Paternal Uniparental Isodisomy Research Articles

Kagami Ogata syndrome: a small deletion refines critical region for imprinting

Kagami–Ogata syndrome is a rare imprinting disorder and its phenotypic overlap with multiple different etiologies hampers diagnosis. Genetic etiologies include paternal uniparental isodisomy (upd(14)pat), maternal allele deletions of differentially methylated regions (DMR) in 14q32.2 or pure primary epimutations. We report a patient with Kagami–Ogata syndrome and an atypical diagnostic odyssey with several negative standard-of-care genetic tests followed by epigenetic testing using methylation microarray and a targeted analysis of whole-genome sequencing to reveal a 203 bp deletion involving the MEG3 transcript and MEG3:TSS-DMR. Long-read sequencing enabled the simultaneous detection of the deletion, phasing, and biallelic hypermethylation of the MEG3:TSS-DMR region in a single assay. This case highlights the challenges in the sequential genetic testing paradigm, the utility of long-read sequencing as a single comprehensive diagnostic assay, and the smallest reported deletion causing Kagami–Ogata syndrome allowing important insights into the mechanism of imprinting effects at this locus.

Severe Congenital Neutropenia-Type 5: Impaired T Cell Proliferation, Aberrant Th1 Cytokine Production, Abnormal Megakaryocytes, and Impaired Platelet Granule Formation in a Patient with VPS45 Deficiency Caused By Uniparental Isodisomy

Introduction VPS45 is essential in early endosome formation with rabenosyn-5 and syntaxin 16. VPS45 deficiency is one of the inborn errors of immunity characterized by severe congenital neutropenia and myelofibrosis. Impaired production and function of neutrophils, increased cell death, and abnormal hematopoiesis have been reported, whereas there are several undetermined pathophysiologies, such as T and/or NK lymphopenia or myelofibrosis. Here, we experienced a girl with VPS45 deficiency presenting with neutropenia at birth, progressive T and NK lymphopenia, hepatosplenomegaly, and myelofibrosis in infancy. We examined the pathophysiology of VPS45 deficiency focusing on hematologic disorder, T cell function, and myelofibrosis. Methods We sequentially evaluated peripheral blood and bone marrow cell counts and morphologic features. Genetic analysis was performed using DNA from peripheral blood. We evaluated T cell proliferation using the CFDA-SE cell tracer kit with the stimulation of PHA-L or anti-CD3/CD28 beads. Serum cytokine analysis was performed by beads array. Protein expression was examined in platelets from the patient and the healthy control by western blot analysis. Results Case: The patient was born to nonconsanguineous Japanese parents. She received a blood examination for mild respiratory distress at birth. This examination demonstrated neutropenia, the emergence of myeloid cells, and nucleated red blood cells in the peripheral blood, whereas mature neutrophils were confirmed in the bone marrow. Genetic analysis demonstrated homozygous pathogenic variants of p.E238K in VPS45. The same heterozygous variant was confirmed in her father, but not in her mother. SNP array analysis demonstrated that she inherited chromosome 1 only from her father and developed VPS45 deficiency by paternal uniparental isodisomy. At 7 months, she demonstrated T and NK lymphocytopenia, macrothrombocytopenia, and hepatosplenomegaly. Bone marrow examination demonstrated the presence of blast cells, micro or separated megakaryocytes, and pseudo-Pelger-Huet anomaly. Electronic microscopy of peripheral blood demonstrated abnormal granules in neutrophils and macro-thrombocytes with reduced alpha granules and open channel enlargement. Elevated interferon-gamma, IL-12, and IL-23 levels, representing T helper 1 (Th1) activation were found. We initiated ruxolitinib at 7 months to suppress aberrant Th1 activation and extra-medullar hematopoiesis which could be associated with massive hepatosplenomegaly. Ruxolitinib was effective for hepatosplenomegaly and reduced Th1 cytokine levels without significant complications. She received hematopoietic cell transplantation with bone marrow from an HLA-matched unrelated donor 30 days after the initiation of ruxolitinib. T cell function: With anti-CD3/CD28 beads stimulation, the patient's CD8-positive cells were significantly less proliferative. Either CD4-positive or CD8-positive cells did not proliferate with PHA-L stimulation. Platelet analysis: Western blot analysis of platelet demonstrated a reduced amount of alpha granule proteins (von Willebrand factor and PF4), not of p-selectin. Discussion VPS45 deficiency was characterized by severe congenital neutropenia and myelofibrosis. Furthermore, T cell deficiency, especially CD8-positive T lymphopenia was observed in some patients with VPS45 deficiency. Our study suggested that T cell lymphopenia would be associated with impaired TCR signaling and mitogen response, although the detailed mechanism remains to be elucidated. The impaired platelet alpha granule formation confirmed by electron microscopy and western blot analysis in our patients was compatible with the previous VPS45 deficiency patient. A similar manifestation is observed in gray platelet syndrome which is also associated with affected endosomal transport. Affected endosomal transport would be responsible for myelofibrosis. We hypothesized that massive hepatosplenomegaly was attributable to the hyper-activated Th1 cells and extra-medullar hematopoiesis associated with JAK1 and JAK2 signaling. Indeed, JAK1/ JAK2 inhibitor, ruxolitinib improved hepatosplenomegaly in this patient. Conclusion VPS45 deficiency could broadly affect not only neutropenia and myelofibrosis but T cell, NK cell, megakaryocyte, and platelet function.

