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Background: Uniparental isodisomy (UPiD) refers to a condition, in which both homologous chromosomes are inherited from only one parental homolog, which can result in either imprinting disorders or autosomal recessive conditions., Methods: We performed chromosomal microarray analysis, exome sequencing (ES), and RNA sequencing (RNA-seq) using the patient's urine-derived cells on a patient with growth retardation and multiple congenital anomalies., Results: We identified a homozygous ~0.53 kb microdeletion at 5q12.1, which was transmitted from the father with paternal UPiD(5). The deletion encompassed the first exon of both the ERCC8 and NDUFAF2 genes, which are responsible for Cockayne syndrome (CS) and mitochondrial complex I deficiency, respectively. Furthermore, RNA-seq confirmed the reduced expression of both genes. Indeed, in addition to clinical features common to both syndromes, such as growth retardation, developmental delay, and feeding difficulties, the patient exhibited blended phenotypes: the characteristic features of CS, including arthrogryposis, microcephaly, and facial dysmorphisms, and those of mitochondrial complex I deficiency, including high serum lactate levels and lethal apnea resulting in a severe clinical course., Conclusion: The results imply that ES in combination with RNA-seq could be a powerful method for the detection of underlying factors responsible for rare genetic conditions, such as UPD., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Near the C-terminus of histone H2A in the yeast S. cerevisiae, there are two serines (S122 and S129) that are targets of phosphorylation. The phosphorylation of Serine 129 in response to DNA damage is dependent on the Tel1 and Mec1 kinases. In S. pombe and S. cerevisiae, the phosphorylation of Serine 122 is dependent on the Bub1 kinase, and S. pombe strains with an alanine mutation of this serine have elevated levels of lagging chromosomes in mitosis. Strains that lack both Tel1 and Mec1 in S. cerevisiae have very elevated rates of non-disjunction. To clarify the functional importance of phosphorylation of serines 122 and 129 in H2A, we measured chromosome loss rates in single mutant strains and double mutant combinations. We also examined the interaction of mutations of BUB1, TEL1, and MEC1 in combination with mutations of serine 122 and 129 in H2A. We conclude that the phosphorylation state of S129 has no effect on chromosome disjunction whereas mutations that inactivate Bub1 or a S122A mutation in the histone H2A greatly elevate the rate of chromosome non-disjunction. Based on this analysis, we suggest that Bub1 exerts its primary effect on chromosome disjunction by phosphorylating S122 of histone H2A. However, Tel1, Mec1 and Bub1 also functionally redundant in a second pathway affecting chromosome disjunction that is at least partially independent of phosphorylation of S122 of H2A., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Background: Tetralogy of Fallot (TOF) and hypertrophic cardiomyopathy (HCM) are common types of congenital heart disease with unique pathophysiologic features. Mutations in LBX1, a key regulator of muscle precursor cell migration, may disrupt these critical developmental processes, resulting in severe developmental abnormalities., Case Presentation: This case reports on a 4-year-old girl diagnosed with both TOF and HCM. Genetic analysis revealed iUPI-F (uniparental disomy) on the entire chromosome 10, with a c.808G > A (p. Glu270Lys) pure mutation in the LBX1., Conclusion: This patient exhibited both TOF and HCM with mutations in the LBX1 gene, suggesting a potentially novel genetic link. This case study emphasizes the need for further studies on the function of the LBX1 gene in cardiac development and its potential impact on TOF and HCM., (© 2024. The Author(s).)

Alazami syndrome is an autosomal recessive disease characterized by global developmental delay, growth restriction, and distinctive facial features. Fewer than 50 individuals are currently reported with biallelic loss of function variants in LARP7. We report the case of a 3.5-year-old boy born from nonconsanguineous parents, presenting with syndromic global developmental delay. Exome sequencing identified a homozygous frameshift pathogenic variant in LARP7. Parental analysis failed to detect the variant in the paternal sample, although the father's biological paternity was confirmed. Targeted secondary bioinformatic analyses at the LARP7 locus suggested a 45 Mb loss of heterozygosity (LOH), further confirmed by a single nucleotide polymorphism array that identified four LOH regions on chromosome 4, including one encompassing LARP7. This LOH exposes the recessive LARP7 pathogenic variant, resulting in the manifestation of Alazami syndrome. To our knowledge, this is the first reported case of Alazami syndrome due to uniparental disomy (UPD). UPD is a rare cause of autosomal recessive disorders. Its identification is crucial for genetic counseling to adjust recurrence risk for siblings. This case highlights the effectiveness and usefulness of bioinformatics algorithms applied to next generation sequencing in detecting such events., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of maternal UBE3A. The major cause of AS is a maternal deletion in 15q11.2-q13, and the minor causes are a UBE3A mutation, uniparental disomy (UPD), and imprinting defect (ID). Previous reports suggest that all patients with AS exhibit developmental delay, movement or balance disorders, behavioral characteristics, and speech impairment. In contrast, a substantial number of AS patients with a UBE3A mutation, UPD, or ID were reported not to show these consistent features and to show age-dependent changes in their features. In this study, we investigated 134 patients with AS, including 57 patients with a UBE3A mutation and 48 patients with UPD or ID. Although developmental delay was present in all patients, 20% of patients with AS caused by UPD or ID did not exhibit movement or balance disorders. Differences were also seen in hypopigmentation and seizures, depending on the causes. Moreover, patients with a UBE3A mutation, UPD, or ID tended to show fewer of the specific phenotypes depending on their age. In particular, in patients with UPD or ID, easily provoked laughter and hyperactivity tended to become more pronounced as they aged. Therefore, the clinical features of AS based on cause and age should be understood, and genetic testing should not be limited to patients with the typical clinical features of AS., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Short stature is a complex disorder with phenotypic and genetic heterogeneity. This study aimed to investigate clinical phenotypes and molecular basis of a cohort of patients with short stature., Methods: Trio whole-exome sequencing (Trio-WES) was performed to explore the genetic aetiology and obtain a molecular diagnosis in twenty Chinese probands with syndromic and isolated short stature., Results: Of the twenty probands, six (6/20, 30%) patients with syndromic short stature obtained a molecular diagnosis. One novel COMP pathogenic variant c.1359delC, p.N453fs*62 and one LZTR1 likely pathogenic variant c.509G>A, p.R170Q were identified in a patient with short stature and skeletal dysplasia. One novel de novo NAA15 pathogenic variant c.63T>G, p.Y21X and one novel de novo KMT2A pathogenic variant c.3516T>A, p.N1172K was identified in two probands with short stature, intellectual disability and abnormal behaviours, respectively. One patient with short stature, cataract, and muscle weakness had a de novo POLG pathogenic variant c.2863 T>C, p.Y955H. One PHEX pathogenic variant c.1104G>A, p.W368X was identified in a patient with short stature and rickets. Maternal uniparental disomy 7 (mUPD7) was pathogenic in a patient with pre and postnatal growth retardation, wide forehead, triangular face, micrognathia and clinodactyly. Thirteen patients with isolated short stature had negative results., Conclusion: Trio-WES is an important strategy for identifying genetic variants and UPD in patients with syndromic short stature, in which dual genetic variants are existent in some individuals. It is important to differentiate between syndromic and isolated short stature. Genetic testing has a high yield for syndromic patients but low for isolated patients., Competing Interests: Author GZ was employed by Beijing Chigene Translational Medical Research Center Company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sun, Zhang, Li and Bu.)

