Deletion Syndrome Research Articles

Genetic analysis of a child with 18q terminal deletion and aortic regurgitation and a literature review

To explore the genetic characteristics of a child with 18q terminal deletion syndrome. Clinical data of a child presented at the Lianyungang Maternal and Child Health Care Hospital on July 20, 2023 was collected. Peripheral blood sample from the child was subjected to G-banded chromosomal karyotyping and chromosomal microarray analysis (CMA). Relevant literature was searched from CNKI, WanFang and PubMed databases over the past decade (from November 1, 2013 to November 1, 2023) using keywords including "18q-syndrome", "18q deletion syndrome" and "18q terminal deletion". This study was approved by the Lianyungang Maternal and Child Health Care Hospital (Ethics No. LYG-MER2021017). The child, a 4-year-and-6-month-old female, had manifested short stature, intellectual disability, distinctive facial features, aortic regurgitation, auditory canal atresia, and white matter lesions. She was found to have a karyotype of 46,XX,del(18)(q21), whilst the result of CMA was arr[GRCh37]18q21.33q23(60065821_77317445)×1. Both of her parents were found to have a normal karyotype. Literature review has retrieved 7 reports which involved 11 cases with a terminal 18q23 deletion. The phenotypes of cardiac abnormalities have been diverse, with pulmonary stenosis, atrial septal defect and ventricular septal defect being most common. The 18q terminal deletion probably underlay the multiple congenital anomalies and mental retardation in this child.

2q31 microdeletion syndrome with the velocardiofacial phenotype and review of the literature: a case report

BackgroundThe 2q31 deletion results in a distinct phenotype characterized by varying degrees of developmental delay, short stature, facial dysmorphism, and variable limb defects. Dysmorphic features include microcephaly, downslanting palpebral fissures, a long and flat philtrum, micrognathia, and dysplastic, low-set ears. To date, comparative genomic hybridization has identified this deletion in 38 patients. Consequently, additional patients with comprehensive clinical data are required to fully understand the spectrum of clinical manifestation associated with a deletion in the 2q31 cytoband.Case presentationWe present the case of an 8-year-old female patient with clinical features of velocardiofacial syndrome, which include facial dysmorphism, congenital heart disease (persistent truncus arteriosus and ostium secundum-type atrial septal defect), and a seizure syndrome. Array comparative genomic hybridization revealed a non-continous deletion spanning cytobands 2q31.1-to 2q31.3, confirming a diagnosis of 2q31 microdeletion syndrome. The patient has undergone supportive therapies for swallowing and speech. Additionally, we provide a review of the literature on previous cases to give context.ConclusionIn this report, we present the first documented case of a complex, discontinuous deletion spanning in the 2q31-2q32 regions. This case contributes to our understanding of the phenotypic and mutational spectrum observed in individuals with deletions in these cytobands. It underscores the significance of employing high-resolution techniques and comprenhensive analysis in diagnosing patients with complex phenotypes. Such approaches are crucial for differentiating this condition from more common microdeletion syndromes, such as the 22q11 deletion syndrome.