(Epi)genotype and Timing of Tongue Reduction Predict Safety and Long-Term Outcomes in Beckwith-Wiedemann Syndrome.

Macroglossia is a cardinal feature of Beckwith-Wiedemann syndrome (BWS) with a clinical spectrum where the indication and timing for surgery remain to be validated. This study leverages a cohort of molecularly characterized patients with BWS to correlate epigenetic diagnosis with phenotype and treatment outcome. Patients with BWS seen in consultation for macroglossia from 2009-2022 were reviewed for phenotype, molecular diagnosis, tongue reduction status, timing of surgery (early = under 12 months), and perioperative complications. Two hundred thirty-seven patients were included. Imprinting control region 2 loss of methylation (IC2 LOM) was the most common epigenotype (61%). Paternal uniparental isodisomy for chromosome 11 (pUPD11) comprised a larger proportion of patients undergoing tongue reduction (18%) than those not undergoing surgery (8%, p = 0.024) and was associated with need for repeat surgery (OR 4.49, 95% CI 1.06-18.98, p = 0.041). Complications including wound dehiscence, ventilator associated pneumonia, and unplanned extubation were more common in patients undergoing early surgery (20%) than late surgery (4%, OR 5.70, 95% CI 1.14-28.55, p = 0.034). This study presents one of the largest cohorts correlating molecular diagnosis with clinical course of macroglossia treatment in BWS. Macroglossia in patients with pUPD11 is associated with higher rates of reoperation. Relief of obstructive sleep apnea with early tongue reduction must be weighed against risk of perioperative complications, most of which are non-surgical. This study highlights how molecular diagnosis advances clinical care by risk stratifying clinical outcomes in a center providing integrated multidisciplinary care for the BWS population.

Biallelic KCTD3 nonsense variant derived from paternal uniparental isodisomy of chromosome 1 in a patient with developmental epileptic encephalopathy and distinctive features

A biallelic nonsense variant of the potassium channel tetramerization domain-containing protein 3 gene (KCTD3) [c.1192C>T; p.R398*] was identified in a patient with developmental epileptic encephalopathy with distinctive features and brain structural abnormalities. The patient showed isodisomy of chromosome 1, where KCTD3 is located, and the father was heterozygous for the same variant. Based on these findings, paternal uniparental disomy was considered to cause the biallelic involvement of KCTD3.

