Chromosome 9p21 Research Articles

Influence of pharmacogenomic polymorphisms on allopurinol-induced cutaneous adverse drug reactions in Thai patients

BackgroundAllopurinol has been causing substantial morbidity and mortality particularly in Asian population by producing cutaneous adverse drug reactions (cADRs). Nonetheless, there are no data describing whether other genetics are a valid marker for prediction of allopurinol-induced cADRs patients in addition to HLA-B*58:01 allele. The goal of this study was to identify suitable single nucleotide polymorphisms (SNPs) for allopurinol induced cADRs among Thai patients. Methods: We conducted a case-control association study after enrolling 57 Thai patients with allopurinol induced cADRs and 101 allopurinol-tolerant controls. The genetic biomarkers and associated SNPs located on chromosome 6p21 were examined by TaqMan® SNP genotyping assays in both the cases and the controls.ResultsOut of fifteen SNPs in nine genes, we found four combined SNPs (rs3099844 of HCP5, rs9263726 of PSORS1C1, rs9263733 of POLR2LP, and rs9263745 of CCHCR1) were significantly associated with allopurinol-induced cADRs compared to the tolerant controls (OR 73.2; 95% CI 24.2–266.8; P = 1.9 × 10− 24). The overall sensitivity, specificity, positive predictive value and negative predictive value of these combinations were 84%, 94%, 9%, and 100%, respectively. However, the variant alleles of these SNP combinations were detected in 89.5% (51/57) of the cases. Moreover, the HLA-B*58:01 allele was observed in 86.0% of patients with allopurinol-induced cADRs, but only in 4.0% of tolerant controls (OR: 137.2; 95% CI: 38.3–670.5 and p-value = 1.7 × 10− 27).ConclusionsThus, this research confirms the association between the specific HLA-B*58:01 allele and all phenotypes of allopurinol-induced cADRs in Thais. Furthermore, there was found the combined four SNPs (rs3099844, rs9263726, rs9263733, and rs9263745) could be used as alternative novel biomarkers for predicting cADRs in patients taking allopurinol.

Loss of MTAP Expression by Immunohistochemistry Is a Surrogate Marker for Homozygous 9p21.3 Deletion in Urothelial Carcinoma

Homozygous deletion of the chromosomal region 9p21.3 is common in urothelial carcinoma (UC) and leads to loss of several genes, including CDKN2A and MTAP, resulting in loss of MTAP protein expression. Here, we aimed to explore the diagnostic potential of MTAP immunohistochemistry (IHC) as a surrogate marker for homozygous 9p21.3 deletion (9p21 homozygous deletion [HD]) in UC. MTAP status was determined by IHC on 27 UC tissue specimens with known 9p21.3 status as defined by fluorescence in situ hybridization in matched cytological specimens, by IHC and fluorescence in situ hybridization on a tissue microarray (TMA) containing 359 UC at different stages, and by IHC on 729 consecutive UC from routine practice. Moreover, we analyzed a longitudinal series of matched specimens from 38 patients with MTAP-negative recurrent UC. MTAP loss by IHC was found in all 17 patients with 9p21 HD and in 2/8 cases without 9p21 HD. In the TMA, MTAP loss was more common in metastases (53%) than in muscle-invasive (33%) and non–muscle-invasive UC (29%) (P = .03). In the consecutive series, 164/729 (22%) cases showed loss of MTAP expression. In 41 of these 164 cases (25%), loss of MTAP expression was heterogenous. We also discovered loss of MTAP expression in flat urothelium adjacent to MTAP-negative low-grade UC, suggesting true flat low-grade neoplasia that could not be diagnosed by morphology alone. Longitudinal analysis of recurrences showed persistent negative MTAP status over time in 37/38 (97%) patients. MTAP IHC can serve as a surrogate marker for 9p21 HD in UC and as a diagnostic tool to differentiate reactive urothelium from urothelial neoplasia. It also provides a unique opportunity to study clinicopathological associations and the heterogeneity of 9p21 HD across the whole spectrum of UC manifestations.

TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitors

Deletions of chromosome 1p (del(1p)) are a recurrent genomic aberration associated with poor outcome in Multiple myeloma (MM.) TRIM33, an E3 ligase and transcriptional co-repressor, is located within a commonly deleted region at 1p13.2. TRIM33 is reported to play a role in the regulation of mitosis and PARP-dependent DNA damage response (DDR), both of which are important for maintenance of genome stability. Here, we demonstrate that MM patients with loss of TRIM33 exhibit increased chromosomal instability and poor outcome. Through knockdown studies, we show that TRIM33 loss induces a DDR defect, leading to accumulation of DNA double strand breaks (DSBs) and slower DNA repair kinetics, along with reduced efficiency of non-homologous end joining (NHEJ). Furthermore, TRIM33 loss results in dysregulated ubiquitination of ALC1, an important regulator of response to PARP inhibition. We show that TRIM33 knockdown sensitizes MM cells to the PARP inhibitor Olaparib, and this is synergistic with the standard of care therapy bortezomib, even in co-culture with bone marrow stromal cells (BMSCs). These findings suggest that TRIM33 loss contributes to the pathogenesis of high-risk MM and that this may be therapeutically exploited through the use of PARP inhibitors.

GLI1 Coamplification in Well-Differentiated/Dedifferentiated Liposarcomas: Clinicopathologic and Molecular Analysis of 92 Cases

GLI1(12q13.3) amplification is identified in a subset of mesenchymal neoplasms with a distinct nested round cell/epithelioid phenotype. MDM2 and CDK4 genes are situated along the oncogenic 12q13-15 segment, amplification of which defines well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). The 12q amplicon can occasionally include GLI1, a gene in close proximity to CDK4. We hereby describe the first cohort of GLI1/MDM2/CDK4 coamplified WD/DDLPS. The departmental database was queried retrospectively for all cases of WD/DDLPS having undergone next-generation (MSK-IMPACT) sequencing with confirmed MDM2, CDK4, and GLI1 coamplification. Clinicopathologic data was obtained from a review of the medical chart and available histologic material. Four hundred eighty-six WD/DDLPS cases underwent DNA sequencing, 92 (19%) of which harbored amplification of the GLI1 locus in addition to that of MDM2 and CDK4. These included primary tumors (n = 60), local recurrences (n = 29), and metastases (n = 3). Primary tumors were most frequently retroperitoneal (47/60, 78%), mediastinal (4/60, 7%), and paratesticular (3/60, 5%). Average age was 63 years, with a male:female ratio of 3:2. The cohort was comprised of DDLPS (86/92 [93%], 6 of which were WDLPS with early dedifferentiation) and WDLPS without any longitudinal evidence of dedifferentiation (6/92, 7%). One-fifth (13/86, 17%) of DDLPS cases showed no evidence of a well-differentiated component in any of the primary, recurrent, or metastatic specimens. Dedifferentiated areas mostly showed high-grade undifferentiated pleomorphic sarcoma-like (26/86,30%) and high-grade myxofibrosarcoma-like (13/86,16%) morphologies. A disproportionately increased incidence of meningothelial whorls with/without osseous metaplasia was observed as the predominant pattern in 16/86 (19%) cases, and GLI1-altered morphology as described was identified in a total of 10/86 (12%) tumors. JUN (1p32.1), also implicated in the pathogenesis of WD/DDLPS, was coamplified with all 3 of MDM2, CDK4, and GLI1 in 7/91 (8%) cases. Additional loci along chromosomal arms 1p and 6q, including TNFAIP3, LATS1, and ESR1, were also amplified in a subset of cases. In this large-scale cohort of GLI1 coamplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorl-like and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and coamplification of other spatially discrete genomic segments (1p and 6q) might aid in distinction from tumors with true driver GLI1 alterations.

Chromosome 20p11.2 deletions cause congenital hyperinsulinism via the loss of FOXA2 or its regulatory elements.

Persistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI. Here, we used genome sequencing to search for novel large (>1 Mb) deletions in 180 probands with HI of unknown cause and replicated our findings in a large cohort of 883 genetically unsolved individuals with HI using off-target copy number variant calling from targeted gene panels. We identified overlapping heterozygous deletions in five individuals (range 3-8 Mb) spanning chromosome 20p11.2. The pancreatic beta-cell transcription factor gene, FOXA2, a known cause of HI was deleted in two of the five individuals. In the remaining three, we found a minimal deleted region of 2.4 Mb adjacent to FOXA2 that encompasses multiple non-coding regulatory elements that are in conformational contact with FOXA2. Our data suggests that the deletions in these three children may cause disease through the dysregulation of FOXA2 expression. These findings provide new insights into the regulation of FOXA2 in the beta-cell and confirm an aetiological role for chromosome 20p11.2 deletions in syndromic HI.

Evaluation of 100 Dutch cases with 16p11.2 deletion and duplication syndromes; from clinical manifestations towards personalized treatment options.

The 16p11.2 deletion syndrome is a clinically heterogeneous disorder, characterized by developmental delay, intellectual disability, hyperphagia, obesity, macrocephaly and psychiatric problems. Cases with 16p11.2 duplication syndrome have similar neurodevelopmental problems, but typically show a partial 'mirror phenotype' with underweight and microcephaly. Various copy number variants (CNVs) of the chromosomal 16p11.2 region have been described. Most is known about the 'typical' 16p11.2 BP4-BP5 (29.6-30.2 Mb; ~600 kb) deletions and duplications, but there are also several published cohorts with more distal 16p11.2 BP2-BP3 CNVs (28.8-29.0 Mb; ~220 kb), who exhibit clinical overlap. We assessed 100 cases with various pathogenic 16p11.2 CNVs and compared their clinical characteristics to provide more clear genotype-phenotype correlations and raise awareness of the different 16p11.2 CNVs. Neurodevelopmental and weight issues were reported in the majority of cases. Cases with distal 16p11.2 BP2-BP3 deletion showed the most severe obesity phenotype (73.7% obesity, mean BMI SDS 3.2). In addition to the more well defined typical 16p11.2 BP4-BP5 and distal 16p11.2 BP2-BP3 CNVs, we describe the clinical features of five cases with other, overlapping, 16p11.2 CNVs in more detail. Interestingly, four cases had a second genetic diagnosis and 18 cases an additional gene variant of uncertain significance, that could potentially help explain the cases' phenotypes. In conclusion, we provide an overview of our Dutch cohort of cases with various pathogenic 16p11.2 CNVs and relevant second genetic findings, that can aid in adequately recognizing, diagnosing and counseling of individuals with 16p11.2 CNVs, and describe the personalized medicine for cases with these conditions.

Pediatric-type high-grade gliomas with PDGFRA amplification in adult patients with Li-Fraumeni syndrome: clinical and molecular characterization of three cases

Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene. Central nervous system tumors, such as choroid plexus tumors, medulloblastomas, and diffuse gliomas, are frequently found in patients with LFS. Although molecular profiles of diffuse gliomas that develop in pediatric patients with LFS have been elucidated, those in adults are limited. Recently, diffuse gliomas have been divided into pediatric- and adult-type gliomas, based on their distinct molecular profiles. In the present study, we investigated the molecular profiles of high-grade gliomas in three adults with LFS. These tumors revealed characteristic histopathological findings of high-grade glioma or glioblastoma and harbored wild-type IDH1/2 according to whole exome sequencing (WES). However, these tumors did not exhibit the key molecular alterations of glioblastoma, IDH-wildtype such as TERT promoter mutation, EGFR amplification, or chromosome 7 gain and 10 loss. Although WES revealed no other characteristic gene mutations or copy number alterations in high-grade gliomas, such as those in histone H3 genes, PDGFRA amplification was found in all three cases together with uniparental disomy of chromosome 17p, where the TP53 gene is located. DNA methylation analyses revealed that all tumors exhibited DNA methylation profiles similar to those of pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (pHGG H3-/IDH-wt), RTK1 subtype. These data suggest that high-grade gliomas developed in adult patients with LFS may be involved in pHGG H3-/IDH-wt. PDGFRA and homozygous alterations in TP53 may play pivotal roles in the development of this type of glioma in adult patients with LFS.

