Variety Of Mutations Research Articles

The Diagnostic Yield of Genetic Testing in Patients With Multiple Colorectal Adenomas: A Specialist Center Cohort Study.

Adenoma multiplicity is associated with increased colorectal cancer (CRC) risk. The utility of genetic testing in patients with multiple colorectal adenomas (MCRA) remains uncertain. We evaluated the diagnostic yield of mutations in polyposis- and CRC-associated genes in patients with MCRA. We performed a cross-sectional review of adult patients with 10-99 cumulative adenomas from the prospective database at the St Mark's Hospital Polyposis Registry and Family Cancer Clinic between 1999 and 2021. Genetic testing was performed for adenomatous polyposis-associated genes, hamartomatous polyposis-associated genes, and nonpolyposis colorectal cancer-associated genes. Clinicopathological outcomes were extracted for multiple logistic regression analysis. Two hundred fifty-nine patients with MCRA (median age 61 [interquartile range 53-69] years) were identified. Sixty-six patients (25.5%) had a pathogenic variant or likely pathogenic variant, with APC and biallelic MUTYH mutations constituting the majority of identified pathogenic variant/likely pathogenic variants. Diagnostic yields were greater than 10% at any adenoma burden. In univariate analysis, higher adenoma burden and younger age were associated with higher yield (both P < 0.0001). In patients with MCRA with 10-19 adenomas without a relevant personal or family history of CRC, the diagnostic yield was nil. In multiple logistic regression analysis, higher adenoma burden, younger age, personal history of CRC, and first-degree familial history of CRC were associated with higher diagnostic yield. Diagnostic yield of >10% at any adenoma burden supports current guidance for constitutional genetic testing in patients with MCRA, although the low yield in people older than 60 years with 10-19 adenomas suggests that a stratified approach might be appropriate.

Machine learning methods and harmonized datasets improve immunogenic neoantigen prediction

The accurate selection of neoantigens that bind to class I human leukocyte antigen (HLA) and are recognized by autologous Tcells is a crucial step in many cancer immunotherapy pipelines. We reprocessed whole-exome sequencing and RNA sequencing (RNA-seq) data from 120 cancer patients from two external large-scale neoantigen immunogenicity screening assays combined with an in-house dataset of 11 patients and identified 46,017 somatic single-nucleotide variant mutations and 1,781,445 neo-peptides, of which 212 mutations and 178 neo-peptides were immunogenic. Beyond features commonly used for neoantigen prioritization, factors such as the location of neo-peptides within protein HLA presentation hotspots, binding promiscuity, and the role of the mutated gene in oncogenicity were predictive for immunogenicity. The classifiers accurately predicted neoantigen immunogenicity across datasets and improved their ranking by up to 30%. Besides insights into machine learning methods for neoantigen ranking, we have provided homogenized datasets valuable for developing and benchmarking companion algorithms for neoantigen-based immunotherapies.