Chromosomal microarrays (CMA) incorporate single nucleotide polymorphisms to enable the detection of regions of homozygosity (ROH). Here, we retrospectively analyzed 6288 prenatal cases who performed CMA to explored the clinical implications of large ROH in prenatal diagnosis. We analyzed cases with ROH larger than 10 megabases and reviewed the ultrasound findings; karyotype results and pregnancy follow-up data. Cases with possible imprinting disorders were assessed by methylation-specific multiplex ligation-dependent probe amplification. In total, we identified 50 cases with large ROH and chromosomes 1 and 2 were the most affected. About 59.18% of the ROH cases had ultrasound abnormalities, with the most common findings being ultrasound soft-marker abnormalities. There were seven fetuses had ROH which covered almost the entire chromosome and four had terminal ROH that involved almost the entire long arm of the chromosomes, which indicated uniparental disomy (UPD), of which 70% showed abnormal ultrasound findings. Ten cases with multiple ROH on different chromosomes indicated the third to fifth degree of consanguinity. In this study, we highlighted the clinical relevance of large ROH related to UPD. The analysis of ROH allowed us to gain further understanding of complex cytogenetic and disease mechanisms in prenatal diagnosis., (© 2024 Wiley Periodicals LLC.)

Purpose: Lipopolysaccharide-responsive beige-like anchor protein (LRBA) encodes a widely expressed cytosolic protein that participates in polarized vesicle trafficking. Homozygous loss-of-function LRBA mutations can lead to immune deficiency due to the lack of immune regulation, classified as a part of Tregopathies. We present a case of a 49-year-old female, with polyarthralgia in metacarpophalangeal and proximal interphalangeal joints bilaterally, and morning stiffness, leading to the diagnosis of rheumatoid arthritis treated with pulse steroid therapy. She had experienced sepsis and in-depth scrutiny revealed panhypogammaglobulinemia. After being referred to the immunology clinic, she was followed under the diagnosis of common variable immunodeficiency (CVID)-like inborn errors of immunity (IEI)., Methods and Results: Physical examination and diagnostic follow-up revealed massive splenomegaly accompanied by portal hypertension, and ulcerations in the colon. She also presented with periodic hematuria and dysuria. Cystoscopic biopsy revealed mast cell-derived interstitial cystitis which has not been previously reported in LRBA deficiency in the literature to our knowledge. A multi-gene next-generation sequencing panel performed for immune deficiencies (264 genes and 524 amplicons), resulted in the identification of an apparently homozygous LRBA mutation (p.Arg722His) in the Beige and Chediak-Higashi (BEACH) domain. The SNP array showed copy neutral absence of heterozygosity of the entire chromosome 4, which is consistent with uniparental isodisomy of chromosome 4., Conclusion: In conclusion, this case study underscores the critical role of LRBA in immune regulation and highlights the clinical heterogeneity associated with LRBA deficiency. The patient's presentation with severe immune dysregulation, including massive splenomegaly, portal hypertension, and the novel finding of mast cell-derived interstitial cystitis, expands the clinical spectrum of LRBA mutations. The identification of an apparently homozygous LRBA mutation via next-generation sequencing further emphasizes the importance of genetic analysis in diagnosing monogenic defects manifested as CVID-like phenotype. This is the first reported case of LRBA deficiency due to whole chromosome UPD to our knowledge. Future research should focus on elucidating the full range of clinical manifestations and developing targeted therapies for patients with LRBA deficiency., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Competing interests: The authors declare no conflict of Interest.

Uniparental disomies (UPD) refers to the inheritance of both homologs of a chromosome from only one parent with no representative copy from the other parent. UPD was with an estimated prevalence of 0.15‰ in population. Current understanding of UPD was limited to subjects for which UPD was associated with clinical manifestation due to imprinting disorders or recessive diseases. Segmental UPD was rare, especially for a segmental UPD with a combination of hetero- and isodisomy. This paper presents a couple with reciprocal translocation 46,XY, t(14;22)(q32.3;q12.2) for PGT-SR. Among 8 biopsied blastocysts, one euploid blastocyst (No.4) with segmental loss of heterozygosity (LOH)(22) [arr[hg19] q12.1q22.3 (28,160,407 - 35,407,682)] was detected by B allele frequency. We found the chromosome contained both UPiD(22) [arr[hg19] q12.1q22.3 (28,160,407 - 35,407,682) ×2 hmz mat] and UPhD(22) [arr[hg19] q22.3qter(35,407,682 - 51,169,045) ×2 htz mat] by haplotype analysis. UPDtool software confirmed the result. What's more, the segmental UPD and reciprocal translocation shared the same breakpoint, chr22q12.1 (28,160,407), while the breakpoint between iso- and heterodisomy was chr22q22.3 (35,407,682). We reported the first segmental UPD with a combination of hetero- and isodisomy, which may result from aneuploidy rescue. This case emphasizes the importance of the combination of comprehensive chromosome screening and haplotype analysis to reduce the risk of misdiagnosis., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Kagami-Ogata syndrome (KOS) is a clinically recognizable syndrome in the neonatal period. It is characterized by specific skeletal anomalies and facial dysmorphisms. It is typically caused by paternal uniparental disomy of chromosome 14, while epimutations and microdeletions are less commonly reported causes. In the pediatric setting, KOS is a well delineated syndrome. However, there is a dearth of literature describing the natural history of the condition in adults. Herein, we describe a 35-year-old man, the first adult with KOS reported due to paternal uniparental disomy 14, and review reports of KOS in other affected adults. This highlights the variability in neurocognitive phenotypes, the presence of connective tissue abnormalities, and the uncertainties around long-term cancer risk., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