Outcome of illuminated microcatheter-assisted circumferential trabeculotomy following failed angle surgery in PAX6 aniridic glaucoma: a case report and literature review

BackgroundAniridia is a rare eye disorder with a high incidence of glaucoma, and surgical intervention is often needed to control the intraocular pressure (IOP). Here, we reported a case of illuminated microcatheter-assisted circumferential trabeculotomy (MAT) performed on an aniridic glaucoma patient following a previous failed angle surgery. The surgical procedures for aniridic glaucoma were also reviewed.Case presentationA 21-year-old man, diagnosed with aniridic glaucoma, came to our hospital consulting for the poor control of left eye’s IOP despite receiving goniotomy surgery 3 years ago. The IOP was 26 mmHg with maximum topical antiglaucoma eyedrops. The central cornea was opaque and the majority of iris was absent. The gonioscopy and ultrasound biomicroscopy (UBM) demonstrated that 360° anterior chamber angle was closed. The whole exome sequencing of peripheral blood confirmed a 13.39 Mb copy number loss at chromosome 11p15.1p13, containing PAX6 and WT1 gene. The 360° MAT surgery was performed on his left eye. At 1-year follow-up, the IOP was 19mmHg with 2 kinds of topical antiglaucoma medications, and the postoperative UBM demonstrated the successful incision of the anterior chamber angle.ConclusionsThe case presented here exhibited a case of aniridic glaucoma treated by MAT surgery. The MAT surgery may be an effective option for IOP control in aniridic glaucoma patients following a previous failed angle surgery.

Abstract NG03: Functional and computational approaches to uncover selection advantages of cancer aneuploidy

Abstract Aneuploidy, including the gain or loss of whole chromosomes or chromosome arms, is a near-universal feature of cancer. We previously applied methods that define chromosome arm aneuploidy to over 10,000 tumors in the Cancer Genome Atlas (TCGA). Cancer subtypes are often characterized by tumor specific patterns of chromosome arm copy number alterations and breakpoints; for example, squamous cell carcinomas (SCCs) from different tissues of origin are characterized by chromosome 3p (chr3p) loss and chromosome 3q (chr3q) gain. From the TCGA aneuploidy data, we developed an algorithm called BISCUT to distinguish peak regions of aneuploidy breakpoints on each chromosome arm. BISCUT identified loci affected by broad copy number alterations that provide fitness advantages or disadvantages both within individual cancer types and across cancers. Our analyses are consistent with selection being the primary driver of aneuploidy events in cancer. We next wanted to validate some BISCUT peaks without a known driver, to identify potential gene deletions that are beneficial in cancer cells. We focused on chromosome 8p (chr8p), as this arm is frequently deleted across cancer types, but no strong tumor suppressors have been identified. Recent advances in genome engineering allow generation of large chromosomal alterations and validation of findings from patient genomic data. For this study, we used our CRISPR-Cas9 arm-deletion system to delete chr8p in human immortalized epithelial cells. Cells with chr8p deletion showed lower amounts of cell death in culture. Knockdown of WRN, one of the two genes in the smallest chr8p BISCUT peak, was sufficient to reproduce this phenotype, suggesting that WRN haploinsufficiency may be beneficial to tumor development. As aneuploidy occurs in tissue-specific patterns, we also wanted to explore the role of chr3 arm aneuploidies in squamous cancers. We again used the CRISPR-Cas9 system to delete one copy of chr3p in a human immortalized lung epithelial cell line similar to the putative cell-of-origin in lung SCC. Consistent with patient data, expression of chr3p genes was decreased upon deletion, as well as increased expression of interferon response genes. Cells with chr3p deletion initially proliferated more slowly than their siblings. Interestingly, after several passages in culture, this proliferation defect was rescued in chr3p deleted cells. Genome sequencing and karyotype analyses suggested that this was partially the result of chr3 duplication, with cells transitioning to a state of chr3q gain. Culturing these cells as organoids also demonstrated that chr3p deletion and chr3q gain can affect basal cell differentiation, consistent with their high frequency in squamous cancers. Our genome engineering approach to model chromosome arm aneuploidies provides a robust model to validate drivers from aneuploidy events, which will be critical to address the gap in our understanding of aneuploidy in cancer. In addition, our methods have identified consequences of individual aneuploidy events, which will lead to new precision oncology targets for patients. Citation Format: Alison M. Taylor. Functional and computational approaches to uncover selection advantages of cancer aneuploidy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr NG03.