THU432 Severe Osteoporosis Associated With A Novel Plastin 3 (PLS3) Mutation

Abstract Disclosure: A. Ibrahim: None. L. Esper: None. S.M. Gandhi: None. E.S. Nylen: None. Early Onset Osteoporosis (EOOP) affects children and young adults and can be caused by endocrinopathies, chronic medical conditions, nutritional deficiencies, and/or genetic mutations. The most common inherited cause is osteogenesis imperfecta(OI), and a rare variant linked to OI includes a defect in the X chromosomal gene encoding Plastin 3 (PLS3). In our case, a 34-year-old male was referred for severe osteoporosis. He had been diagnosed with osteopenia at age 21. At age 24, imaging revealed multiple vertebral compression fractures and DXA scan confirmed severe osteoporosis. He required L3-L5 kyphoplasty and started on oral bisphosphonates for presumed OI despite negative gene mutation (i.e., COL1A1/COL1A2). He continued treatment for only 2 years. 8 years later, he had persistent osteoporosis (DXA L2-4 Z-score -3.6, LFN Z-score -3.2). He had no evidence of kyphosis or scoliosis and no extraskeletal manifestations such as blue-grey sclera or any dysmorphic features. The workup was negative for secondary causes of EOOP and he denied a family history of osteoporosis. Labs showed normal 24-hour urine calcium, bone markers, and bone Alkaline Phosphatase. Karyotyping showed normal XY and gene analysis was again negative for OI. He started treatment with intravenous Zoledronic acid, however, had a 2-year gap between doses initially causing BMD to drop by 6.5% in L2-L4 (Z -4.1) and by 5.7% in LFN (Z -3.1). Subsequently, he received a total of 5 doses of Zoledronic acid to date and had no further fractures. DXA significantly improved by 10.4% in L2-4 (Z -2.6), and 16.3% in LFN (Z -2.0). Repeated expanded gene testing showed a novel PLS3 hemizygous mutation (deletion at site C.234_237+10del of Exon 3). This case demonstrates a novel PLS3 mutation variant to be a plausible cause of adulthood EOOP which was responsive to bisphosphonate treatment. PLS3 is an F-actin binding and bundling protein involved in cytoskeletal remodeling and may have roles in calcium homeostasis, cell migration, endocytosis, DNA repair, and membrane trafficking. Currently, less than 30 loss of function variants of PLS3 have been identified and all lead to severe osteoporosis- particularly in children. However, our patient’s known onset of bone loss occurred much later- in his twenties and he had no evidence of extra-skeletal manifestations. The cause for such late presentation is unclear but may be attributed to this specific variant of PLS3. This case highlights that PLS3 mutation should be on the differential for EOOP even in early adulthood. Our patient’s BMD has markedly improved with bisphosphonates and he sustained no further fractures after starting therapy. Timely diagnosis and earlier detection will allow for appropriate genetic counseling, earlier screening, and treatment of affected family members. Presentation: Thursday, June 15, 2023

THU506 A Not-So-Simple Case Of Hyperparathyroidism

Abstract Disclosure: P.J. Bhatt: None. S. Rabiei: None. V. Kantorovich: None. Multiple endocrine neoplasia 1 (MEN-1) is a rare autosomal dominant disorder caused by an inactivating mutation of the MEN-1 tumor suppressor gene and is associated with tumors of the parathyroid (95%), endocrine pancreas (40-70%) and anterior pituitary (30-40%). Primary hyperparathyroidism is the most frequent and earliest expression of MEN1 syndrome with a typical onset at age 20-25 in inherited cases, reaching 100% penetrance after age 50. Current guidelines recommend genetic testing in all individuals with primary hyperparathyroidism diagnosed at a young age, with multiglandular disease, or with family history of primary hyperparathyroidism. A 58 year old female with a history of L. breast cancer, pulmonary embolisms, DM2, and recurrent nephrolithiasis was diagnosed with primary hyperparathyroidism at age 36 and had a parathyroidectomy with 3.5 gland removal and later a total thyroidectomy. She continued to be symptomatic and was found to have an ectopic parathyroid gland in her chest requiring parathyroid gland reimplantation 18 years later. After 3 years, she was admitted for a CHF exacerbation and a pancreatic tail lesion was incidentally discovered. There was no mention of pancreatic lesions prior to this reading. Family history was pertinent for a father with nephrolithiasis. Her daughter had recurrent nephrolithiasis, hyperparathyroidism and was found to have a MEN 1 variant of uncertain significance, prompting the patient to seek genetic counseling. 22 years after her initial diagnosis of hyperparathyroidism, she tested positive for a likely pathologic heterozygous variant mutation of the MEN1 gene called 1747C&amp;gt;T. At endocrinology follow-up, she was asymptomatic. Labs showed elevated Chromogranin A at 1,799 ng/ dL [&amp;lt;311] and gastrin 174pg/mL [&amp;lt;/=100]. FSH, LH, prolactin, free alpha subunit, cortisol, and IGF-1 were normal. Further imaging confirmed a DOTATATE-avid 1.1cm nodular lesion in the pancreatic tail, concerning for a neuroendocrine tumor. MEN1 gene mutation is associated with MEN1 syndrome, familial isolated hyperparathyroidism and has an autosomal dominant predisposition to thyroid cancer and paraganglioma-pheochromocytoma syndrome. The 1747C&amp;gt;T sequence change creates a premature translational stop signal in the MEN1 gene and disrupts the NLS2 domain of the MEN1 protein, which is important for DNA binding and repression of cell proliferation. Upon diagnosis of multiglandular hyperparathyroidism, the patient should have been sent for genetic testing and instead, became an example of a multisystem failure to identify and provide necessary testing and treatment. Until her variant diagnosis, her pancreatic tumor was not identified as such. The main cause of mortality in MEN-1 patients is malignant spread of neuroendocrine tumors, hence early detection and prompt treatment are of the utmost importance to preserve quality of life and improve survival. Presentation: Thursday, June 15, 2023

