=-0.520, P=0.006) in the IC2-LoM group. Comprehensive molecular analysis of the 11p15.5 region revealed epigenotype-phenotype correlations in our BWS cohort. Bisulfite pyrosequencing can help clarify epigenotypes. Methylation levels were correlated with fetal growth and clinical severity in patients with BWS.

Pigmentary mosaicism as a recurrent clinical manifestation in three new patients with mosaic trisomy 12 diagnosed postnatally: cases report and literature review

BackgroundTo date, only twenty-one cases diagnosed postnatally with mosaic trisomy 12 have been reported. The most frequent phenotypic manifestations are developmental delay, dysmorphic facial features, congenital heart defects, digital alterations, and pigmentary disorders. In the present report, detailed clinical and genetic profiles of three unrelated new patients with mosaic trisomy 12 are described and compared with previously reported cases.Case presentationIn the present report, we include the clinical, cytogenetic, and molecular description of three Mexican patients diagnosed postnatally with mosaic trisomy 12. At phenotypic level, the three patients present with developmental delay, dysmorphic facial features, congenital heart defects and skin pigmentary anomalies. Particularly, patient 1 showed unique eye alterations as bilateral distichiasis, triple rows of upper lashes, and digital abnormalities. In patient 2 redundant skin, severe hearing loss, and hypotonia were observed, and patient 3 presented with hypertelorism and telecanthus. Hyperpigmentation with disseminated pigmentary anomalies is a common trait in all of them. The cytogenetic study was carried out under the strict criteria of analysis, screening 50–100 metaphases from three different tissues, showing trisomy 12 mosaicism in at least one of the three different tissues analyzed. With SNParray, the presence of low-level mosaic copy number variants not previously detected by cytogenetics, and uniparental disomy of chromosome 12, was excluded. STR markers allowed to confirm the absence of uniparental disomy as well as to know the parental origin of supernumerary chromosome 12.ConclusionsThe detailed clinical, cytogenetic, and molecular description of these three new patients, contributes with relevant information to delineate more accurately a group of patients that show a heterogeneous phenotype, although sharing the same chromosomal alteration. The possibility of detecting mosaic trisomy 12 is directly associated with the sensitivity of the methodology applied to reveal the low-level chromosomal mosaicism, as well as with the possibility to perform the analysis in a suitable tissue.

Clinical impacts of genome-wide noninvasive prenatal testing for rare autosomal trisomy

Genome-wide noninvasive prenatal testing identifies several rare autosomal trisomies in the general obstetrical population, but its use is questioned by its low positive predictive value. Furthermore, the origin of rare autosomal trisomies and the clinical effect of reporting them has not been sufficiently investigated. In addition, professional societies express their need for data assessing the clinical use of genome-wide noninvasive prenatal testing for rare autosomal trisomies for years. This study aimed to investigate the origin of rare autosomal trisomies and the clinical effect of disclosing rare autosomal trisomies in clinical settings. Women who received noninvasive prenatal testing between March 2021 and March 2022 were prospectively enrolled. Clinical follow-up and cytogenetic and molecular investigations were performed. Posthoc analysis was performed to investigate the association between placental mosaicism and clinical outcomes. Overall, 154 rare autosomal trisomies were identified in 89,242 pregnancies (0.17%) through noninvasive prenatal testing. In the 120 cases in which cytogenetic and molecular investigations were carried out, the rare autosomal trisomies were found to originate from true fetal mosaicism (n=5), uniparental disomy (n=5), maternal mosaic trisomy (n=3), maternal malignancy (n=1), and confined placental mosaicism (n=106). Clinical follow-up showed that 40% of all rare autosomal trisomy cases had adverse perinatal outcomes. In women with false-positive noninvasive prenatal testing results originating from confined placental mosaicism, the frequency of adverse perinatal outcomes was 26%. More importantly, the placental mosaicism ratio revealed by noninvasive prenatal testing was significantly higher in women who experienced adverse perinatal outcomes than those who did not (0.688 vs 0.332; P<.001). Women with noninvasive prenatal testing results indicative of rare autosomal trisomies are at risk of adverse perinatal outcomes, and that risk can be stratified using chromosomes and the mosaicism ratio revealed by noninvasive prenatal testing. Our data are valuable for obstetrical caregivers advising a patient with a noninvasive prenatal testing result indicative of a rare autosomal trisomy and a false-positive diagnosis and for managing risks during pregnancy.

Temple Syndrome: Clinical Findings, Body Composition and Cognition in 15 Patients.