Loss of GABARAP mediates resistance to immunogenic chemotherapy in multiple myeloma

AbstractImmunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant antitumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABA type A receptor–associated protein (GABARAP) is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment. GABARAP is located on chromosome 17p, which is commonly deleted in patients with high risk MM. GABARAP deletion impaired the exposure of the eat-me signal CRT on the surface of dying MM cells in vitro and in vivo, thus reducing tumor cell phagocytosis by dendritic cells and the subsequent antitumor T-cell response. Low GABARAP was independently associated with shorter survival in patients with MM and reduced tumor immune infiltration. Mechanistically, we found that GABARAP deletion blocked ICD signaling by decreasing autophagy and altering Golgi apparatus morphology, with consequent defects in the downstream vesicular transport of CRT. Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure, and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, such as bortezomib, with an autophagy inducer, such as rapamycin, may improve patient outcomes in MM, in which low GABARAP in the form of del(17p) is common and leads to worse outcomes.

Psoriasis and Schizophrenia: An immunological link

IntroductionSchizophrenia has progressively been seen as a multifactorial disease, with its pathogenesis including immune dysfunction. Studies have leaned into the activation of brain inflammation, influencing the development of schizophrenia in certain subgroups of patients. Additionally, the role of the T helper (Th17) cells and neuromediators associated are implicated in the pathophysiology of psoriasis, a chronic immune-mediated dermatological condition. A significantly elevated risk was found with 41% increased odds of schizophrenia compared with subjects without psoriasis. The concomitant diagnosis of both illnesses has motivated further investigation into their shared pathways.ObjectivesCharacterize the prevalence of psoriasis in patients with schizophrenia and mutual involved mechanisms.MethodsRetrospective analysis of inpatients of a Portuguese Psychiatry department with the established diagnosis of Schizophrenia, between 2018 and 2022. Additionally a literature review on the topic was conducted.ResultsA sample of 94 patients admitted was obtained. The majority of patients were male (80,1%). The prevalence of the diagnosis of Psoriasis was 6,4% (n=6). A previous epidemiological study conducted in the Portuguese general population concluded that the prevalence of psoriasis is on average 4,4%, which is inferior to the value obtained in our sample. Other studies that measured the relationship between both diagnoses corroborated our results, documenting higher prevalences of psoriasis in patients with schizophrenia than the general population.ConclusionsThe relationship between psoriasis and schizophrenia seems to be bidirectional, with schizophrenia patients having higher risk of psoriasis and psoriasis patients having higher risk of schizophrenia. This could be explained by multiple mechanisms, mainly the activation of Th17 cells but also the fact that there may be a genetic susceptibility due to proximal chromosome loci associated with both diseases (chromosome 6p21.3). This information is essential in providing care to patients because treatment must be carefully adapted. It has been demonstrated that atypical antipsychotics might worsen psoriatic manifestations and immunosuppressive agents are linked to psychotic episodes and worse mental health. Thus, there should be increased alertness for the detection of these conditions in patients with either one of them.Disclosure of InterestNone Declared

206 Spinal Meningioma: An Institutional Case Series With Preliminary Results of Molecular Profiling

INTRODUCTION: Spinal meningiomas have historically been considered similar entities to intracranial meningiomas, but recent developments in molecular profiling have identified unique features. METHODS: Retrospective study of patients undergoing resection of spinal meningioma between 2010–2022 at our institution. Patient, radiographic, and clinical characteristics were reviewed and analyzed with standard statistical methods. Molecular profiling was conducted on three tumors. RESULTS: A total of 33 tumors were resected in 26 patients. Median follow-up was 39.5 (0–149) months. Twenty-five (89.3%) procedures were in female patients. The median age at surgery was 62 (18–84) years. The median tumor was 1.9 (0.9–9) cm. Six tumors (18.2%) were in the cervical region, 28 (48.5%) were thoracic, and 2 (6.1%) were lumbar. Sixteen (48.5%) tumors were located dorsally, 11 (33.3%) ventrally, and six (18.2%) extended dorsoventrally. Gross total resection was achieved in 25 (75.8%) tumors. Median progression-free survival was 139 months. On histological analysis of 28 tumors, 26 (92.9%) were WHO grade 1 and 2 (7.1%) were WHO Grade 3 with a median Ki-67 of 3 (1–20)%. Fourteen (50.0%) tumors were psammomatous, seven (25%) were meningothelial, two (7.1%) were anaplastic, and one was transitional. Molecular profiling was available for three tumors. All three were negative for TERT promoter mutations and exhibited loss of chromosome 22. Chromosomal microarray analysis also detected gains in chromosomes 3p, 9, 11, 12, and 20 and loss of chromosomes 16 and 19 in Tumor 1. Tumor 3 also showed loss of chromosomes 12p and X, with copy-neutral loss of heterozygosity affecting chromosomes 5q, 7q, and 14q. CONCLUSIONS: Preliminary molecular profiling studies of spinal meningiomas show features distinct from intracranial meningiomas, so there is a need for their further molecular characterization.