D-bifunctional protein (DBP) deficiency, a fatal peroxisomal enzyme disorder, typically manifests with life-threatening symptoms in the first two years of childhood. We present the case of an infant with elevated lysophosphatidylcholine C26:0 (C26:0-LPC) levels identified during X-linked adrenoleukodystrophy (ALD) screening, leading to a diagnosis of DBP deficiency due to a homozygous HSD17B4 c.1041T>A, p.(Tyr347Ter) variant. Starting at two months of age, the infant experienced seizures, hypotonia, and developmental delays, prompting the initiation of experimental treatment with the readthrough agent PTC124 (ataluren) at six months. The treatment led to a decrease in C26:0-LPC levels from 0.65 μM to 0.53 μM; concomitant fish oil supplementation transiently increased C26:0-LPC to 0.74 μM before returning to 0.53 μM after cessation of supplementation. The patient demonstrated improved swallowing and progressive motor and speech development during a two-year treatment period, with no further seizures. This case report highlights the potential of nonsense readthrough therapy for peroxisomal disorders, a group of metabolic diseases that currently lack targeted treatments., Competing Interests: The authors declare that they have no conflicts of interest., (© 2024 The Authors.)

Background: Mucopolysaccharidosis type I (MPS-I) is a rare autosomal recessive genetic lysosomal storage disorder that is caused by pathogenic variants of the α-L-iduronidase (IDUA) gene. This study aimed to identify the genetic causes of MPS-I in a Chinese patient and construct a minigene of IDUA to analyze its variants upon splicing., Methods: Whole-exome sequencing (WES) and Sanger sequencing were used to confirm the potential causative variants. Single-nucleotide polymorphism (SNP) array was subsequently performed to confirm uniparental disomy (UPD). Minigene assay was performed to analyze the effect on splicing of mRNA. We meanwhile explored the conservative analysis and protein homology simulation., Results: A novel homozygous splicing mutation of IDUA, c.159-9T>A, was identified in an individual presenting with overlapping features of MPS-I. Interestingly, only the father and sisters, but not the mother, carried the variant in a heterozygous state. WES and SNP array analyses validated paternal UPD on chromosome 4. Minigene splicing revealed two aberrant splicing events: exon 2 skipping and intron 1 retention. Moreover, the specific structure of the mutant protein obviously changed according to the results of the homologous model., Conclusions: This study describes a rare autosomal recessive disorder with paternal UPD of chromosome 4 leading to the homozygosity of the IDUA splicing variant in patients with MPS-I for the first time. This study expands the variant spectrum of IDUA and provides insights into the splicing system, facilitating its enhanced diagnosis and treatment., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Uniparental disomy (UPD) is the inheritance of both homologues of a chromosome from only one parent. The detection of UPDs in sequencing data is not well established and a common gap in genetic diagnostics. We applied our in-house UPD detection pipeline to evaluate a cohort of 9212 samples, including multigene panels as well as exome sequencing data in a single, duo or trio constellation. We used the results to inform the design of our publicly available web app altAFplotter. UPDs categorized as heterodisomy, whole chromosome or segmental isodisomy were identified and validated with microsatellites, multiplex ligation-dependent probe amplification as well as Sanger sequencing. We detected 14 previously undiagnosed UPDs including nine isodisomies, four segmental isodisomies as well as one heterodisomy on chromosome 22. We characterized eight findings as potentially causative through homozygous pathogenic variants or imprinting disorders. Overall, our study demonstrates the utility of our UPD detection pipeline with our web app, altAFplotter, to reliably identify UPDs. This not only increases the diagnostic yield of cases with growth and metabolic disturbances, as well as developmental delay, but also enhances the understanding of UPDs that may be relevant for recurrence risks and genetic counseling., (© 2024. The Author(s).)

Objectives: Regions of homozygosity (ROH) could implicate uniparental disomy (UPD) on specific chromosomes associated with imprinting disorders. Though the algorithms for ROH detection in exome sequencing (ES) have been developed, optimal reporting thresholds and when to pursue confirmatory UPD testing for imprinting disorders remain in ambiguity. This study used a data-driven approach to assess optimal reporting thresholds of ROH in clinical practice., Methods: ROH analysis was performed using Automap in a retrospective cohort of 8,219 patients and a prospective cohort of 1,964 patients with ES data. Cases with ROH on imprinting-disorders related chromosomes were selected for additional methylation-specific confirmatory testing. The diagnostic yield, the ROH pattern of eventually diagnosed cases and optimal thresholds for confirmatory testing were analyzed., Results: In the retrospective analysis, 15 true UPD cases of imprinting disorders were confirmed among 51 suspected cases by ROH detection. Pattern of ROH differed between confirmed UPD and non-UPD cases. Maximized yield and minimized false discovery rate of confirmatory UPD testing was achieved at the thresholds of >20 Mb or >25 % chromosomal coverage for interstitial ROH, and >5 Mb for terminal ROH. Current recommendation by ACMG was nearly optimal, though refined thresholds as proposed in this study could reduce the workload by 31 % without losing any true UPD diagnosis. Our refined thresholds remained optimal after independent evaluation in a prospective cohort., Conclusions: ROH identified in ES could implicate the presence of clinically relevant UPD. This study recommended size and coverage thresholds for confirmatory UPD testing after ROH detection in ES, contributing to the development of evidence-based reporting guidelines., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: An investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM#176270) using joint whole genome sequencing (WGS)., Methods: Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected., Results: Results showed maternal isodisomy uniparental disomy (UPD) in chromosome 15, expanding from 15q11.2 to 15q22.2, including PWS regions at 15q11.2-15q13. Maternal heterodisomy was detected from 15q22.2 to 15q26.3. A pathogenic variant, NM_000070.3(CAPN3):c.550del (p.Thr184fs), was identified at 15q15.1 in a heterozygous state in the mother that was homozygous in the proband due to maternal isodisomy., Conclusion: This is the first study of the concurrent molecular etiology of PWS and calpainopathy (OMIM#253600) in the same patient. This report highlights the utility of joint analysis and the need for the assessment of autosomal recessive disease in regions of isodisomy in patients with complex and unexplained phenotypes.