6775 Four Cases with the Beckwith-Wiedemann Syndrome Phenotype Caused by GNAS Defects

Abstract Disclosure: T. Urakawa: None. Y. Kanamaru: None. N. Amano: None. A. Uchida: None. J. Shin: None. M. Fukami: None. M. Kagami: None. Background: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with a heterogeneous phenotypic spectrum, including macroglossia (MG), lateralized overgrowth (LO), and hyperinsulinism (HI). According to the BWS clinical scoring system, the consensus statement recommends conducting genetic testing for patients with two or more scores and doing the clinical diagnosis of BWS for patients with four or more scores. The etiologies of BWS consist of methylation abnormalities of differentially methylated regions (DMRs) on 11p15.5, paternal uniparental disomy of chromosome 11 (UPD(11)pat), and maternal loss of function variants of CDKN1C. However, in 20% of BWS cases, the genetic causes remain unclear. Here, we report on four cases of the BWS phenotype with GNAS defects, known to cause pseudohypoparathyroidism (PHP). Case presentation: Case 1 was born at 37 weeks of gestation with birth weight (BW) of 2964 g (+0.8 SD) and birth length (BL) of 50.5 cm (+1.3 SD) and had MG, LO, HI, ear creases (EC), naevus flammeus, umbilical hernia (UH), and postnatal overgrowth (PO) together with intellectual disability (BWS score 9). Case 2 was born at 32 weeks with BW of 1415 g (-1.4 SD) and BL of 40.0 cm (-0.8 SD), showing MG, HI, UH, and PO (BWS score 5). Case 3 was born at 36 weeks with BW of 2366 g (-0.5 SD) and BL of 44.0 cm (-1.1 SD), exhibiting MG, EC, UH, and PO (BWS score 4). Case 4 was born at 36 weeks with BW of 2762 g (+0.6 SD) and BL of 46.0 cm (-0.4 SD), presenting MG and PO (BWS score 2). Cases 3 and 4 showed elevated intact PTH levels. Genetic analysis: Methylation-specific MLPA (MS-MLPA) for multiple DMRs showed abnormal methylation in DMRs on the GNAS locus in cases 1-3, but normal methylation levels in DMRs on 11p15.5. Case 1 had multi-locus imprinting disturbance (MLID) detected by comprehensive methylation analysis (EPIC, Illumina) and a 9pter-9p24.2 deletion identified by array CGH analysis. Case 2 also had MLID together with UPD(20)pat detected by microsatellite marker analysis. Case 3 showed only abnormal methylation in the DMRs on the GNAS locus confirmed by a comprehensive methylation analysis. Case 4 showed no abnormal methylation in the DMRs examined by MS-MLPA and had a pathogenic variant in GNAS (F219L) detected by exome sequencing. Discussion: We identified GNAS defects in four cases with the BWS phenotype. MG and PO were observed in all cases, and other BWS features in each case. Some clinical features observed in 9p terminal deletion syndrome and PHP overlap those in BWS, such as HI, MG, and PO. Therefore, these diseases should be considered as the differential diagnosis of BWS. MLID was identified in two cases, but the methylation status of DMRs on 11p15.5 was normal. The impact of MLID on the BWS phenotype is unknown. Conclusion:GNAS defects can cause the BWS phenotype. Further genetic analysis including GNAS should be considered in cases with the BWS phenotype without 11p15.5 abnormalities. Presentation: 6/2/2024

Beyond IQ: executive function deficits and their relation to functional, clinical, and neuroimaging outcomes in 3q29 deletion syndrome.

3q29 deletion syndrome (3q29del) is a rare (~1:30 000) genomic disorder associated with a wide array of neurodevelopmental and psychiatric phenotypes. Prior work by our team identified clinically significant executive function (EF) deficits in 47% of individuals with 3q29del; however, the nuances of EF in this population have not been described. We used the Behavior Rating Inventory of Executive Function (BRIEF) to perform the first in-depth assessment of real-world EF in a cohort of 32 individuals with 3q29del (62.5% male, mean age = 14.5 ± 8.3 years). All participants were also evaluated with gold-standard neuropsychiatric and cognitive assessments. High-resolution structural magnetic resonance imaging was performed on a subset of participants (n = 24). We found global deficits in EF; individuals with 3q29del scored higher than the population mean on the BRIEF global executive composite (GEC) and all subscales. In total, 81.3% of study subjects (n = 26) scored in the clinical range on at least one BRIEF subscale. BRIEF GEC T scores were higher among 3q29del participants with a diagnosis of attention deficit/hyperactivity disorder (ADHD), and BRIEF GEC T scores were associated with schizophrenia spectrum symptoms as measured by the Structured Interview for Psychosis-Risk Syndromes. BRIEF GEC T scores were not associated with cognitive ability. The BRIEF-2 ADHD form accurately (sensitivity = 86.7%) classified individuals with 3q29del based on ADHD diagnosis status. BRIEF GEC T scores were correlated with cerebellar white matter and subregional cerebellar cortex volumes. Together, these data expand our understanding of the phenotypic spectrum of 3q29del and identify EF as a core feature linked to both psychiatric and neuroanatomical features of the syndrome.

From diagnosis to postoperative challenges: a comprehensive case report on 2q37 deletion syndrome with CHD.