Smith-Magenis Syndrome associated with Autism Spectrum Disorder with delayed diagnosis due to B12 deficiency: a case report

IntroductionSmith-Magenis syndrome (SMS) is a complex genetic disorder characterised by distinctive physical features, developmental delay, cognitive impairment and a typical behavioural phenotype. SMS is caused by interstitial 17p11.2 deletions (90%) involving multiple genes, including the retinoic acid-induced 1 gene (RAI1), or by pathogenic variants in RAI1 itself (10%).ObjectivesIn this case report, we present a case of Smith-Magenis syndrome with Autism Spectrum Disorder with karyotype 46,XX, 17p 11.2 gene deletion confirmed by Autism Spectrum Disorder, who was followed up in a paediatric neurology outpatient clinic with neuromotor developmental delay and whose diagnosis was delayed due to B12 deficiency. We also update scientific developments in Smith-Magenis syndrome.MethodsWe describe an 18-month-old male with Smith-Magenis syndrome and Autism Spectrum Disorder who was seen in our paediatric psychiatric outpatient clinic and who received B12 replacement with developmental delay.ResultsThe patient was followed up in the paediatric neurology outpatient clinic with delay in neuromotor developmental milestones and this delay was thought to be due to B12 deficiency (B12<100 ng/L). The initial examination revealed delay in neuromotor and behavioural milestones, speech delay, wide and high nasal bridge and hypertelorism. Further physical examination revealed syndactyly of the second and third toes bilaterally and crossed lower teeth. Clinical and psychometric testing (Ankara Developmental Screening Inventory) by 2 consultants and 1 research assistant resulted in a diagnosis of intellectual disability and an additional diagnosis of Autism Spectrum Disorder due to social deficits that could not be explained by intellectual disability.ConclusionsSmith-Magenis syndrome is a well-known disorder involving the deletion of chromosome 17p11.2, which contains the RAI1 gene. This condition is associated with neuromotor and behavioural delay, as well as distinctive dysmorphic features. Clinicians should consider Smith-Magenis syndrome in the differential diagnosis for patients with delayed neuromotor and behavioural milestones, even in the presence of documented blood parameters (such as B12 deficiency) that may account for the delay.Disclosure of InterestNone Declared

Huge mesenchymal hamartoma in a young adult: a case report

Abstract Mesenchymal hamartoma of the liver (MHL) is rare. Less than 50 adult cases have been described. Due to their potential degeneration or recurrence, a complete surgical resection must be performed. We describe a case of a 26-year-old with a palpable solid lesion, which displaced abdominal organs. Percutaneous needle biopsies suggested the diagnosis of MHL. A right hemi-hepatectomy without segment 1 was performed; the post-operative course was uneventful. The mesenchymal component of the tumour was reactive to desmin and smooth muscle actin. Low proliferation index was confirmed (MIB1). Genetic counselling: the sequencing analysis of DICER1 and CDKN1C gene was negative, DNA methylation analysis on the chromosome 11p15 region was normal. After 42 months, there was no recurrence. In conclusion, clinicians should consider MHL in the differential diagnosis. The dimension and the need of radicality impose major liver resections or liver transplantations, which should be performed in referral centres.