Temple syndrome (TS14) is an imprinting disorder caused by a maternal uniparental disomy of chromosome 14 (UPD(14)mat), paternal deletion of 14q32 or an isolated methylation defect of the MEG3-DMR. Studies on phenotypical characteristics in TS14 are scarce and patients with TS14 often experience delay in diagnosis, which has adverse effects on their health. TS14 is often characterized as either Prader-Willi-like, Silver-Russell-like or as a Silver-Russell spectrum disorder. This study describes 15 patients with TS14 who visited the Dutch Reference Center for Prader-Willi-like from December 2018 to January 2022. Eight patients had UPD(14)mat and seven a methylation defect. The most common symptoms were intra-uterine growth retardation (IUGR) (100%), hypotonia (100%), precocious puberty (89%), small for gestational age (SGA) birth (67%), tube feeding after birth (53%) and psycho-behavioral problems (53%). Median (interquartile range (IQR)) IQ was 91.5 (84.25; 100.0), whilst many patients were enrolled in special education (54%). The median (IQR) fat mass % (FM%) SDS was 2.53 (2.26; 2.90) and lean body mass (LBM) SDS -2.03 (-3.22; -1.28). There were no significant differences in clinical characteristics between patients with a UPD(14)mat and a methylation defect. Our patients share a distinct phenotype consisting of IUGR, SGA birth, precocious puberty, hypotonia, tube feeding after birth, psycho-behavioral problems and abnormal body composition with a high FM% and low LBM. Whilst similarities with Prader-Willi syndrome (PWS) and Silver-Russell syndrome (SRS) exist, TS14 is a discernible syndrome, deserving a tailored clinical approach. Testing for TS14 should be considered in patients with a PWS or SRS phenotype in infancy if PWS/SRS testing is negative.

Clinical and Genetic Characteristics of a Cohort with Distal Vaginal Atresia

Distal vaginal atresia is a rare abnormality of female reproductive tract in which the vagina is closed or absent. The distal vagina may be replaced by fibrous tissue and the condition is often not diagnosed until a girl fails to begin having periods at puberty. Although it is a congenital disorder, potential genetic causes of distal vaginal atresia are still unknown. We recruited a cohort of 39 patients with distal vaginal atresia and analyzed their phenotypic and genetic features. In addition to the complaint of distal vaginal atresia, approximately 17.9% (7/39) of the patients had other Müllerian anomalies, and 17.9% (7/39) of the patients had other structural abnormalities, including renal-tract, skeletal and cardiac anomalies. Using genome sequencing, we identified two fragment duplications on 17q12 encompassing HNF1B and LHX1, two dosage-sensitive genes with candidate pathogenic variants, in two unrelated patients. A large fragment of uniparental disomy was detected in another patient, affecting genes involved in cell morphogenesis and connective tissue development. Additionally, we reported two variants on TBX3 and AXL, leading to distal vaginal atresia in mutated mouse model, in our clinical subjects for the first time. Essential biological functions of these detected genes with pathogenic variants included regulating reproductive development and cell fate and patterning during embryogenesis. We displayed the comprehensive clinical and genetic characteristic of a cohort with distal vaginal atresia and they were highly heterogeneous both phenotypically and genetically. The duplication of 17q12 in our cohort could help to expand its phenotypic spectrum and potential contribution to the distal vaginal atresia. Our findings of pathogenic genetic variants and associated phenotypes in our cohort could provide evidence and new insight for further research attempting to reveal genetic causes of distal vaginal atresia.

Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism.

The focal form of CHI is caused by an autosomal recessive pathogenic variant affecting the paternal homologue of genes ABCC8 or KCNJ11 and a second somatic event specifically occurring in the affected islet of Langerhans. The approach of this study was to integrate the genetic changes occurring in pancreatic focal lesions of CHI at the genomic and transcriptional level. Patients receiving therapeutic surgery and with proven ABCC8 or KCNJ11 pathogenic variants were selected and analyzed for loss of heterozygosity (LOH), changes in copy number and uniparental disomy (UPD) on the short am of chromosome 11 by molecular microarray analysis and methylation-specific MLPA. Gene expression was analyzed by RT-PCR and Massive Analysis of cDNA Ends (MACE). Both genes, ABCC8 and KCNJ11, are located in proximity to the Beckwith-Wiedemann (BWS) imprinting control region on chromosome 11p15. Somatic paternal uniparental isodisomy (UPD) at chromosome 11p was identified as second genetic event in focal lesions resulting in LOH and monoallelic expression of the mutated ABCC8/KCNJ11 alleles. Of five patients with samples available for microarray analysis, the breakpoints of UPD on chromosome 11p were different. Samples of two patients were analyzed further for changes in gene expression. Profound downregulation of growth suppressing genes CDKN1 and H19 was detected in focal lesions whereas growth promoting gene ASCL2 and pancreatic transcription factors of the endocrine cell lineage were upregulated. Paternal UPD on the short arm of chromosome 11 appears to be the major second genetic event specifically within focal lesions of CHI but no common breakpoint for UDP can be delineated. We show for the first time upregulation of growth promoting ASCL2 (achaete-scute homolog 2) suggestive of a driving factor in postnatal focal expansion in addition to downregulation of growth suppressing genes CDKN1C and H19.