Mosaicism for autosomal trisomy is uncommon in clinical practice. However, despite its rarity among both prenatally and postnatally diagnoses, there are a large number of characterized and published cases. Surprisingly, in contrast to regular trisomies, no attempts at systematic analyses of mosaic carriers' demographics were undertaken. This is the first study aimed to address this gap. For that, we have screened more than eight hundred publications on mosaic trisomies, reviewing data including gender and clinical status of mosaic carriers, maternal age and reproductive history. In total, 596 publications were eligible for analysis, containing data on 948 prenatal diagnoses, including true fetal mosaicism (TFM) and confined placental mosaicism (CPM), and on 318 cases of postnatally detected mosaicism (PNM). No difference was found in maternal age between normal pregnancy outcomes with appropriate birth weight and those with intrauterine growth restriction. Unexpectedly, a higher proportion of advanced maternal ages (AMA) was found in normal outcomes compared to abnormal ones (abnormal fetus or newborn) and fetal losses, 73% vs. 56% and 50%, p = 0.0015 and p = 0.0011, correspondingly. Another intriguing finding was a higher AMA proportion in mosaic carriers with concomitant uniparental disomy (UPD) for chromosomes 7, 14, 15, and 16 compared to carriers with biparental disomy (BPD) (72% vs. 58%, 92% vs. 55%, 87% vs. 78%, and 65% vs. 24%, correspondingly); overall figures were 78% vs. 48%, p = 0.0026. Analysis of reproductive histories showed a very poor reporting but almost two-fold higher rate of mothers reporting a previous fetal loss from PNM cohort (in which almost all patients were clinically abnormal) compared to mothers from the TFM and CPM cohorts (with a large proportion of normal outcomes), 30% vs. 16%, p = 0.0072. The occurrence of a previous pregnancy with a chromosome abnormality was 1 in 13 in the prenatal cohort and 1 in 16 in the postnatal cohort, which are five-fold higher compared to published studies on non-mosaic trisomies. We consider the data obtained in this study to be preliminary despite the magnitude of the literature reviewed since reporting of detailed data was mostly poor, and therefore, the studied cohorts do not represent "big data". Nevertheless, the information obtained is useful both for clinical genetic counseling and for modeling further studies.

Ovarian mature teratomas (OMTs) originate from post-meiotic germ cells. Malignant transformation occurs in approximately 1-2% of OMTs; however, sebaceous carcinoma arising from OMTs is rare. This is the first report of a detailed genomic analysis of sebaceous carcinoma arising from an OMT. A 36-year-old woman underwent evaluation for abdominal tumors and subsequent hysterectomy and salpingo-oophorectomy. Pathologically, a diagnosis of stage IA sebaceous carcinoma arising from an OMT was established. Eight months post-surgery, the patient was alive without recurrence. Immunohistochemically, the tumor was negative for mismatch repair proteins. A nonsense mutation in TP53 (p.R306*) and a deletion in PIK3R1 were identified. Single nucleotide polymorphisms across all chromosomes displayed a high degree of homozygosity, suggestive of uniparental disomy. Herein, the OMT resulting from the endoreduplication of oocytes underwent a malignant transformation to sebaceous carcinoma via TP53 as an early event and PIK3R1 as a late event.

The pre BCR complex plays a crucial role in B cell production, and its successful expression marks the B cell differentiation from the pro-B to pre-B. The CD79a and CD79b mutations, encoding Igα and Igβ respectively, have been identified as the cause of autosomal recessive agammaglobulinemia (ARA). Here, we present a case of a patient with a homozygous CD79a mutation, exhibiting recurrent respiratory infections, diarrhea, growth and development delay, unique facial abnormalities and microcephaly, as well as neurological symptoms including tethered spinal cord, sacral canal cyst, and chronic enteroviral E18 meningitis. Complete blockade of the early B cell development in the bone marrow of the patient results in the absence of peripheral circulating mature B cells. Whole exome sequencing revealed a Loss of Heterozygosity (LOH) of approximately 19.20Mb containing CD79a on chromosome 19 in the patient. This is the first case of a homozygous CD79a mutation caused by segmental uniparental diploid (UPD). Another key outcome of this study is the effective management of long-term chronic enteroviral meningitis using a combination of intravenous immunoglobulin (IVIG) and fluoxetine. This approach offers compelling evidence of fluoxetine's utility in treating enteroviral meningitis, particularly in immunocompromised patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Due to its rare nature and subtle dysmorphisms, Prader-Willi syndrome can be challenging to recognize and diagnose in the neonatal period. Feeding difficulties and hypotonia ('floppy infant') are the most striking characteristics. Prader-Willi syndrome requires specific follow-up and treatment, emphasizing the importance of early recognition.We encountered an infant of three months old with severe hypotonia. The hypotonia ameliorated spontaneously over time, although feeding per nasogastric tube was necessary. There were no apparent dysmorphisms. Extensive genetic investigations showed a maternal uniparental disomy of chromosome 15, fitting with Prader-Willi syndrome explaining all symptoms. After excluding contraindications, treatment with growth hormone therapy was started. Parents were educated regarding medical emergencies specific for Prader-Willi syndrome ('medical alerts'). Although Prader-Willi syndrome is rare, it should always be considered in cases of neonatal hypotonia. Early recognition is paramount as specific recommendations and treatment are warranted.