Huntington’s disease: A comprehensive case report

Chorea form movements, neuropsychiatric symptoms, and cognitive impairment are hallmarks of Huntington's disease, an inherited progressive neurodegenerative illness that results in severe functional impairment. Between the ages of 30 and 40, it typically shows up. The genetic components of the disease are inherited, meaning that the afflicted individual receives the gene from a parent with the same genetic makeup. It is inherited in an autosomal-dominant manner. It is brought on by increased cytosine-adenine-guanine (CAG) tri-nucleotide repeat in Huntington’s (HTT) gene on chromosome 4p. A patient with a strong family history of Huntington's disease is described, associated with their clinical and genetic features.

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model

BackgroundMicrodeletion of the human chromosomal region 16p11.2 (16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document}) is a prevalent genetic factor associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders. However its pathogenic mechanism remains unclear, and effective treatments for 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} syndrome are lacking. Emerging evidence suggests that the gut microbiota and its metabolites are inextricably linked to host behavior through the gut-brain axis and are therefore implicated in ASD development. Despite this, the functional roles of microbial metabolites in the context of 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} are yet to be elucidated. This study aims to investigate the therapeutic potential of indole-3-propionic acid (IPA), a gut microbiota metabolite, in addressing behavioral and neural deficits associated with 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document}, as well as the underlying molecular mechanisms.ResultsMice with the 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} showed dysbiosis of the gut microbiota and a significant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited significant social and cognitive memory impairments, along with hyperactivation of hippocampal dentate gyrus neurons and reduced inhibitory synaptic transmission in this region. However, oral administration of IPA effectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive deficits of the mice. Remarkably, IPA treatment significantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, without affecting the transcription and translation of the Mapk3 gene.ConclusionsOur study reveals that 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} leads to a decline in gut metabolite IPA levels; however, IPA supplementation notably reverses the behavioral and neural phenotypes of 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} mice. These findings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and present a promising treatment strategy for social and cognitive memory deficit disorders, such as 16p11.2 microdeletion syndrome.92Bbfs5rK2Gd_SbL4an2CwVideo

Study the Association between TP53 (rs12602273C>G) Gene Polymorphism with Susceptibility to the Breast Cancer in North West of Iran

Introduction: The TP53 gene on the short arm of chromosome 17p, which is known as a tumor suppressor gene, encodes the transcription factor p53, and this factor controls cell cycle progression. This study was done to assess the association of TP53 (rs12602273C>G) gene polymorphism with the risk and prognosis of breast cancer in women of northwest of Iran.
 Methods: In this case-control study, the association of TP53 (rs12602273C>G) gene polymorphism with breast cancer risk was studied in a population, including 100 patients and 100 healthy individuals was investigated by Tetra ARMS-PCR technique. The analysis of the resulting data was done using SPSS version 16 software and JavaStat online statistics package.
 Results: In the case group, the frequency of CC, CG, and GG genotypes were 81.52, 16.3, 2.17 percent, respectively and they were 79.34, 17.39, and 3.26 percent for the control group. Similarly, C and G allele frequency in case group was 89.67 and 10.32 percent and those in the control group was 88.04 and 11.95 percent, respectively. Statistical analyzes showed no association between genotypic (P>0.05) and allelic (P>0.05) polymorphism (rs12602273C>G) of TP53 gene with breast cancer. Also, the results showed that the studied polymorphism was not associated with the clinical characteristics of breast cancer patients in the Northwest of Iran (P>0.05).
 Conclusion: These research findings suggest that TP53 polymorphism of rs12602273C>G is not related to the risk of breast cancer. The association of the genotypic distribution of this SNP with the clinical characteristics of the patients was insignificant.

Microbiota profiling reveals alteration of gut microbial neurotransmitters in a mouse model of autism-associated 16p11.2 microduplication.