Prospective Clinical Prognostication of Endometrial Carcinomas Based on Next-Generation Sequencing and Immunohistochemistry-Real-World Implementation and Results at a Tertiary Care Center.

Based on findings from The Cancer Genome Atlas and the Proactive Molecular Risk Classifier for Endometrial Cancer algorithm, endometrial carcinoma can now be stratified into 4 prognostically distinct subgroups based on molecular alterations and immunohistochemical (IHC) aberrations. In this study, we describe the de novo adoption and clinical reporting of prognostic subgroup classification based on next-generation sequencing (NGS) and IHC analyses of all endometrial carcinoma resections at a single institution, framed by the Exploration, Preparation, Implementation, and Sustainment model. Results from the first 13 months show 188 tumors underwent analysis by a combination of IHC and a medium-sized (56 analyzed genes) NGS-based assay. All cases were assigned as either POLE ( POLE -mutated) (5.3%), mismatch repair deficient (27.7%), no specific molecular profile (45.7%), or p53 abnormal (21.3%) inclusive of multiple-classifier cases. NGS-based analysis revealed additional distinctions among the subgroups, including reduced levels of PI3K pathway activation in the p53 abnormal subgroup, an increased rate of CTNNB1 activating mutation in the no specific molecular profile subgroup, and lower TP53 mutation variant allele frequencies in POLE and mismatch repair deficient subgroups compared with the p53 abnormal subgroup. Overall, we describe the testing protocol, reporting, and results of a combination of NGS and IHC to prospectively prognosticate endometrial carcinomas at a single tertiary care center.

Assessment of the frequency of BRCA1/2 mutations detection by means of PCR in State Budgetary Healthcare Institution «Saint-Petersburg clinical scientific and practical center for specialised types of medical care (oncological) named after N.P. Napalkov»

Background.BRCA1/2 germline testing allows us to optimize treatment strategy for patients with breast and ovarian cancer cases,to provide early diagnosis and also prophylactic measures for mutation carriers. Considering absence of large BRCA studies on Russian population, we do not have any clear understanding of approximate BRCA1/2 germline mutation frequency, a whole number of founder mutations and impact of non-founder BRCA1/2 mutations, which are not included in a standard PCR panel. Objective. Assessment of the frequency of BRCA1/2 mutations detection by means of PCR in breast and ovarian cancer patients in real clinical practice in St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (oncological) named after N.P. Napalkov. Analysis of a database for BRCA1/2-negative patients on a presence of risk factors associated with a probability of carrying a germline mutation in BRCA1/2 genes. Materials and methods. We retrospectively evaluated 335 ovarian and 1196 breast cancer patients, tested for germline BRCA1/2 by PCR in SPb CSPC(o) named after N.P. Napalkov from 01.01.2019 to 31.12.2021. For analysis was used patient’s blood plasma and a standard PCR panel detecting 8 mutation variants. A database for BRCA1/2-negative patients was retrospectively analyzed on a presence of risk factors associated with a high probability of hereditary cancer: an early onset and family history of cancer (BRCA associated). Statistical analysis was carried out using the SPSS software package (IBM® SPPS® Statistics v. 20), a number of graphs were carried out using Microsoft® Excel® 2016 programs. Results. BRCA1/2 germline mutations were detected in 6,4% (n= 98). Mean frequency of detection was 12,6% (n=45) for ovarian cancer patients, 4,3% (n=53) for breast cancer patients. Analysis of a database for BRCA1/2-negative patients demonstrated that 22,5% (n=346) BC and OC cases had an early onset. Family history of cancer was identified for 13,6% (n=195) patients with breast or ovarian cancer, including 3,8% (n=43) with 2 and more family cases of BRCA associated cancers. Conclusions. The frequency of detected BRCA1/2 germline mutations by PCR for breast and ovarian cancer patients in SPb CSPC(o) named after N.P. Napalkov is lower than the one described in international data. A large part of patients BRCA1/2 negative by PCR test has characteristics of hereditary breast cancer syndrome and requires further NGS.