Usefulness of the MS-MLPA technique in the diagnosis of Beckwith-Wiedemann syndrome and Silver-Russell syndrome.

Epigenetic and genomic imprinting alterations of the 11p15.5 region cause excessive or deficient growth, which result in Beckwith-Wiedemann syndrome (BWS) or Silver-Russell syndrome (SRS), respectively. To evaluate the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) methylation analysis technique in the diagnosis of BWS and SRS. 11p15.5 methylation and variants were evaluated in patients with clinical diagnosis of BWS and SRS using the MS-MLPA technique in peripheral blood DNA. Paternal uniparental disomy and loss of maternal IC2 methylation were identified in two patients with BWS who had omphalocele and macroglossia, respectively. Paternal IC1hypomethylation was recorded in two patients with SRS of classic phenotype. Adequate genotype-phenotype correlation was observed with the methylation defects that were identified, which confirms the usefulness of MLPA as a first-line study in patients diagnosed with BWS and SRS.

Genetic variation in placental insufficiency: What have we learned over time?

Genetic variation shapes placental development and function, which has long been known to impact fetal growth and pregnancy outcomes such as miscarriage or maternal pre-eclampsia. Early epidemiology studies provided evidence of a strong heritable component to these conditions with both maternal and fetal-placental genetic factors contributing. Subsequently, cytogenetic studies of the placenta and the advent of prenatal diagnosis to detect chromosomal abnormalities provided direct evidence of the importance of spontaneously arising genetic variation in the placenta, such as trisomy and uniparental disomy, drawing inferences that remain relevant to this day. Candidate gene approaches highlighted the role of genetic variation in genes influencing immune interactions at the maternal-fetal interface and angiogenic factors. More recently, the emergence of molecular techniques and in particular high-throughput technologies such as Single-Nucleotide Polymorphism (SNP) arrays, has facilitated the discovery of copy number variation and study of SNP associations with conditions related to placental insufficiency. This review integrates past and more recent knowledge to provide important insights into the role of placental function on fetal and perinatal health, as well as into the mechanisms leading to genetic variation during development.

Recessive Dystrophic Epidermolysis bullosa due to Hemizygous 40 kb Deletion of COL7A1 and the Proximate PFKFB4 Gene Focusing on the Mutation c.425A>G Mimicking Homozygous Status

Background: Dystrophic Epidermolysis bullosa (DEB) is a rare inherited mechanobullous disease characterised by the hyperfragility of the skin and mucous membranes. It is (typically) caused by (loss-of-function) mutations in the COL7A1 gene that impair the formation of collagen type VII, which represents the major constituent of anchoring fibrils within the basement membrane zone of epithelialised tissues. In a 4-year-old patient diagnosed with the clinical features of recessive DEB, genotyping via Next-Generation EB Panel Sequencing initially revealed the homozygosity of the maternal c.425A>G mutation, while the paternal heterozygosity in exon 3 was lacking. This genetic profile suggested incongruent gene transmission due to uniparental isodisomy (UPD) or the occurrence of a hemizygous deletion of unknown size. Methods: Thus, the EB panel sequencing of genomic DNA, followed by a paternity test and analysis of microsatellite markers, as well as multiplex ligation-dependent probe amplification (MLPA) copy number analysis using patient and parental DNA, were performed. Results: This approach revealed a paternally derived hemizygous deletion spanning from exon 3 to exon 118. Linear amplification-mediated PCR (LAM-PCR) determined the breaking points within intron 2 of the COL7A1 gene, comprising a 40kb segment within intron 1 of the adjacent PFKFB4 gene. Conclusion: This report highlights the relevance of advanced molecular profiling to determine new/exceptional/unusual genotypes and the accurate mode of genetic transmission in DEB.