The gut-brain axis is evident in modulating neuropsychiatric diseases including autism spectrum disorder (ASD). Chromosomal 16p11.2 microduplication 16p11.2dp/+ is among the most prevalent genetic copy number variations (CNV) linked with ASD. However, the implications of gut microbiota status underlying the development of ASD-like impairments induced by 16p11.2dp/+ remains unclear. To address this, we initially investigated a mouse model of 16p11.2dp/+, which exhibits social novelty deficit and repetitive behavior characteristic of ASD. Subsequently, we conducted a comparative analysis of the gut microbial community and metabolomic profiles between 16p11.2dp/+ and their wild-type counterparts using 16S rRNA sequencing and liquid chromatography-mass spectrometry (LC/MS). Our microbiota analysis revealed structural dysbiosis in 16p11.2dp/+ mice, characterized by reduced biodiversity and alterations in species abundance, as indicated by α/β-diversity analysis. Specifically, we observed reduced relative abundances of Faecalibaculum and Romboutsia, accompanied by an increase in Turicibacter and Prevotellaceae UCG_001 in 16p11.2dp/+ group. Metabolomic analysis identified 19 significantly altered metabolites and unveiled enriched amino acid metabolism pathways. Notably, a disruption in the predominantly histamine-centered neurotransmitter network was observed in 16p11.2dp/+ mice. Collectively, our findings delineate potential alterations and correlations among the gut microbiota and microbial neurotransmitters in 16p11.2dp/+ mice, providing new insights into the pathogenesis of and treatment for 16p11.2 CNV-associated ASD.

Особенности патологии органа зрения при орфанном синдроме Pierson вследствие мутации гена LAMB2 у детей: обзор литературы и клиническое наблюдение

Pierson syndrome is an orphan disease with an autosomal recessive mode of inheritance, characterized by combined pathology of the organ of vision, kidneys and central nervous system. Pierson syndrome is caused by a mutation in the LAMB2 gene, mapped on chromosome 3p21, encoding β2-laminin. The pathology of the organ of vision in Pierson syndrome in children is quite diverse. They are characterized by the presence of cataract, posterior lenticonus, iris hypoplasia, glaucoma, retinal detachment, etc. Microcoria (pupil diameter less than 2 mm) is also often observed due to atrophy of the pupillary dilator. The final diagnosis of Pierson syndrome can only be made based on the results of a molecular genetic study. Due to the severe lifethreatening renal manifestations of Pierson syndrome, for a long time the description of ophthalmological pathology was rather superficial. However, considering the high frequency and clinical severity of vision pathology in Pierson syndrome, it seems especially important to study in detail the features of the ocular phenotype in this disease. We have described a clinical observation of a child with Pierson syndrome, who was diagnosed with a missense mutation of the LAMB2 gene, a previously undescribed variant (rs143405268) in exon 18. The disease manifested itself as a combined pathology of the organ of vision, kidneys and the central nervous system. The ocular phenotype of the probands represented by microcoria, diffuse congenital cataract, and later by secondary glaucoma (after cataract surgery). Features of the renal phenotype of the proband were revealed – a horseshoe-shaped kidney, proteinuria not reaching the level of nephrotic syndrome, with preserved renal function. The peculiarity of this case of a child with Pierson syndrome is the absence of nephrotic syndrome in combination with the classic ocular phenotype with a previously undescribed variant of the LAMB2 gene mutation identified. Key words: pierson syndrome, LAMB 2, congenital cataract, microcoria, secondary glaucoma

Family case of Potocki-Lupski syndrome

BackgroundPotocki-Lupski syndrome (PTLS, OMIM # 610883) is a rare genetic developmental disorder resulting from a partial heterozygous microduplication at chromosome 17p11.2. The condition is characterized by a wide variability of clinical expression, which can make its clinical and molecular diagnosis challenging.Case presentationWe report here a family (mother and her two children) diagnosed with PTLS. When examining children, neurological and psychological (neuropsychiatric) manifestations (speech delay, mild mental retardation), motor disorders, craniofacial dysmorphism (microcephaly, dolichocephaly, triangular face, wide bulging forehead, long chin, antimongoloid slant, "elfin" ears) were revealed. The suspected clinical diagnosis was confirmed by MLPA and CMA molecular genetic testing which revealed the presence of a segmental aneusomy; microduplication in the 17p11.2 region.ConclusionsChildren with PTLS can have a clinically recognizable and specific phenotype: craniofacial dysmorphism, motor and neurological manifestations, which may implicate a possible genetic disease to the attending physician. Moreover, each child with this syndrome is unique and may have a different clinical picture. The management of such patients requires a multidisciplinary team approach, including medical genetic counseling.