Molecular Subtypes and Outcomes in a Multi-Institutional Review of Rectal Cancer Patients

Colorectal cancer (CRC) is a heterogeneous malignancy associated with a variety of genetic mutations. More recent data indicates that CRC can be broken down into unique biologically distinct consensus molecular subtypes (CMS) based on different pathological and genetic signatures. The purpose of this study is to evaluate the outcomes of rectal cancer patients in a multi-institutional network based on tumor mutational assessment and CMS group. Patient exome and transcriptome sequencing data and clinical outcomes were collected under the Total Cancer Care Protocol and Avatar® project within the Oncology Research Information Exchange Network (ORIEN). A total of 101 patients with demographic and outcomes information had data for microsatellite instability (MSI), tumor mutation burden (TMB), transcriptome, and whole exome sequencing (WES). Molecular subclasses (CMS1, CMS2, CMS3, CMS4, CMS-Mixed) were assigned based on transcriptional signatures by the R package "CMS Caller." Survival analysis was performed with the R packages "Survival" and "Survminer." A total of 101 rectal cancer patients, with a median age of 56.8, had a median follow up of 3.5 years (range 0.26-23.5). 78 patients were treated with curative intent for clinically localized disease and 35% of these patients developed metastatic disease. The remaining 23 patients had synchronous metastatic disease at presentation. There were 5 (5%) CMS1, 29 (29%) CMS2, 13 (13%) CMS 3, 49 (49%) CMS 4, and 5 (5%) CMS-Mixed patients in our cohort respectively. The cohort included 5 (5%) BRAF, 51 (50%) KRAS, and 63 (62%) TP53 mutated patients and 5 (5%) MSI high patients. Median survival was 18.8, 117.2, 125.7 and 119 months for CMS1, CMS2, CMS3, and CMS4 patients respectively, with insufficient events in CMS-mixed for calculation (p = 0.15). CMS1 patients had a significantly shorter survival compared to the other cohorts (p = 0.02), with 2 of 5 of these patients having received immunotherapy. 40% (2,0) CMS1, 52% (7,8) of CMS2, 15% (1,1) of CMS3, 59% (13,15) of CMS4, and 40% (1,1) of CMS-Mixed presented with or developed metastatic disease respectively. When divided into mutation groups, median survival was 43 versus 119, 119 versus 117, and 126 versus 119 months for BRAF, KRAS, and TP53 mutated and wild type patients respectively (p = 0.18, p = 0.48, p = 0.93). Evaluation of TMB and MSI status did not reveal significant differences in outcomes (p = 0.54, p = 0.7), with median survival of 126 months versus 117 in TMB high versus low patients and unreached versus 119 months in MSI versus MSS patients respectively. Of note, 3 of the 5 MSI patients were also CMS1, with the other two coming from CMS4 and CMS-mixed cohorts. CMS classification and tumor mutation status are associated with differential outcomes for rectal cancer patients, with some groups having a large likelihood of developing metastatic disease. Further work on optimizing and personalizing treatments for these high-risk populations is necessary.