Chromosomal 2q37 deletion syndrome, marked by developmental delays, distinctive facial features, and a spectrum of congenital anomalies, presents significant challenges in the cardiac management of affected individuals. This paper details the case of an 8-month-old male with 2q37 deletion syndrome, manifesting atrial and ventricular septal defects, patent ductus arteriosus, and right ventricular outflow tract stenosis, leading to a demanding postoperative course. Despite an initially stable post-surgery phase, the onset of junctional ectopic tachycardia necessitated prolonged veno-arterial extracorporeal membrane oxygenation support, highlighting the syndrome's potential for intricate postoperative courses. The complexities encountered in this case, including extended renal replacement therapy and delayed thoracic closure, underscore the syndrome's multisystem impact and the critical need for tailored, multidisciplinary care approaches. This report contributes to the growing body of knowledge on the cardiac implications of 2q37 deletion syndrome, emphasising the importance of individualised surgical strategies and the ongoing exploration of genotype-phenotype correlations in this rare genetic disorder.

P1.06C.04 Low-Level Deletion of Chromosome 19p Genes May Be Sufficient to Drive Histology-Dependent Phenotypes in Lung Cancer

P1.06C.04 Low-Level Deletion of Chromosome 19p Genes May Be Sufficient to Drive Histology-Dependent Phenotypes in Lung Cancer

Kidney Prognosis in Patients with TSC2/PKD1 Contiguous Gene Deletion Syndrome

Kidney Prognosis in Patients with TSC2/PKD1 Contiguous Gene Deletion Syndrome

Hearing Loss in Children with 22q11.2 Deletion Syndrome

Hearing Loss in Children with 22q11.2 Deletion Syndrome

Monozygotic triplets with juvenile-onset autoimmunity and 18p microdeletion involving PTPRM.

Abnormal gene dosage from copy number variants has been associated with susceptibility to autoimmune disease. This includes 18p deletion syndrome, a chromosomal disorder with an estimated prevalence of 1 in 50,000 characterized by intellectual disability, facial dysmorphology, and brain abnormalities. The underlying causes for autoimmune manifestations associated with 18p deletions, however, remain unknown. Our objective was to investigate a distinctive case involving monozygotic triplets concordant for developmental delay, white matter abnormalities, and autoimmunity, specifically juvenile-onset Graves' thyroiditis. By chromosomal microarray analysis and whole genome sequencing, we found the triplets to carry a de novo interstitial 5.9Mb deletion of chromosome 18p11.31p11.21 spanning 19 protein-coding genes. We conducted a literature review to pinpoint genes affected by the deletion that could be associated with immune dysregulation and identified PTPRM as a potential candidate. Through dephosphorylation, PTPRM serves as a negative regulator of STAT3, a key factor in the generation of Th17 cells and the onset of specific autoimmune manifestations. We hypothesized that PTPRM hemizygosity results in increased STAT3 activation. We therefore performed assays investigating PTPRM expression, STAT3 phosphorylation, Th1/Th2/Th17 cell fractions, Treg cells, and overall immunophenotype, and in support of the hypothesis, our investigations showed an increase in cells with phosphorylated STAT3 and higher levels of Th17 cells in the triplets. We propose that PTPRM hemizygosity can serve as a contributing factor to autoimmune susceptibility in 18p deletion syndrome. If confirmed in unrelated 18p/PTPRM deletion patients, this susceptibility could potentially be treated by targeted inhibition of IL-17.

Clinical and Molecular Aspects of Craniofrontonasal Syndrome due to Contiguous Gene Deletion Involving AWAT2, EFNB1, EDA, OTUD6A, and PJA1 Genes

AbstractCraniofrontonasal syndrome (CFNS; Online Mendelian Inheritance in Man [OMIM] 340110) is an infrequent X linked disorder characterized by specific facial features and digital abnormalities with or without visceral anomalies. There is a peculiar paradoxical difference in severity of the phenotype in heterozygous females compared to hemizygous males. Here, we present a case where the mother, with clinical features of the syndrome, had terminated her previous pregnancy as the fetus had partial agenesis of the corpus callosum. Exome sequencing of the mother revealed no pathogenic variants related to the phenotype. Chromosomal microarray revealed 1.3-Mb pathogenic heterozygous deletion in chromosome X encompassing the Xq13.1 region with five OMIM genes, including EFNB1 gene related to craniofrontonasal syndrome. Detailed phenotyping of the parents and exact genetic etiology with molecular mechanism is important to arrive at a definitive diagnosis crucial for genetic counseling and definitive prenatal testing.

An Assessment of Adverse Events in Patients with 22q11.2 Deletion Syndrome Undergoing Palatoplasty: An Analysis of the NSQIP Pediatric Database.