Objective: Herein, we present a case of mosaic trisomy 6 detected by amniocentesis., Case Report: Amniocentesis (G-banding) was performed at 17 weeks of gestation; the results were 47,XY,+6[3]/46,XY[12]. Fetal screening ultrasonography showed no morphological abnormalities, and the parents desired to continue the pregnancy. The infant was delivered vaginally at 39 weeks' gestation. The male infant weighed 3002 g at birth with no morphological abnormalities. G-banding karyotype analysis performed on the infant's peripheral blood revealed 46,XY[20]. FISH analysis revealed trisomy signals on chromosome 6 in 1-4 out of 100 cells from the placenta. The single nucleotide polymorphism microarray of the umbilical cord blood revealed no abnormalities. Methylation analysis of umbilical cord blood revealed no abnormalities in PLAGL1. No disorders were observed at one year of age., Conclusion: When amniocentesis reveals chromosomal mosaicism, it is essential to provide a thorough fetal ultrasound examination and careful genetic counseling to support the couples' decision-making., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interests., (Copyright © 2024. Published by Elsevier B.V.)

Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining T cells had limited T cell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired β-ring/β-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

A single-center retrospective study of G-band karyotyping and chromosomal microarray analysis (CMA) for the invasive prenatal diagnosis of 6159 fetuses with ultrasound abnormalities was conducted. This study aimed to investigate the incidence rates of chromosomal abnormalities and pregnancy outcomes and postpartum clinical manifestations by long-term follow-up and to explore the correlation between different types of prenatal ultrasound abnormalities and pathogenic chromosomal abnormalities. The overall incidence of pathogenic chromosomal aberrations in fetuses with ultrasound abnormalities was 7.58% (467/6159), which comprised 41.7% (195/467) with chromosome number abnormalities, 57.6% (269/467) with pathogenic copy-number variations (pCNVs), and 0.64% (3/467) with uniparental disomy (UPD). In addition, 1.72% (106/6159) with likely pathogenic copy-number variations (lpCNVs) and 3.04% (187/6159) with variants of unknown significance (VOUS) were detected by CMA. Ultrasound abnormalities were categorized into structural anomalies and soft marker anomalies. The incidence rate of pathogenic and likely pathogenic chromosomal abnormalities was significantly higher among fetuses with structural anomalies than soft markers (11.13% vs 7.59%, p < 0.01). We retrospectively analyzed the prenatal genetic outcomes for a large cohort of fetuses with different types of ultrasound abnormalities. The present study showed that the chromosomal abnormality rate and clinical outcomes of fetuses with different types of ultrasound abnormalities varied greatly. Our data have important implications for prenatal genetic counseling for fetuses with different types of ultrasound abnormalities., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Uniparental disomy (UPD) is a rare type of chromosomal aberration that may hinder the analysis of kinship during forensic identification. Here, we investigated these genetic findings to avoid false exclusions during parentage testing. Thirty-nine fluorescently labeled, autosomal short tandem repeats (STR) were amplified in three cases, to detect parent-child relationships. Twenty-three fluorescently labeled Y-chromosome STRs were also employed. These were subjected to capillary electrophoresis. The parentage index was calculated by the bipartite or tripartite model. Single nucleotide polymorphism (SNP) microarrays were performed to further investigate the genetic mechanisms. The conclusions supported the biological mother-child relationship in three cases. However, in all cases, the alleged father and child had three autosomal STR markers, constrained to a single chromosome, which did not conform to Mendelian inheritance rules. The genotyping of 23 Y-chromosome STRs did not reveal any violations of Mendelian law. The combination of STR profiling and SNP microarrays suggested that two children had maternal UPD of chromosome 7, whilst one had UPD of chromosome 2. After excluding the three incompatible loci, the conclusions supported the biological father-child relationship in all cases. The same results were obtained when parentage testing of trios was used. Uniparental disomy may complicate the judgment of kinship in parentage testing. The possibility of UPD should be considered when incompatible STR loci are found on the same chromosome. Genetic evidence obtained through additional molecular techniques can provide better interpretation of kinship in the presence of UPD and avoid false exclusions of biological relationships., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Chromosomal microarray (CMA) is the reference in evaluation of copy number variations (CNVs) in individuals with neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and/or autism spectrum disorder (ASD), which affect around 3-4% of the world's population. Modern platforms for CMA, also include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH). These regions result from complete or segmental chromosomal homozygosis and may be indicative of uniparental disomy (UPD), inbreeding, population characteristics, as well as replicative DNA repair events. In this retrospective study, we analyzed CMA reading files requested by geneticists and neurologists for diagnostic purposes along with available clinical data. Our objectives were interpreting CNVs and assess the frequencies and implications of LCSH detected by Affymetrix CytoScan HD (41%) or 750K (59%) platforms in 1012 patients from the south of Brazil. The patients were mainly children with NDDs and/or congenital anomalies (CAs). A total of 206 CNVs, comprising 132 deletions and 74 duplications, interpreted as pathogenic, were found in 17% of the patients in the cohort and across all chromosomes. Additionally, 12% presented rare variants of uncertain clinical significance, including LPCNVs, as the only clinically relevant CNV. Within the realm of NDDs, ASD carries a particular importance, owing to its escalating prevalence and its growing repercussions for individuals, families, and communities. ASD was one clinical phenotype, if not the main reason for referral to testing, for about one-third of the cohort, and these patients were further analyzed as a sub-cohort. Considering only the patients with ASD, the diagnostic rate was 10%, within the range reported in the literature (8-21%). It was higher (16%) when associated with dysmorphic features and lower (7%) for "isolated" ASD (without ID and without dysmorphic features). In 953 CMAs of the whole cohort, LCSH (≥ 3 Mbp) were analyzed not only for their potential pathogenic significance but were also explored to identify common LCSH in the South Brazilians population. CMA revealed at least one LCSH in 91% of the patients. For about 11.5% of patients, the LCSH suggested consanguinity from the first to the fifth degree, with a greater probability of clinical impact, and in 2.8%, they revealed a putative UPD. LCSH found at a frequency of 5% or more were considered common LCSH in the general population, allowing us to delineate 10 regions as potentially representing ancestral haplotypes of neglectable clinical significance. The main referrals for CMA were developmental delay (56%), ID (33%), ASD (33%) and syndromic features (56%). Some phenotypes in this population may be predictive of a higher probability of indicating a carrier of a pathogenic CNV. Here, we present the largest report of CMA data in a cohort with NDDs and/or CAs from the South of Brazil. We characterize the rare CNVs found along with the main phenotypes presented by each patient and show the importance and usefulness of LCSH interpretation in CMA results that incorporate SNPs, as well as we illustrate the value of CMA to investigate CNV in ASD., (© 2024. The Author(s).)