Molecular Characterization of Glucose-6-phosphate Dehydrogenase Deficiency in Oman.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most encountered abnormality of red blood cell metabolism worldwide and has a high prevalence in Oman. The objective of the study was to characterize the mutation variants of G6PD deficiency in a cohort of the Omani population with partial and complete enzyme deficiency. This prospective study included newborns and children less than one year of age with partial or complete G6PD enzyme deficiency identified on routine screening using a fluorescent spot test from 31 January 2017 to 12 September 2017 in Sultan Qaboos University Hospital. The identified samples were analyzed for the presence of C563T, G1003A, and other mutations using direct DNA sequencing of the polymerase chain reaction. Out of 3679 newborn samples screened, 21.0% were found to have complete or partial G6PD enzyme deficiency. A total of 145 participants were included in the genetic analysis, of which 133 (91.7%) were completely deficient in G6PD enzyme activity and 12 (8.3%) had partial deficiency. The Mediterranean variant (C563T) was identified in 129 (89.0%). Other variants were found as follows: eight (5.5%) had variant A-, three (2.1%) had the Chatham variant (G1003A), one (0.7%) had the Cosenza variant, and one (0.7%) had exon 11 variant. No mutation was found in two subjects. The most common mutation in the Omani population is the Mediterranean mutation (C563T) followed by the variant A- mutation. However, not all participants were found to have a mutation.

Statistical Mechanics Metrics in Pairing and Parsing In Silico and Phenotypic Data of a Novel Genetic NFκB1 (c.T638A) Variant.

(1) Background: Mutations in NFκB1, a transcriptional regulator of immunomodulating proteins, are a known cause of inborn errors of immunity. Our proband is a 22-year-old male with a diagnosis of common variable immunodeficiency (CVID), cytopenias with massive splenomegaly, and nodular regenerative hyperplasia of the liver. Genetic studies identified a novel, single-point mutation variant in NFκB1, c. T638A p. V213E. (2) Methods: Next-generation panel sequencing of the patient uncovered a novel single-point mutation in the NFκB1 gene that was modeled using the I-TASSER homology-modeling software, and molecular dynamics were assessed using the YASARA2 software (version 20.14.24). (3) Results: This variant replaces valine with glutamic acid at position 213 in the NFκB1 sequence. Molecular modeling and molecular dynamic studies showed altered dynamics in and around the rel homology domain, ankyrin regions, and death domain of the protein. We postulate that these changes alter overall protein function. (4) Conclusions: This case suggests the pathogenicity of a novel variant using protein-modeling techniques and molecular dynamic simulations.

Structure adaptation in Omicron SARS-CoV-2/hACE2: Biophysical origins of evolutionary driving forces

Since its emergence, the COVID-19 threat has been sustained by a series of transmission waves initiated by new variants of the SARS-CoV-2 virus. Some of these arise with higher transmissivity and/or increased disease severity. Here, we use molecular dynamics simulations to examine the modulation of the fundamental interactions between the receptor binding domain (RBD) of the spike glycoprotein and the host cell receptor (human angiotensin-converting enzyme 2 [hACE2]) arising from Omicron variant mutations (BA.1 and BA.2) relative to the original wild-type strain. Our key findings are that glycans play a vital role at the RBD···hACE2 interface for the Omicrons, and the interplay between glycans and sequence mutations leads to enhanced binding. We find significant structural differences in the complexes, which overall bring the spike protein and its receptor into closer proximity. These are consistent with and attributed to the higher positive charge on the RBD conferred by BA.1 and BA.2 mutations relative to the wild-type. However, further differences between subvariants BA.1 and BA.2 (which have equivalent RBD charges) are also evident: mutations reduce interdomain interactions between the up chain and its clockwise neighbor chain in particular for the latter, resulting in enhanced flexibility for BA.2. Consequently, we see occurrence of additional close contacts in one replica of BA.2, which include binding to hACE2 by a second RBD in addition to the up chain. Although this motif is not seen in BA.1, we find that the Omicrons can directly/indirectly bind a down-RBD to hACE2 through glycans: the role of the glycan on N90 of hACE2 switches from inhibiting to facilitating the binding to Omicron spike protein via glycan-protein lateral interactions. These structural and electrostatic differences offer further insight into the mechanisms by which viral mutations modulate host cell binding and provide a biophysical basis for evolutionary driving forces.