The National Surgical Quality Improvement Program (NSQIP) Pediatric database has been used to identify factors related to adverse surgical outcomes in pediatric and craniofacial surgical procedures. Focusing on a historically "higher-risk" population, our aim was to assess the impact of demographics, comorbidities, and 22q11.2 deletion syndrome (22QDS) diagnosis on 30-day postoperative complications in patients undergoing primary palatoplasty. We used the 2012-2020 NSQIP Pediatric database to identify patients ≤3 years with and without 22q11.2 deletion syndrome who underwent primary palatoplasty. Demographics, comorbidities, and perioperative characteristics were compared between those with and without 22QDS. Logistic regression was used to determine if children with 22QDS were more likely to experience a 30-day postoperative complication or readmission. There were 10,745 patients ≤3 years old who underwent primary palatoplasty; 83 (0.8%) of whom had 22QDS and 10,662 (99.8%) did not. Children with 22QDS were older when they underwent primary palatoplasty and more likely to have comorbidities. A total of 513 patients (4.8%) experienced a postoperative complication within 30 days and 255 were readmitted (2.4%). Of the 513, 8 (9.6%) had a 22QDS diagnosis and 505 (4.7%) did not. A diagnosis of 22QDS was not a significant independent risk factor for a complication (adjusted odds ratio (aOR) = 1.13; 95% confidence interval (CI): 0.50-2.54) or readmission (aOR = 1.74; 95% CI: 0.74-4.13) within 30 days. This study found that the diagnosis of 22QDS was not an independent predictor of post-palatoplasty complication risk, and in fact 30-day complications are rare for those patients undergoing cleft palate repair, even among those patients with 22QDS.

Clinical phenotype and genetic analysis of a rare case with 6p duplication and terminal deletion syndrome

To explore the genetic basis for a child with developmental delay and intellectual deficit (DD/ID). A child who was admitted to the Maternal and Child Health Care Hospital of Longhua District of Shenzhen City on June 3, 2023 due to DD/ID, craniofacial malformations, and recurrent infections of upper respiratory tract was selected as the study subject. G-banded chromosomal karyotyping was carried out for the child and her parents. Low-depth genome-wide copy number variation sequencing (CNV-seq) and chromosomal microarray analysis (CMA) were used to screen for genome-wide copy number variations (CNV), and fluorescence in situ hybridization (FISH) was used to verify the origin of candidate CNV. The child, an 8-year-old girl, had featured unexplained growth and intellectual development delay, multiple craniofacial malformations, and recurrent infections of the upper respiratory tract. She was found to have a karyotype of 46,XX,der(6)add(6)(q23), while both of her parents were normal. Both CNV-seq and CMA showed that the child has harbored a 21.38 Mb interstitial duplication at 6p25.3p22.3 and a 0.78 Mb terminal deletion at 6p25. FISH verified that both the duplication and deletion had occurred de novo. The abnormal phenotype of the child may be attributed to the 6p duplication and terminal deletion.

Interhemispheric CA1 projections support spatial cognition and are affected in a mouse model of the 22q11.2 deletion syndrome.

Untangling the hippocampus connectivity is critical for understanding the mechanisms supporting learning and memory. However, the function of interhemispheric connections between hippocampal formations is still poorly understood. So far, two major hippocampal commissural projections have been characterized in rodents. Mossy cells from the hilus of the dentate gyrus project to the inner molecular layer of the contralateral dentate gyrus and CA3 and CA2 pyramidal neuron axonal collaterals to contralateral CA3, CA2 and CA1. In contrary, little is known about commissural projection from the CA1 region. Here, we show that CA1 pyramidal neurons from the dorsal hippocampus project to contralateral dorsal CA1 as well as dorsal subiculum. We further demonstrate that the interhemispheric projection from CA1 to dorsal subiculum supports spatial memory and spatial working memory in WT mice, two cognitive functions impaired in male mice from the Df16(A) +/- model of 22q11.2 deletion syndrome (22q11.2DS) associated with schizophrenia. Investigation of the CA1 interhemispheric projections in Df16(A) +/- mice revealed that these projections are disrupted with male mutants showing stronger anatomical defects compared to females. Overall, our results characterize a novel interhemispheric projection from dCA1 to dorsal subiculum and suggest that dysregulation of this projection may contribute to the cognitive deficits associated with the 22q11.2DS.

Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy-Walker malformation spectrum: expanding the known phenotype

BackgroundChromosome 16p11.2 deletions and duplications were found to be the second most common copy number variation (CNV) reported in cases with clinical presentation suggestive of chromosomal syndromes. Chromosome 16p11.2 deletion syndrome shows remarkable phenotypic heterogeneity with a wide variability of presentation extending from normal development and cognition to severe phenotypes. The clinical spectrum ranges from neurocognitive and global developmental delay (GDD), intellectual disability, and language defects (dysarthria /apraxia) to neuropsychiatric and autism spectrum disorders. Other presentations include dysmorphic features, congenital malformations, insulin resistance, and a tendency for obesity. Our study aims to narrow the gap of knowledge in Saudi Arabia and the Middle Eastern and Northern African (MENA) region about genetic disorders, particularly CNV-associated disorders. Despite their rarity, genetic studies in the MENA region revealed high potential with remarkable genetic and phenotypic novelty.ResultsWe identified a heterozygous de novo recurrent proximal chromosome 16p11.2 microdeletion by microarray (arr[GRCh38]16p11.2(29555974_30166595)x1) [(arr[GRCh37]16p11.2(29567295_30177916)x1)] and confirmed by whole exome sequencing (arr[GRCh37]16p11.2(29635211_30199850)x1). We report a Saudi girl with severe motor and cognitive disability, myoclonic epilepsy, deafness, and visual impairment carrying the above-described deletion. Our study broadens the known phenotypic spectrum associated with recurrent proximal 16p11.2 microdeletion syndrome to include developmental dysplasia of the hip, optic atrophy, and a flat retina. Notably, the patient exhibited a rare combination of microcephaly, features consistent with the Dandy-Walker spectrum, and a thin corpus callosum (TCC), which are extremely infrequent presentations in patients with the 16p11.2 microdeletion. Additionally, the patient displayed areas of skin and hair hypopigmentation, attributed to a homozygous hypomorphic allele in the TYR gene.ConclusionThis report expands on the clinical phenotype associated with proximal 16p11.2 microdeletion syndrome, highlighting the potential of genetic research in Saudi Arabia and the MENA region. It underscores the importance of similar future studies.

Platelet changes and bleeding symptoms in children, adolescents, and adults with 22q11.2 deletion syndrome.

The deletion region of 22q11.2 deletion syndrome (22q11.2DS) contains a gene encoding glycoprotein Ibβ (GPIbβ), which is required to express the GPIb/IX/V complex on the platelet surface. Therefore, patients with 22q11.2DS may have congenital platelet disorders. However, information is limited on platelets and bleeding symptoms. In this study, we investigated clinical information, including bleeding symptoms, platelet counts, and GPIb expression levels in children and adolescents/adults with 22q11.2DS. Thirty-two patients with 22q11.2DS were enrolled in a prospective cohort study between 2022 and 2023 at outpatient clinics within our institute. The median platelet counts in adolescents/adults with 22q11.2DS were significantly lower than those in children (p<.0001). A gradual decrease was found along with increasing age (p=.0006). Values of median GPIb expression on platelet surfaces (66% in children and 70% in adolescents/adults) were significantly lower than those in healthy controls (p<.0001 and p=.0002). Bleeding symptoms included surgery-related bleeding (52%), purpura (31%), and epistaxis (22%); most of them were minor. The median International Society on Thrombosis and Hemostasis bleeding assessment tool score was not significantly different between children and adolescents/adults (p=.2311). Although there was an age-related decrease in platelet count and a disease-related decrease in GPIb expression, no difference in bleeding symptoms was found between children and adolescents/adults. 22q11.2DS overall had minor bleeding symptoms in daily life, and the disease had little effect on spontaneous bleeding. However, some patients had major bleeding events; further accumulation of data on hemostasis during surgery and trauma is required.