Background: Chromosomal microarray analysis (CMA) is a valuable tool in prenatal diagnosis for the detection of chromosome uniparental disomy (UPD). This retrospective study examines fetuses undergoing invasive prenatal diagnosis through Affymetrix CytoScan 750 K array analysis. We evaluated both chromosome G-banding karyotyping data and CMA results from 2007 cases subjected to amniocentesis., Results: The detection rate of regions of homozygosity (ROH) ≥ 10 Mb was 1.8% (33/2007), with chromosome 11 being the most frequently implicated (17.1%, 6/33). There were three cases where UPD predicted an abnormal phenotype based on imprinted gene expression., Conclusion: The integration of UPD detection by CMA offers a more precise approach to prenatal genetic diagnosis. CMA proves effective in identifying ROH and preventing the birth of children affected by imprinting diseases., (© 2024. The Author(s).)

Background: Uniparental disomy (UPD) is a rare genetic condition leading to potential disease risks. Maternal UPD of chromosome 6 upd(6)mat is exceptionally rare, with limited cases reported. This study reported two new cases of upd(6)mat and reviewed the literature of previous cases., Case Presentation: Both cases exhibited intrauterine growth restriction (IUGR), and genetic analysis confirmed upd(6)mat in each case. The literature review identified a total of 19 cases. IUGR and preterm labor were the most common two symptoms observed, and additional anomalies and genetic variations were also reported in some cases., Conclusion: upd(6)mat is potentially associatied with IUGR, but the precise genotype-phenotype relationship remains unclear. The cases with upd(6)mat may present clinical features due to imprinting disorders., (© 2024. The Author(s).)

A hydatidiform mole (HM) or molar pregnancy is the most common benign form of gestational trophoblastic disease characterized by a proliferation of the trophoblastic epithelium and villous edema. Hydatidiform moles are classified into two forms: complete and partial hydatidiform moles. These two types of HM present morphologic, histopathologic and cytogenetic differences. Usually, hydatidiform moles are a unique event, but some women present a recurrent form of complete hydatidiform moles that can be sporadic or familial. The appearance of hydatidiform moles is correlated with some genetic events (like uniparental disomy, triploidy or diandry) specific to meiosis and is the first step of embryo development. The familial forms are determined by variants in some genes, with NLRP7 and KHDC3L being the most important ones. The identification of different types of hydatidiform moles and their subsequent mechanisms is important to calculate the recurrence risk and estimate the method of progression to a malign form. This review synthesizes the heterogeneous mechanisms and their implications in genetic counseling.

Background: Few co-occurrence cases of mosaic aneuploidy and uniparental disomy (UPD) chromosomes have been reported in prenatal periods. It is a big challenge for us to predict fetal clinical outcomes with these chromosome abnormalities because of their highly heterogeneous clinical manifestations and limited phenotype attainable by ultrasound., Methods: Amniotic fluid samples were collected from four cases. Karyotype, chromosome microarray analysis, short tandem repeats, and whole exome sequencing were adopted to analyze fetal chromosomal aneuploidy, UPD, and gene variation. Meanwhile, CNVseq analysis proceeded for cultured and uncultured amniocytes in case 2 and case 4 and MS-MLPA for chr11 and chr15 in case 3., Results: All four fetuses showed mosaic chromosomal aneuploidy and UPD simultaneously. The results were: Case 1: T2(7%) and UPD(2)mat(12%). Case 2: T15(60%) and UPD(15)mat(40%). Case 3: 45,X(13%) and genome-wide paternal UPD(20%). Case 4: <10% of T20 and > 90% UPD(20)mat in uncultured amniocyte. By analyzing their formation mechanism of mosaic chromosomal aneuploidy and UPD, at least two adverse genetic events happened during their meiosis and mitosis. The fetus of case 1 presented a benign with a normal intrauterine phenotype, consistent with a low proportion of trisomy cells. However, the other three fetuses had adverse pregnancy outcomes, resulting from the UPD chromosomes with imprinted regions involved or a higher level of mosaic aneuploidy., Conclusion: UPD is often present with mosaic aneuploidy. It is necessary to analyze them simultaneously using a whole battery of analyses for these cases when their chromosomes with imprinted regions are involved or known carriers of a recessive allele. Fetal clinical outcomes were related to the affected chromosomes aneuploidy and UPD, mosaic levels and tissues, methylation status, and homozygous variation of recessive genes on the UPD chromosome. Genetic counseling for pregnant women with such fetuses is crucial to make informed choices., (© 2023. The Author(s).)

Rhabdomyosarcomas (RMS) constitute a heterogeneous spectrum of tumors with respect to clinical behavior and tumor morphology. The paternal uniparental disomy (pUPD) of 11p15.5 is a molecular change described mainly in embryonal RMS. In addition to LOH, UPD, the MLPA technique (ME030kit) also determines copy number variants and methylation of H19 and KCNQ1OT1 genes, which have not been systematically investigated in RMS. All 127 RMS tumors were divided by histology and PAX status into four groups, pleomorphic histology (n = 2); alveolar RMS PAX fusion-positive (PAX+; n = 39); embryonal RMS (n = 70) and fusion-negative RMS with alveolar pattern (PAX-RMS-AP; n = 16). The following changes were detected; negative (n = 21), pUPD (n = 75), gain of paternal allele (n = 9), loss of maternal allele (n = 9), hypermethylation of H19 (n = 6), hypomethylation of KCNQ1OT1 (n = 6), and deletion of CDKN1C (n = 1). We have shown no difference in the frequency of pUPD 11p15.5 in all groups. Thus, we have proven that changes in the 11p15.5 are not only specific to the embryonal RMS (ERMS), but are often also present in alveolar RMS (ARMS). We have found changes that have not yet been described in RMS. We also demonstrated new potential diagnostic markers for ERMS (paternal duplication and UPD of whole chromosome 11) and for ARMS PAX+ (hypomethylation KCNQ1OT1)., (© 2023 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Uniparental disomy (UPD) is a rare chromosomal condition, which apart from its importance in medical genetics can affect an outcome of parentage DNA testing, often causing pseudo exclusions. We describe a case of trio paternity test using 24 informative STR loci with potential exclusion at 2 systems located on chromosome 21. Consequent genotyping of an additional 25 autosomal and 27 Y-specific STRs revealed one other inconsistency, also located on this chromosome. All three inconsistent markers had the same heteroallelic state between the child and the biological mother providing evidence for maternal heterodisomy of chromosome 21. The case highlights the importance of considering UPD as a cause of genetic inconsistencies, especially when the inconsistent marker systems are located on the same chromosome., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Uniparental disomy (UPD) refers to as both homologous chromosomes inherited from only one parent without identical copies from the other parent. Studies on clinical phenotypes in UPDs are usually focused on the documented UPD 6, 7, 11, 14, 15, and 20, which directly lead to imprinting disorders. This study describes clinical phenotypes and genetic findings of three patients with UPD 2, 9, and 14, respectively. Chromosomal microarray (CMA), UPDtool, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and whole-exome sequencing (WES) analysis were performed to characterize the genetic etiology. The CMA revealed a homozygous region involving the whole chromosome 2 and 9, a partial region of homozygosity in chromosome 14. UPD-tool revealed a paternal origin of the UPD2. MS-MLPA showed hypomethylation of imprinting gene MEG3 from maternal origin in the UPD14 case. In addition, UPD14 case displayed complex symptoms including growth failure, hypotonia and acute respiratory distress syndrome (ARDS), accompanied by several gene mutations with heterozygous genotype by WES analysis. Furthermore, we reviewed the documented UPDs and summarized the clinical characteristics and prognosis. This study highlighted the importance to confirm the diagnosis and origin of UPD using genetic testing. Therefore, it is suggested that expanding of the detailed phenotypes and genotypes provide effective guidance for molecule testing and genetic counseling, and promote further biological investigation to the underlying mechanisms of imprinted disorders and accompanied copy number variations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Chen, Shi, Tao, Li, Zhu, Yang and Xu.)