Associations between the timing of tongue reduction surgery, (Epi)genotype, and dentoskeletal development in patients with Beckwith-Wiedemann syndrome

Tongue reduction surgery is often pursued to manage the adverse effects of macroglossia in patients with Beckwith-Wiedemann syndrome (BWS). This study characterized dental outcomes in patients with BWS based on surgical timing and molecular diagnosis. A retrospective study was designed to include patients with BWS over the age of two who had clinical or radiographic documentation of dental development. Patients were grouped by history of tongue reduction surgery and surgical timing (early: <12 months). One hundred three patients were included (55 no tongue reduction, 18 early, 30 late). Patients who underwent late surgery had lower odds of class I occlusion (OR 0.11, 95% CI 0.02–0.58, p = 0.009) and higher odds of anterior open bite (OR 7.5, 95% CI 1.14–49.4, p = 0.036). Patients with clinical diagnoses and negative molecular testing had anterior open bite less frequently than patients with imprinting center 2 loss of methylation and paternal uniparental isodisomy of 11p15.5 (p = 0.009). Compared to reference values, patients who had tongue reductions had an increased mandibular plane angle (32.0 ± 4.5° versus 36.9 ± 5.0°, p = 0.001), indicative of hyperdivergent growth. The results of this study help to understand the complex nature of dentoskeletal growth in BWS and shed insight on how surgical timing and molecular diagnosis influence prognosis.

Paternal Uniparental Isodisomy of Chromosome 2 in a Patient with Congenital Hypothyroidism: Ruling Out Recessive Inheritance or a Kinship/Laboratory Sequencing Error.

Paternal Uniparental Isodisomy of Chromosome 2 in a Patient with Congenital Hypothyroidism: Ruling Out Recessive Inheritance or a Kinship/Laboratory Sequencing Error.

Occurrence of Hepatoblastomas in Patients with Beckwith-Wiedemann Spectrum (BWSp).

Patients with Beckwith-Wiedemann syndrome (BWS), an epigenetic imprinting disorder involving alterations in genes at the 11p15 chromosomal location, are predisposed to develop hepatoblastomas (HBs), which are rare embryonal liver tumors. Tumors can develop after a BWS diagnosis or, conversely, can be the presenting feature leading to a subsequent diagnosis. While HBs are the cardinal tumors of BWS, not all patients with the BWS spectrum will develop HBs. This observation has led to many hypotheses, including genotype-associated risk, tissue mosaicism, and tumor-specific second hits. To explore these hypotheses, we present the largest cohort of patients with BWS and HBs to date. Our cohort comprised 16 cases, and we broadened our sample size by searching the literature for all cases of BWS with HBs. From these isolated case studies, we amassed another 34 cases, bringing the total number to 50 cases of BWS-HB. We observed that paternal uniparental isodisomy (upd(11)pat) was the most common genotype, representing 38% of cases. The next most common genotype was IC2 LOM, representing 14% of cases. Five patients had clinical BWS without a molecular diagnosis. To investigate the potential mechanism of HBs in BWS, we analyzed normal liver and HB samples from eight cases and isolated tumor samples from another two cases. These samples underwent methylation testing, and 90% of our tumor samples underwent targeted cancer next-generation sequencing (NGS) panels. These matched samples provided novel insights into the oncogenesis of HBs in BWS. We found that 100% of the HBs that underwent NGS panel testing had variants in the CTNNB1 gene. We further identified three distinct groups of BWS-HB patients based on epigenotype. We also demonstrated epigenotype mosaicism, where 11p15 alterations can differ between the blood, HB, and normal liver. In light of this epigenotype mosaicism, tumor risk assessment based on blood profiling may not be accurate. Therefore, universal screening is recommended for all patients with BWS.

Large heterozygous deletion and uniparental disomy masquerading as homozygosity in CHKB gene.

CHKB mutations have been described in 49 patients with megaconial congenital muscular dystrophy, which is a rare autosomal recessive disorder, of which 40 patients showed homozygosity. Peripheral blood genomic DNA samples were extracted from patients and their parents and were tested by whole exome sequencing. Quantitative PCR was performed to detect deletion. Single nucleotide polymorphism analysis was performed to identify uniparental disomy. Quantitative PCR and western blot were used to measure the expression level of CHKB in patient 1-derived immortalized lymphocytes. Mitochondria were observed in lymphocytes by electron microscopy. Two unrelated cases born to non-consanguineous parents were diagnosed with megaconial congenital muscular dystrophy due to apparently homozygous mutations (patient 1: c.225-2A>T; patient 2: c.701C>T) in the CHKB gene using whole exome sequencing. Quantitative PCR revealed that patient 1 had a large deletion encompassing the CHKB gene, inherited from the mother. Single nucleotide polymorphism analysis revealed patient 2 had paternal uniparental isodisomy containing the CHKB gene. In the immortalized lymphocytes from patient 1, decreased expression of CHKB was revealed by quantitative PCR and western blot, and giant mitochondria were observed using electron microscopy. We provide a possibility to detect giant mitochondria in other cells when muscle was not available. Moreover, clinicians should be aware that homozygous variants can be masqueraded by uniparental disomy or large deletions in offspring of non-consanguineous parents, and excessive homozygosity may be misdiagnosed.