VP.74 Uniparental disomy unmasks a homozygous mutation of POMGNT1 in a case of muscle-eye-brain disease

VP.74 Uniparental disomy unmasks a homozygous mutation of POMGNT1 in a case of muscle-eye-brain disease

Dealing with symptoms in the general population: lessons learned from the Danish Symptom Cohort

<b>Background:</b> Placental mesenchymal dysplasia (PMD) is a distinct syndrome of unknown aetiology that is associated with significant fetal morbidity and mortality. Intrauterine growth restriction is common, yet, paradoxically, many of the associated fetuses/newborns have been diagnosed with Beckwith-Wiedemann syndrome (BWS). <b>Methods:</b> We report two cases of PMD with high levels of androgenetic (complete paternal uniparental isodisomy) cells in the placenta and document, in one case, a likely androgenetic contribution to the fetus as well. <b>Results:</b> The same haploid paternal complement found in the androgenetic cells was present in coexisting biparental cells, suggesting origin from a single fertilisation event. <b>Conclusions:</b> Preferential allocation of the normal cells into the trophoblast explains the absence of trophoblast overgrowth, a key feature of this syndrome. Interestingly, the distribution of androgenetic cells appears to differ from that reported for artificially created androgenetic mouse chimeras. Androgenetic mosaicism for the first time provides an aetiology for PMD, and may be a novel mechanism for BWS and unexplained intrauterine growth restriction.

First report of paternal uniparental disomy of chromosome 8 with SLC52A2 mutation in Brown-vialetto-van laere syndrome type 2 and an analysis of genotype-phenotype correlations.

Purpose: This study reports the clinical and genetic features of Brown-Vialetto-Van Laere syndrome (BVVL) type 2 in a case of uniparental disomy of chromosome 8 in mainland China and analyzes the genotype-phenotype correlation through a review of the literature of BVVL type 2 cases. Methods: The clinical characteristics, treatment, and follow-up data of the patient were summarized, and the etiology was identified by whole-exome sequencing and gene chip analysis. Correlations between the genotype and phenotype were analyzed by collecting clinical and genetic data of published cases and our patient. Results: We identified a homozygous mutation in SLC52A2 (NM_001253815.2 c.1255G>A) by trio-WES. Sanger sequencing confirmed that his father was heterozygous and his mother was wild type. Subsequently, paternal uniparental disomy of chromosome 8 [UPD (8)pat] was confirmed by chromosomal microarray analysis.The patient received long-term oral riboflavin treatment (7 mg/kg.d) and was followed up for 40 months by which time the child’s bulbar palsy, ataxia, and motor function had improved. A review of the literature and statistical analysis found that the symptoms of BVVL type 2 appear at the earliest shortly after birth and at the latest at 10 years of age. The median age of onset was 2.5 years, but the overall delay in diagnosis was a median of 5.6 years. The most common symptoms were hearing loss (83.9%), followed by muscle weakness (80.6%), visual impairment (64.5%), and ataxia (61.3%). To date, a total of 32 mutations in the SLC52A2 gene have been reported, with the most common being a missense mutation. Mutations occur throughout the length of the gene apart from at the N-terminus. In patients with missense mutations, homozygous pattern was more likely to present with ataxia as the first symptom (p < 0.05), while compound heterozygous pattern was more likely to develop respiratory insufficiency during the course of disease (p < 0.001). Moreover, patients with one missense mutation located in inside the transmembrane domain were more likely to have respiratory insufficiency than those with mutations both inside and outside the domain (p < 0.05). Riboflavin supplementation was an important factor in determining prognosis (p < 0.001). Conclusion: We report the first UPD(8)pat with SLC52A2 homozygous pathogenic mutation case in BVVL type 2, which expand the mutation spectrum of gene.

Uniparental disomy screen of Irish rare disorder cohort unmasks homozygous variants of clinical significance in the TMCO1 and PRKRA genes.

A uniparental disomy (UPD) screen using whole genome sequencing (WGS) data from 164 trios with rare disorders in the Irish population was performed to identify large runs of homozygosity of uniparental origin that may harbour deleterious recessive variants. Three instances of whole chromosome uniparental isodisomy (UPiD) were identified: one case of maternal isodisomy of chromosome 1 and two cases of paternal isodisomy of chromosome 2. We identified deleterious homozygous variants on isodisomic chromosomes in two probands: a novel p (Glu59ValfsTer20) variant in TMCO1, and a p (Pro222Leu) variant in PRKRA, respectively. The overall prevalence of whole chromosome UPiD in our cohort was 1 in 55 births, compared to 1 in ∼7,500 births in the general population, suggesting a higher frequency of UPiD in rare disease cohorts. As a distinct mechanism underlying homozygosity compared to biallelic inheritance, the identification of UPiD has important implications for family planning and cascade testing. Our study demonstrates that UPD screening may improve diagnostic yields by prioritising UPiD chromosomes during WGS analysis.