Single nucleotide polymorphism (SNP) chromosome microarray is well established for investigation of children with intellectual deficit/development delay and prenatal diagnosis of fetal malformation but has also emerged for uniparental disomy (UPD) genotyping. Despite published guidelines on clinical indications for testing there are no laboratory guidelines published for performing SNP microarray UPD genotyping. We evaluated SNP microarray UPD genotyping using Illumina beadchips on family trios/duos within a clinical cohort (n=98) and then explored our findings in a post-study audit (n=123). UPD occurred in 18.6% and 19.5% cases, respectively, with chromosome 15 most frequent (62.5% and 25.0%). UPD was predominantly maternal in origin (87.5% and 79.2%), highest in suspected genomic imprinting disorder cases (56.3% and 41.7%) but absent amongst children of translocation carriers. We assessed regions of homozygosity among UPD cases. The smallest interstitial and terminal regions were 2.5 Mb and 9.3 Mb, respectively. We found regions of homozygosity confounded genotyping in a consanguineous case with UPD15 and another with segmental UPD due to non-informative probes. In a unique case with chromosome 15q UPD mosaicism, we established the detection limit of mosaicism as ∼5%. From the benefits and pitfalls identified in this study, we propose a testing model and recommendations for UPD genotyping by SNP microarray., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Imprinting disorders are congenital diseases caused by dysregulation of genomic imprinting, affecting growth, neurocognitive development, metabolism and cancer predisposition. Overlapping clinical features are often observed among this group of diseases. In rare cases, two fully expressed imprinting disorders may coexist in the same patient. A dozen cases of this type have been reported so far. Most of them are represented by individuals affected by Beckwith-Wiedemann spectrum (BWSp) and Transient Neonatal Diabetes Mellitus (TNDM) or BWSp and Pseudo-hypoparathyroidism type 1B (PHP1B). All these patients displayed Multilocus imprinting disturbances (MLID). Here, we report the first case of co-occurrence of BWS and PHP1B in the same individual in absence of MLID. Genome-wide methylation and SNP-array analyses demonstrated loss of methylation of the KCNQ1OT1 :TSS-DMR on chromosome 11p15.5 as molecular cause of BWSp, and upd(20)pat as cause of PHP1B. The absence of MLID and the heterodisomy of chromosome 20 suggests that BWSp and PHP1B arose through distinct and independent mechanism in our patient. However, we cannot exclude that the rare combination of the epigenetic defect on chromosome 11 and the UPD on chromosome 20 may originate from a common so far undetermined predisposing molecular lesion. A better comprehension of the molecular mechanisms underlying the co-occurrence of two imprinting disorders will improve genetic counselling and estimate of familial recurrence risk of these rare cases. Furthermore, our study also supports the importance of multilocus molecular testing for revealing MLID as well as complex cases of imprinting disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pignata, Cecere, Acquaviva, D’Angelo, Cioffi, Pellino, Palumbo, Palumbo, Carella, Sparago, De Brasi, Cerrato and Riccio.)