Glioma genetic profiles associated with electrophysiologic hyperexcitability.

Distinct genetic alterations determine glioma aggressiveness, however, the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures over the course of the disease is uncertain. This study aimed to identify tumor somatic mutation profiles associated with clinically significant hyperexcitability. A single center cohort of adults with WHO grades 1-4 glioma and targeted exome sequencing (n = 1716) was analyzed and cross-referenced with a validated EEG database to identify the subset of individuals who underwent continuous EEG monitoring (n = 206). Hyperexcitability was defined by the presence of lateralized periodic discharges and/or electrographic seizures. Cross-validated discriminant analysis models trained exclusively on recurrent somatic mutations were used to identify variants associated with hyperexcitability. The distribution of WHO grades and tumor mutational burdens were similar between patients with and without hyperexcitability. Discriminant analysis models classified the presence or absence of EEG hyperexcitability with an overall accuracy of 70.9%, regardless of IDH1 R132H inclusion. Predictive variants included nonsense mutations in ATRX and TP53, indel mutations in RBBP8 and CREBBP, and nonsynonymous missense mutations with predicted damaging consequences in EGFR, KRAS, PIK3CA, TP53, and USP28. This profile improved estimates of hyperexcitability in a multivariate analysis controlling for age, sex, tumor location, integrated pathologic diagnosis, recurrence status, and preoperative epilepsy. Predicted somatic mutation variants were over-represented in patients with hyperexcitability compared to individuals without hyperexcitability and those who did not undergo continuous EEG. These findings implicate diverse glioma somatic mutations in cancer genes associated with peritumoral hyperexcitability. Tumor genetic profiling may facilitate glioma-related epilepsy prognostication and management.

CAV-3-related age-dependent muscle diseases: A novel mutation in mother and son

The caveolin-3 protein encoded by the CAV-3 gene is a muscle-specific protein found in skeletal, smooth, and cardiac muscle. Caveolin-3 defects lead to several muscle diseases: rippling muscle disease (RMD), limb-girdle muscular dystrophy (LGMD1C), distal myopathy, familial hypertrophic cardiomyopathy, and asymptomatic hyper-CK-emia. While some variants that cause mutations in this gene cause a pure type of disease, some variants may appear as overlap syndromes. Even in the same variants of CAV-3 mutation, the type of muscle disease, its severity, and time of occurrence can be variable. For this reason, it should be known that CAV-3-related diseases and all overlapping diseases can be seen over time, and the patient should be followed up. We report here a 9-year- old boy and his 38-year-old mother who were investigated for asymptomatic hyper-CK-emia and diagnosed with caveolinopathy. The boy had calf hypertrophy and percussion-induced rapid muscle contraction (PIRCs). His mother had calf hypertrophy, contractions due to percussion, and proximal muscle weakness. Mother’s proximal muscles and m. gastrocnemius magnetic resonance imaging (MRI) was normal. The mother had complaints of weakness, showing slow progression starting from the second decade. Heterozygous (ENST000003cav3849.2) c.298A&gt;T p.Ile100Phe variant in exon 2 was detected in the CAV-3 gene. This mutation is classified as pathogenic according to The American College of Medical Genetics and Genomics (ACMG) criteria (PM1, PM2, PP3, PM5). In conclusion, calves’ pseudohypertrophy and mildly raised CK without weakness can be the initial presentation of caveolinopathy. Percussion-induced muscle contractions, rather than muscle rippling, can occur at a young age. The onset of muscle weakness can be delayed during adolescence and can have a slowly deteriorating course associated with myalgia.