Genetic Aspects Of Autism Spectrum Disorder

Autism spectrum disorder is a clinically and etiologically heterogeneous group, affecting 1 in 59 children. The etiopathogenesis of these, basically, neurodevelopment disorders, has been the subject of research by numerous researchers for more than two decades, and involves complex genetic, environmental, and epigenetic mechanisms. Hundreds of genes have been identified that contribute to serious deficits in communication, social relations and patient behavior. So the main objective of the paper is to explain the way in which genetic modifiers and epigenetic changes have a key role in modulating the phenotypic spectrum of patients with autism spectrum disorder. The systematic review of literature is based on a review of the available scientific papers. Following PRISMA’s instructions, a systematic review of published papers in the period from 2016 to 2024 was performed. Our study included literature published in the MEDLINE/PubMed database in which the following keywords were used during the search: “autismspectrum disorder”, “pervasive developmental disorder”, “risk factors”, “genetics”, “phenotypic spectrumof ASD”, “genes”, “epigenetic mechanisms”. Тhe obtained results show that the genetic factor increases the risk for development of autism spectrum disorder. More genes have been identified that are involved in the development of autism spectrum disorder, such as: ADNP, ANK2, CHD2, CNTN4, DSCAM, etc. In addition to genetic variants, there is also evidence of de novo gene variants. At the same time, chromosomal deletions or duplications were found in patients, such as the following: 15q11.2, BP1-BP2, 16p11.2 and 15q13.3. Copy number variations are submicroscopic, structural variants in chromosomes that include duplications, deletions, translocations, and inversions, sometimes stretching several kilo bases. Many genes may be affected with these changes, but not all are necessarily drivers of disease. Epigenetic mechanisms, DNA methylation and chemical histone modification are mechanisms that affect gene expression without changing the primary structure of genes. Genetic research so far has enabled us to consider autism spectrum disorder from a different angle, and understand its etiopathogenesis as a complex interaction between genes and environmental factors as a predisposition for its occurrence

Sensory Processing Challenges in Children with Neurodevelopmental Disorders and Genetic Conditions: An Observational Study.

Sensory processing challenges are crucial yet often neglected aspects in the care of children with neurodevelopmental disorders and genetic conditions. They represent a key area of interest in neuroscience, as they significantly impact children's daily functioning and quality of life. This observational study examines these challenges in a group of 614 children, aged 3 to 14 years and 11 months, divided into three groups: 183 with neurodevelopmental disorders (autism spectrum disorder, attention deficit hyperactivity disorder, developmental delays, and learning disorders), 89 with genetic conditions (22q11.2 deletion syndrome, Williams syndrome, and pseudohypoparathyroidism), and 342 controls. Sensory processing was assessed using Sensory Profile 2 (SP2). Results indicated that children with neurodevelopmental disorders and genetic conditions exhibited significant sensory processing difficulties compared to controls. SP2 identified distinct sensory challenges across different sensory systems, varying by diagnosis. Notably, genetic conditions appeared to have a more generalised impact across multiple sensory systems, while neurodevelopmental disorders tended to affect specific systems more narrowly. These findings highlight the importance of early identification and tailored evidence-based interventions to address these specific sensory processing issues. Further research should explore the long-term impact of these interventions in these different populations and their integration into broader therapeutic programmes.

Genetic disorders and their association with morbidity and mortality in early preterm small for gestational age infants

BackgroundEarly preterm (< 34 weeks gestation) small for gestational age infants (< 10th percentile birth weight for sex and gestational age) experience high rates of morbidity and mortality, the causes of which are poorly understood. Mounting evidence suggests that genetic disorders contribute. Scarce data exist regarding the prevalence of genetic disorders and their contribution to morbidity and mortality. ObjectiveThis study aimed to determine the proportion of genetic disorders in early preterm small for gestational age infants (with and without congenital anomalies) compared to early preterm appropriate for gestational age infants and the association of genetic disorders with morbidity or mortality. Study DesignThis is a retrospective cohort study of infants delivered at 23 and 0/7 to 33 and 6/7 weeks’ gestation from 2000–2020 from the Pediatrix Clinical Data Warehouse. Data included diagnosed genetic disorders and congenital anomalies, baseline characteristics, and morbidity or mortality. We excluded cases of death in the delivery room before NICU admission, multiple gestations, and cases transferred after birth or before death or discharge. ResultsWe identified 223,431 early preterm infants, including 21,180 small for gestational age. Genetic disorders were present in 441 (2.3%) of small for gestational age infants without congenital anomalies, in 194 (10.8%) of small for gestational age infants with congenital anomalies, and in 304 (4.5%) of small for gestational age infants that experienced morbidity or mortality (with or without congenital anomalies). Trisomies 13, 18, and 21 were the most prevalent genetic disorders in these groups, together accounting for 145 small for gestational age infants without congenital anomalies, 117 small for gestational age infants with congenital anomalies, and 166 small for gestational age infants with morbidity or mortality (with or without congenital anomalies). Less prevalent genetic disorders consisted of other aneuploidy (45, X and 47, XXY), copy number variants (13q14 deletion syndrome, cri du chat syndrome, DiGeorge syndrome) and single gene disorders (cystic fibrosis, Fanconi anemia, G6PD deficiency, hemophilia, hypophosphatasia, sickle cell disease, and thalassemia). Comparatively, genetic disorders were found in 1792 (1.0%) appropriate for gestational age infants without congenital anomalies, in 572 (5.8%) appropriate for gestational age infants with congenital anomalies, and 809 (2.0%) appropriate for gestational age infants that experienced morbidity or mortality (with or without congenital anomalies). Genetic disorders were associated with an adjusted odds ratio (95% confidence interval) of 2.10 (1.89–2.33) of isolated small for gestational age and 12.84 (11.47–14.35) of small for gestational age accompanied by congenital anomalies. Genetic disorders were associated with an adjusted odds ratio of 2.24 (1.83–2.74) of morbidity or mortality. ConclusionsThese findings suggest that genetic disorders are more prevalent in early preterm small for gestational age infants, particularly those with congenital anomalies. These findings also suggest that genetic disorders are associated with increased morbidity and mortality. These associations were primarily driven by trisomies 13, 18, and 21. Genetic diagnoses in this cohort were made through routine clinical care, principally via karyotype, chromosomal microarray, and single gene-testing. These findings support evolving clinical guidelines for genetic testing of small for gestational age infants. Our study is limited due to the lack of prospective, genome-wide testing.