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.

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 case report of complete paternal isodisomy of chromosome 10 harbouring a novel variant in COL17A1 that causes junctional epidermolysis bullosa intermediate

BackgroundUniparental disomy (UPD) is a condition in which both chromosomes are inherited from the same parent, except for imprinting disorders. Uniparental isodisomy (UPiD) may result in a homozygous variant contributing to an autosomal recessive disorder in the offspring of a heterozygous carrier. Junctional epidermolysis bullosa intermediate (JEB intermediate) is an autosomal recessive inherited disease that is associated with a series of gene variants, including those of COL17A1.Case presentationWe report the first case of complete paternal UPiD of chromosome 10 harbouring a novel homozygous variant in COL17A1: c.1880(exon23)delG (p.G627Afs*56). This variant led to the clinical phenotype of junctional epidermolysis bullosa intermediate in a 5-year-old child. Trio-whole exome sequencing (Trio-WES) and in silico data analysis were used for variant identification, Sanger sequencing was performed for variant validation, and pathological examination was performed as the gold standard for phenotype confirmation.ConclusionsWe recommend the use of WES as a first-tier test for the diagnosis of epidermolysis bullosa, especially for paediatric patients. Moreover, UPD events should be detected and analysed routinely through WES data in the future.

Maxillo-Facial Morphology in Beckwith-Wiedemann Syndrome: A Preliminary Study on (epi)Genotype-Phenotype Association in Caucasians.

Beckwith–Wiedemann syndrome (BWS) is a congenital overgrowth disorder caused by various (epi)genetic alterations affecting the expression of genes on chromosome 11p15. Cardinal features include abdominal wall defects, macroglossia, and cancer predisposition. Several (epi)genotype–phenotype associations were described so far, but specific studies on the evolution over time of maxillo-facial phenotype in the molecular subtypes still are scanty. The aim of this cross-sectional study was to associate maxillo-facial morphology and growth pattern with genoype in 25 Caucasian children with BWS and macroglossia. Twelve patients experienced a loss of metilation at imprinting center 2 (IC2-LoM), five had mosaic paternal uniparental isodisomy of chromosome 11 (UPD(11)pat), and eight were negative. A more marked tongue enlargement was detected in patients with IC2-LoM and negative genotype, while UPD(11)pat children showed mild macroglossia (p = 0.048). A cluster analysis did not demonstrate any specific relationship between (epi)genotype and maxillo-facial phenotype, but separated BWS patients based on their cephalometric characteristics. Children with IC2-LoM or negative genotype displayed hyperdivergence values > 30°, clockwise growth tendency, and skeletal class II into the same cluster. They had a negative prognostic score. These preliminary data suggest the need for developing individualized protocols for early monitoring of the craniofacial growth in such patients.

Follow-up for a Preterm Infant with Beckwith-Wiedemann Syndrome.

Follow-up for a Preterm Infant with Beckwith-Wiedemann Syndrome.

Prenatal diagnosis of complete paternal uniparental isodisomy for chromosome 3: a case report

BackgroundUniparental disomy (UPD) is defined as an inheritance of two chromosomes from only one of the parents with no representative copy from the other. Paternal-origin UPD of chromosome 3 is a very rare condition, with only five cases of paternal UPD(3) reported.Case presentationHere, we report a prenatal case that is only the second confirmed paternal UPD(3) reported with no apparent disease phenotype. The fetus had a normal karyotype and normal ultrasound features throughout gestation. Copy neutral regions of homozygosity on chromosome 3 were identified by single nucleotide polymorphism (SNP) array. Subsequent SNP array data of parent–child trios showed that the fetus carried complete paternal uniparental isodisomy (isoUPD) of chromosome 3. The parents decided to continue with the pregnancy after genetic counseling, and the neonate had normal physical findings at birth and showed normal development after 1.5 years.ConclusionsThese findings provided further evidence to confirm that there were no important imprinted genes on paternal chromosome 3 that caused serious diseases and a reference for the prenatal diagnosis and genetic counseling of UPD(3) in the future.