The pathophysiology of bilateral and multifocal Wilms tumors: What we can learn from the study of predisposition syndromes.

Approximately 5% of patients with Wilms tumor present with synchronous bilateral disease. The development of synchronous bilateral Wilms tumor (BWT) is highly suggestive of a genetic or epigenetic predisposition. Patients with known germline predisposition to Wilms tumor (WT1 variants, Beckwith Wiedemann spectrum, TRIM28 variants) have a higher incidence of BWT. This Children's Oncology Group (COG)-International Society for Pediatric Oncology (SIOP-) HARMONICA initiative review for pediatric renal tumors details germline genetic and epigenetic predisposition to BWT development, with an emphasis on alterations in 11p15.5 (ICR1 gain of methylation, paternal uniparental disomy, and postzygotic somatic mosaicism), WT1, TRIM28, and REST. Molecular mechanisms that result in BWT are often also present in multifocal Wilms tumor (multiple separate tumors in one or both kidneys). We identify priority areas for international collaborative research to better understand how predisposing genetic or epigenetic factors associate with response to neoadjuvant chemotherapy, oncologic outcomes, and long-term renal function outcomes.

Maternal uniparental disomy of chromosome 7 underlying argininosuccinic aciduria and Silver-Russell syndrome

We describe a patient presenting with argininosuccinic aciduria and Silver-Russell syndrome (SRS). SRS was caused by maternal uniparental disomy of chromosome 7 (UPD(7)mat). UPD(7)mat also unmasked a maternally inherited splicing variant in ASL on chromosome 7, leading to the onset of argininosuccinic aciduria. The phenotype of the present case was more severe than that of a previous case, demonstrating a phenotypic variation in the combination of argininosuccinic aciduria and SRS.

Whole-exome sequencing analysis in a case of primary congenital glaucoma due to the partial uniparental isodisomy.

We described a clinical, laboratory, and genetic presentation of a pathogenic variant of the CYP1B1 gene through a report of a case of primary congenital glaucoma and a trio analysis of this candidate variant in the family with the Sanger sequencing method and eventually completed our study with the secondary/incidental findings. This study reports a rare case of primary congenital glaucoma, an 8-year-old female child with a negative family history of glaucoma and uncontrolled intraocular pressure. This case’s whole-exome sequencing data analysis presents a homozygous pathogenic single nucleotide variant in the CYP1B1 gene (NM_000104:exon3:c.G1103A:p.R368H). At the same time, this pathogenic variant was obtained as a heterozygous state in her unaffected father but not her mother. The diagnosis was made based on molecular findings of whole-exome sequencing data analysis. Therefore, the clinical reports and bioinformatics findings supported the relation between the candidate pathogenic variant and the disease. However, it should not be forgotten that primary congenital glaucoma is not peculiar to the CYP1B1 gene. Since the chance of developing autosomal recessive disorders with low allele frequency and unrelated parents is extraordinary in offspring. However, further data analysis of whole-exome sequencing and Sanger sequencing method were applied to obtain the type of mutation and how it was carried to the offspring.

The hemoglobinopathies, molecular disease mechanisms and diagnostics.

Hemoglobinopathies are the most common monogenic disorders in the world with an ever increasing global disease burden each year. As most hemoglobinopathies show recessive inheritance carriers are usually clinically silent. Programmes for preconception and antenatal carrier screening, with the option of prenatal diagnosis are considered beneficial in many endemic countries. With the development of genetic tools such as Array analysis and Next Generation Sequencing in addition to state of the art screening at the hematologic, biochemic and genetic level, have contributed to the discovery of an increasing number of rare rearrangements and novel factors influencing the disease severity over the recent years. This review summarizes the basic requirements for adequate carrier screening analysis, the importance of genotype–phenotype correlation and how this may lead to the unrevealing exceptional interactions causing a clinically more severe phenotype in otherwise asymptomatic carriers. A special group of patients are β‐thalassemia carriers presenting with features of β‐thalassemia intermedia of various clinical severity. The disease mechanisms may involve duplicated α‐globin genes, mosaic partial Uniparental Isodisomy of chromosome 11p15.4 where the HBB gene is located or haplo‐insufficiency of a non‐linked gene SUPT5H on chromosome 19q, first described in two Dutch families with β‐thalassemia trait without variants in the HBB gene.

Whole-exome analysis of 177 pediatric patients with undiagnosed diseases

Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24–35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.