Pyruvate Dehydrogenase E3 Deficiency - Heterozygous Mutation in Dihydrolipoamide Dehydrogenase (DLD) Gene Associated with Symptomatic Hypoglycaemia. A Case Report

Background: Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial disorder that presents with lactic acidemia and neurological manifestations. It is a very rare genetic disorder, a potentially life-threatening one with the usual presentation of hypotonia, lethargy, and developmental delay. It is commonly associated with structural brain abnormalities. We report a very rare case of transient severe symptomatic hypoglycaemia probably due to pyruvate dehydrogenase E3 deficiency; a component of pyruvate dehydrogenase complex (PDC). Case Presentation: Our patient is a 12-day-old neonate with lethargy, and vomiting presented with severe symptomatic hypoglycaemia with a critical sample suggestive of hyperinsulinism and raised lactate levels. A TMS-GCMS for metabolic abnormality screening was normal, however, a whole genome sequencing(nuclear + mitochondrial) revealed heterozygous missense variants (c.763A&gt;C) in exon 9 of the DLD gene that results in the amino acid substitution from Methionine to Leucine at codon 255 (p.Met255Leu) and another heterozygous mutation of heterozygous missense variant (c.5277A&gt;T) in exon 34 of the LAMB1 gene that results in the amino acid substitution from Glutamine to Histidine at codon 1759 (p.Gln1759His). Conclusion: There is no effective treatment for PDCD but reports of treatment with supplements like thiamine, biotin, and coenzyme Q may play a role in preventing the severity of the disease.

Aortic Dissection and a Previously Unreported ACTA2 Missense Variant Mutation in a Young Patient: A Case Report.

Hereditary connective tissue disease is known to cause aortic lesions at an early age. Familial aortic aneurysm/dissection is caused due to an ACTA2 mutation that affects smooth muscle structure. We present a case of a 15-year-old boy with a mild developmental disorder in whom no abnormalities were identified on previous physical examinations. The patient presented with severe left heart failure, extensive dissection from the ascending aorta to the common iliac artery, and myocardial and cerebral infarctions. He underwent an urgent Bentall surgery. Six months later, the patient underwent surgical reconstruction of the abdominal aorta from the aortic arch and returned to normal daily activities. Pathological examination demonstrated the absence of elastic fibers but presence of abundant reticular fibers and mucopolysaccharides from the tunica intima to the media. Genetic testing revealed a heterozygous missense variant of the ACTA2 gene. To the best of our knowledge, this is the first sporadic case of structurally abnormal smooth muscle organization resulting in clinical symptoms with no previously reported pathogenicity.

Landscape of somatic mutated genes and inherited susceptibility genes in gynecological cancer.

Traditionally, gynecological cancers have been classified based on histology. Since remarkable advancements in next-generation sequencing technology have enabled the exploration of somatic mutations in various cancer types, comprehensive sequencing efforts have revealed the genomic landscapes of some common forms of human cancer. The genomic features of various gynecological malignancies have been reported by several studies of large-scale genomic cohorts, including The Cancer Genome Atlas. Although recent comprehensive genomic profiling tests, which can detect hundreds of genetic mutations at a time from cancer tissues or blood samples, have been increasingly used as diagnostic clinical biomarkers and in therapeutic management decisions, germline pathogenic variants associated with hereditary cancers can also be detected using this test. Gynecological cancers are closely related to genetic factors, with approximately 5% of endometrial cancer cases and 20% of ovarian cancer cases being caused by germline pathogenic variants. Hereditary breast and ovarian cancer syndrome and Lynch syndrome are the two major cancer susceptibility syndromes among gynecological cancers. In addition, several other hereditary syndromes have been reported to be associated with gynecological cancers. In this review, we highlight the genes for somatic mutation and germline pathogenic variants commonly seen in gynecological cancers. We first describe the relationship between clinicopathological attributes and somatic mutated genes. Subsequently, we discuss the characteristics and clinical management of inherited cancer syndromes resulting from pathogenic germline variants in gynecological malignancies.

Gut Microbiome Dysbiosis as a Potential Risk Factor for Idiopathic Toe-Walking in Children: A Review.