Hürthle cell carcinoma (HCC) is a rare type of thyroid cancer with high rates of distant metastasis and recurrence. Along with the scarcity of effective systemic therapies for HCC, these factors contribute to poor clinical outcomes. The immunologic features of HCC are poorly defined and response rates with immune checkpoint blockade have not been reported. A more comprehensive understanding of the immune landscape and factors that predict response to checkpoint inhibitors is needed. We performed RNA sequencing on 40 tumors to characterize the neoantigen landscape and immune microenvironment of HCC. We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T-cell activation/dysfunction and correlated these to genetic features such as tumor mutation burden, neoantigen burden, mitochondrial mutations, and LOH from chromosomal uniparental disomy. Finally, immune profiles of patients with recurrence were compared with those of patients without recurrence. HCC tumors exhibited low levels of immune infiltration, with the more aggressive widely invasive phenotype associated with more immune depletion. There was a negative correlation between tumor mutation burden, neoantigen burden, programmed cell death ligand 1 (PD-L1) expression, and the immune infiltration score. HCC tumors that exhibited a global LOH from chromosomal uniparental disomy or haploidization had the lowest level of immune infiltration. HCC tumors that recurred displayed an immune-depleted microenvironment associated with global LOH and aerobic glycolysis. These findings offer new insights into the functional immune landscapes and immune microenvironment of HCC. Our data identify potential immunologic vulnerabilities for these understudied and often fatal cancers., Significance: The immune landscape of HCC is poorly defined and response rates to immunotherapy have not been reported. The authors found the immune microenvironment in HCC to be depleted. This immunosuppression is associated with a global LOH from haploidization and uniparental disomy, resulting in whole chromosome losses across the genome., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Chromosomal abnormalities are a major cause of early pregnancy loss. However, models synthesizing existing genetic technologies to improve pregnancy outcomes are lacking. We aim to provide an integrated laboratory algorithm for the genetic etiology of couples who experienced pregnancy loss. Methods: Over a 6-year period, 3,634 products of conception (POCs) following early pregnancy loss were collected. The clinical outcomes from a laboratory algorithm based on single nucleotide polymorphism (SNP) array, fluorescence in situ hybridization (FISH), and parental chromosomal karyotyping assays were comprehensively evaluated. Results: In total, 3,445 of 3,634 (94.8%) POCs had no maternal-cell contamination. Of those POCs, the detection rate of abnormal results was 65.2% (2,247/3,445), of which 91.2% (2,050/2,247) had numerical chromosomal abnormalities, 2.7% (60/2,247) had copy-number variations (CNVs) ≥10 Mb, 2.7% (61/2,247) had CNVs of terminal deletion and duplication, 2.8% (62/2,247) had CNVs <10 Mb, and 0.6% (14/2,247) had uniparental disomy. Furthermore, FISH confirmed 7 of the 60 POCs with mosaic aneuploids below 30% based on the SNP array results as tetraploid. Of the 52 POCs with CNVs of terminal deletion and duplication, 29 couples had balanced rearrangements based on chromosomal karyotyping. Conclusion: The integrated SNP array-based algorithm combined with optional FISH and parental chromosomal karyotyping is an effective laboratory testing strategy, providing a comprehensive and reliable genetic investigation for the etiology of miscarriage, regardless of the number of miscarriages and the method of conception., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liao, Zhang, Liu, Wang, Hu, Xiao, Yang, Lai, Zhu, Li, Liu, Wang and Hu.)

Background: Our previous study suggested that assisted reproductive technology (ART) may be a possible risk factor for the development of epimutation-mediated imprinting disorders (epi-IDs) for mothers aged ≥ 30 years. However, whether ART or advanced parental age facilitates the development of uniparental disomy-mediated IDs (UPD-IDs) has not yet been investigated., Results: We enrolled 130 patients with aneuploid UPD-IDs including various IDs confirmed by molecular studies and obtained ART data of the general population and patients with epi-IDs from a robust nationwide database and our previous report, respectively. We compared the proportion of ART-conceived livebirths and maternal childbearing age between patients with UPD-IDs and the general population or patients with epi-IDs. The proportion of ART-conceived livebirths in patients with aneuploid UPD-IDs was consistent with that in the general population of maternal age ≥ 30 years and was lower than that in the patients with epi-IDs, although there was no significant difference. The maternal childbearing age of patients with aneuploid UPD-IDs was skewed to the increased ages with several cases exceeding the 97.5th percentile of maternal childbearing age of the general population and significantly higher than that of patients with epi-IDs (P < 0.001). In addition, we compared the proportion of ART-conceived livebirths and parental age at childbirth between patients with UPD-IDs caused by aneuploid oocytes (oUPD-IDs) and that by aneuploid sperm (sUPD-IDs). Almost all ART-conceived livebirths were identified in patients with oUPD-IDs, and both maternal age and paternal age at childbirth were significantly higher in patients with oUPD-IDs than in patients with sUPD-IDs. Because maternal age and paternal age were strongly correlated (r s  = 0.637, P < 0.001), higher paternal age in oUPD-IDs was explained by the higher maternal age in this group., Conclusions: Different from the case of epi-IDs, ART itself is not likely to facilitate the development of aneuploid UPD-IDs. We demonstrated that advanced maternal age can be a risk factor for the development of aneuploid UPD-IDs, particularly oUPD-IDs., (© 2023. The Author(s).)

Purpose: The aim of this case series is to present the outcomes of surgical correction of hyperkyphosis, and subsequent management of complications for three patients with a rare chromosomopathy, Trisomy 9 Mosaicism (T9M)., Methods: Case series with 2 year outcomes following index surgery., Results: Case 1 presented at 9 years of age with 103° of kyphosis (T3-T10), which progressed to 118° despite bracing. Case 2 presented at 7 years of age with 113° of kyphosis (T3-T11). Case 3 presented at 4 years of age with 103° of kyphosis (T1-T11). Cases 1 and 2 underwent T2-L2 posterior instrumented spinal fusion (PISF). Upon follow up, radiographs for Cases 1 and 2 revealed severe, symptomatic proximal junctional kyphosis (PJK) of 71° and 50°, respectively, requiring surgical revision proximally to the C4 level. Case 3 underwent placement of magnetically controlled growing rods given young age and growth potential. Surgical levels for Case 3 were extended from C4-pelvis in an attempt to prevent development of symptomatic PJK. Most recent radiographs for Case 3 taken 21 months postoperatively demonstrate a stable 50° of kyphosis. PJK above C4 was noted but is stable and asymptomatic., Conclusion: T9M often presents with progressive hyperkyphosis. Despite instrumentation above the upper end vertebra (UEV), PJK may be a common complication in this small patient population. This novel report on spine deformity correction in the T9M population may provide preliminary guidance for the treatment of hyperkyphosis in patients with T9M and help surgeons avoid common pitfalls., Level of Evidence: IV., (© 2022. The Author(s), under exclusive licence to Scoliosis Research Society.)

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic imprinting disorders resulting from absent or reduced expression of paternal or maternal genes in chromosome 15q11q13 region, respectively. The most common etiology is deletion of the maternal or paternal 15q11q13 region. Methylation is the first line for molecular diagnostic testing; MS-MLPA is the most sensitive test. The molecular subtype of PWS/AS provides more accurate recurrence risk information for parents and for the individual affected with the condition. Management should include a multidisciplinary team by various medical subspecialists and therapists. Developmental and behavioral management of PWS and AS in infancy and early childhood includes early intervention services and individualized education programs for school-aged children. Here, we compare and discuss the mechanisms, pathophysiology, clinical features, and management of the two imprinting disorders, PWS and AS., Competing Interests: Dr. SP Shankar is Albert Rowe endowed chair in Genetics II & receives salary and research support. The authors report no other conflicts of interest in this work., (© 2023 Ma et al.)