Double paternal uniparental isodisomy 7 and 15 presenting with Beckwith-Wiedemann spectrum features.

Here we describe for the first time double paternal uniparental isodisomy (iUPD) 7 and 15 in a baby boy with features in the Beckwith–Wiedemann syndrome spectrum (BWSp) (placentomegaly, hyperinsulinism, enlarged viscera, hemangiomas, and earlobe creases) in addition to conjugated hyperbilirubinemia. His phenotype was also reminiscent of genome-wide paternal uniparental isodisomy. We discuss the most likely origin of the UPDs: a maternal double monosomy 7 and 15 rescued by duplication of the paternal chromosomes after fertilization. So far, paternal UPD7 is not associated with an abnormal phenotype, whereas paternal UPD15 causes Angelman syndrome. Methylation analysis for other clinically relevant imprinting disorders, including BWSp, was normal. Therefore, we hypothesized that the double UPD affected other imprinted genes. To look for such effects, patient fibroblast RNA was isolated and analyzed for differential expression compared to six controls. We did not find apparent transcription differences in imprinted genes outside Chromosomes 7 and 15 in patient fibroblast. PEG10 (7q21.3) was the only paternally imprinted gene on these chromosomes up-regulated beyond double-dose expectation (sixfold). We speculate that a high PEG10 level could have a growth-promoting effect as his phenotype was not related to aberrations in BWS locus on 11p15.5 after DNA, RNA, and methylation testing. However, many genes in gene sets associated with growth were up-regulated. This case broadens the phenotypic spectrum of UPDs but does not show evidence of involvement of an imprinted gene network.

Prenatal molecular testing and diagnosis of Beckwith-Wiedemann syndrome.

The objective of this study was to describe molecular findings and phenotypic features among individuals referred for prenatal Beckwith-Wiedemann syndrome (BWS) testing. Molecular diagnostic testing was performed using a sensitive quantitative real-time PCR-based assay capable of detecting mosaic methylation to the level of 3% at IC1 and IC2. Sanger sequencing of CDKN1C was performed in cases with normal methylation. Of the 94 patients tested, a molecular diagnosis was identified for 25.5% of cases; 70.9% of diagnosed cases had loss of methylation at IC2, 4.2% had gain of methylation at IC1, 12.5% had paternal uniparental isodisomy, and 12.5% had CDKN1C loss-of-function variants. Methylation level changes in prenatal cases were significantly greater than changes identified in cases tested after birth. Cases with a prenatal molecular diagnosis had a significantly greater number of BWS-associated phenotypic features. The presence of either macroglossia or placentomegaly was most predictive of a BWS diagnosis. Our results support the consensus statement advocating BWS molecular testing for all patients with one or more BWS-associated prenatal features and suggest that low-level mosaic methylation changes may be uncommon among prenatal BWS diagnoses.

Molecular Definition of Pseudohypoparathyroidism Variants.

Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several differentially methylated regions (DMRs). GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. PHP type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal exons 1-13. Heterozygosity of these maternal GNAS mutations cause PTH-resistant hypocalcemia and hyperphosphatemia because paternal Gsα expression is suppressed in certain organs thus leading to little or no Gsα protein in the proximal renal tubules and other tissues. Besides biochemical abnormalities, PHP1A patients show developmental abnormalities, referred to as Albright’s hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who carry paternal Gsα-specific mutations and typically show no laboratory abnormalities. Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss of methylation at the A/B DMR alone or at all maternally methylated GNAS exons. Loss of methylation of exon A/B and the resulting biallelic expression of A/B transcript reduces Gsα expression thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, which is the most frequent PHP1B variant. However, this disease variant remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q).