Mutations in starch BRANCHING ENZYME 2a suppress the traits caused by the loss of ISOAMYLASE1 in barley

Key messageThe hvbe2a mutations restore the starch-deficient phenotype caused by the hvisa1 and hvflo6 mutations in barley endosperm.The genetic interactions among starch biosynthesis genes can be exploited to alter starch properties, but they remain poorly understood due to the various combinations of mutations to be tested. Here, we isolated two novel barley mutants defective in starch BRANCHING ENZYME 2a (hvbe2a-1 and hvbe2a-2) based on the starch granule (SG) morphology. Both hvbe2a mutants showed elongated SGs in the endosperm and increased resistant starch content. hvbe2a-1 had a base change in HvBE2a gene, substituting the amino acid essential for its enzyme activity, while hvbe2a-2 is completely missing HvBE2a due to a chromosomal deletion. Further genetic crosses with barley isoamylase1 mutants (hvisa1) revealed that both hvbe2a mutations could suppress defects in endosperm caused by hvisa1, such as reduction in starch, increase in phytoglycogen, and changes in the glucan chain length distribution. Remarkably, hvbe2a mutations also transformed the endosperm SG morphology from the compound SG caused by hvisa1 to bimodal simple SGs, resembling that of wild-type barley. The suppressive impact was in competition with floury endosperm 6 mutation (hvflo6), which could enhance the phenotype of hvisa1 in the endosperm. In contrast, the compound SG formation induced by the hvflo6 hvisa1 mutation in pollen was not suppressed by hvbe2a mutations. Our findings provide new insights into genetic interactions in the starch biosynthetic pathway, demonstrating how specific genetic alterations can influence starch properties and SG morphology, with potential applications in cereal breeding for desired starch properties.

CIMPACT-NOW Update 8: Clarifications on molecular risk parameters and recommendations for WHO grading of meningiomas.

Meningiomas are the most frequent primary intracranial tumors. Hence, they constitute a major share of diagnostic specimens in neuropathology practice. The 2021 WHO Classification of Central Nervous System Tumors ("CNS5") has introduced the first molecular grading parameters for meningioma with oncogenic variants in the TERT promoter and homozygous deletion of CDKN2A/B as markers for CNS WHO grade 3. However, after publication of the new classification volume, clarifications were requested, not only on novel but also on long-standing questions in meningioma grading that were beyond the scope of the WHO "blue book". In addition, more recent research into possible new molecular grading parameters could not yet be implemented in the 2021 classification but constitute a compelling body of literature. Hence, the cIMPACT-NOW Steering Committee convened a working group to provide such clarification and assess the evidence of possible novel molecular criteria. As a result, this cIMPACT-NOW update provides guidance for more standardized morphological evaluation and interpretation, most prominently pertaining to brain invasion, identifies scenarios in which advanced molecular testing is recommended, proposes to assign CNS WHO grade 2 for cases with CNS WHO grade 1 morphology but chromosomal arm 1p deletion in combination with 22q deletion and/or NF2 oncogenic variants, and discusses areas in which the current evidence is not yet sufficient to result in new recommendations.