Uniparental isodisomy as a cause of mitochondrial complex I respiratory chain disorder due to a novel splicing NDUFS4 mutation

Uniparental disomy (UPD) is an underestimated cause of autosomal recessive disorders. In this study, we aim to raise awareness about the possibility of UPD in mitochondrial disorders - where it is a hardly described event -, by functionally characterizing a novel variant in a structural subunit of complex I (CI) of the mitochondrial oxidative phosphorylation system.Using next-generation sequencing, we identified a new intronic homozygous c.350 + 5G > A variant in the NDUFS4 gene in a one-year-old girl (being alive at the age of 7) belonging to a non-consanguineous family presenting with encephalopathy, psychomotor delay, lactic acidosis and a single CI deficiency, a less severe phenotype than those previously reported in most NDUFS4 patients. One parent lacked the variant, and microsatellite genotyping showed complete paternal uniparental isodisomy of the non-imprinted chromosome 5.We demonstrated in patient's skeletal muscle and fibroblasts splicing abnormalities, low expression of NDUFS4, undetectable NDUFS4 protein, defects in cellular respiration (decreased oxygen consumption and ATP production), and impaired assembly or stability of mitochondrial supercomplexes containing CI.Our findings support that c.350 + 5G > A variant is pathogenic, and reinforce that UPD, although rare, should be considered as a possible cause of mitochondrial diseases in order to provide accurate genetic counselling.

Phenotypes and epigenetic errors in patients with Beckwith-Wiedemann syndrome in China.

BackgroundBeckwith-Wiedemann syndrome (BWS) is primarily caused by epigenetic errors. This study aimed to analyze the relationship between the epigenetic errors and phenotypes of BWS and to evaluate the efficacy of diagnosing BWS using patients’ clinical characteristics.MethodsPatients clinically diagnosed with BWS were subjected to methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) for (epi)genotyping. The patients’ clinical characteristics were analyzed and compared using regression models. The diagnostic efficacy of previous criteria and scoring systems was compared using area under the receiving operating curve (ROC).ResultsThe most common clinical features observed in BWS patients were macroglossia (83.2%), abdominal wall defects (71.3%), and ear creases/pits (55.3%). Patients with the loss of methylation at imprinting control 2 (IC2-LOM) and gaining of methylation at imprinting control 1 (IC1-GOM) subtypes had significantly higher frequencies of ear creases/pits and facial nevus flammeus, and visceromegaly, respectively. Paternal uniparental isodisomy (pUPD) was characterized by significantly less macroglossia but more hemihypertrophy. The area under the curve (AUC) was comparably good in both recently developed scoring systems (0.87 for Ibrahim and 0.82 for Brioude.) and in the scoring system developed using the current cohort (0.88).ConclusionsThis study, which is the largest cohort study of BWS cases in China published to date, confirmed the diagnostic efficacy of a recently developed symptom-based BWS scoring system in a Chinese population. Significant differences exist between the phenotypes of BWS epigenetic subtypes; however, the pattern is similar between Asian and European populations.

Warburg Micro Syndrome 1 due to Segmental Paternal Uniparental Isodisomy of Chromosome 2 Detected by Whole-Exome Sequencing and Homozygosity Mapping

Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by microcephaly, cortical dysplasia, intellectual disability, ocular abnormalities, spastic diplegia, and microgenitalia. WARBM has 4 subtypes arising from pathogenic variants in 4 genes (RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20). Here, we report on a patient with a homozygous pathogenic c.665delC (p.Pro222HisfsTer30) variant in the RAB3GAP1 gene identified by whole-exome sequencing (WES) analyses. Only his father was a heterozygous carrier, and homozygosity mapping analysis of the WES data revealed large loss-of-heterozygosity regions in both arms of chromosome 2, interpreted as uniparental isodisomy. This uniparental disomy pattern could be due to paternal meiosis I nondisjunction because of the preserved heterozygosity in the pericentromeric region. This report provides novel insights, including a rare form of UPD, usage of homozygosity mapping analysis for the evaluation of isodisomy, and the first reported case of WARBM1 as a result of uniparental isodisomy.