Idiopathic toe walking (ITW) occurs in about 5% of children. Orthopedic treatment of ITW is complicated by the lack of a known etiology. Only half of the conservative and surgical methods of treatment give a stable positive result of normalizing gait. Available data indicate that the disease is heterogeneous and multifactorial. Recently, some children with ITW have been found to have genetic variants of mutations that can lead to the development of toe walking. At the same time, some children show sensorimotor impairment, but these studies are very limited. Sensorimotor dysfunction could potentially arise from an imbalanced production of neurotransmitters that play a crucial role in motor control. Using the data obtained in the studies of several pathologies manifested by the association of sensory-motor dysfunction and intestinal dysbiosis, we attempt to substantiate the notion that malfunction of neurotransmitter production is caused by the imbalance of gut microbiota metabolites as a result of dysbiosis. This review delves into the exciting possibility of a connection between variations in the microbiome and ITW. The purpose of this review is to establish a strong theoretical foundation and highlight the benefits of further exploring the possible connection between alterations in the microbiome and TW for further studies of ITW etiology.

A Novel Mutation of MSH2 Gene in a Patient with Lynch Syndrome Presenting with Thirteen Metachronous Malignancies.

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), accounts for 2-3% of all colorectal cancers. This autosomal dominant disorder is associated with a predisposition to endometrial, stomach, small bowel, pancreatic, biliary tract, ovary, urinary tract, brain, and skin tumors. Lynch syndrome is caused by the mutation of the MLH1, MSH2 (EPCAM), MSH6, and PMS2 genes. In this article, a case study of a 70-year-old female patient with Lynch syndrome is presented. Over a span of 30 years, the patient underwent multiple surgical procedures for a total of thirteen different malignancies. She was found to have a deleterious pathogenic gene MSH2 (NM_000251.2) variant (mutation) c.1774_1775insT in the 12th exon. This variant, c.1774_1775insT, represents a novel finding, as it has not been previously reported in existing databases or literature. No other case of 13 metachronous tumors in a patient with Lynch syndrome was found in the literature.

Synonymous Myocilin mutations break their silence in a Zambian population attending selected referral eye health facilities

Objective: Primary open-angle glaucoma in Zambia has an earlier age of onset and appears to be more clinically severe. Myocilin mutations are associated with primary open angle glaucoma in multiple populations. Therefore, we investigated the role of myocilin gene mutations in Primary Open Angle Glaucoma in a Zambian population. Methods: The unrelated primary open-angle glaucoma patients and unaffected controls recruited were from the University Teaching Hospitals Eye Hospital, Kitwe Teaching Eye Hospital and Lusaka Adventist Eye Hospital. A complete eye examination, including visual field assessment, was performed in all cases and controls.Genomic DNA was extracted from whole peripheral blood, then subjected to polymerase chain reaction to amplify exons, flanking introns and promoter regions of the myocilingene. The amplified products were screened for base mutations by auto sequence based on the Sanger method. The analyses of findings included odds ratios, chi-square, bivariate, multivariate and conditional logistic regression with 95% confidence interval and at a 5% level of significance.There was also a comparison between the identified mutations and the previously reported myocilinmutations. Results: Unrelated 165 Primary Open-Angle Glaucoma patients and unaffected 173 controls enrolled for the study. The analysis revealed 4 variants of MYOC mutations in 49 participants of the 338. The mutations included one synonymous (silent) mutation (Thr474Thr; 45/338) and three missense mutations (Ala446Thr; 16/338), (Leu158Arg; 4/338) and (Arg342Lys; 1/338). The study observed two previously reported mutations, Ala446Thr and Arg342Lys, as glaucoma causing mutations. The missense mutation, Ala446Thr, was found in 16 participants who also had silent mutations broken down as eight cases and eight controls. One control had two variants, Ala446Thr and Arg342Lys. Twenty (20) controls and 25 cases had the synonymous or silent (neutral) mutation, (Thr474Thr). The occurrence of Thr474Thr and Ala446Thr in the same cases and controls was compelling evidence to think that the synonymous mutations were not as silent as previously reported. The Thr474Thr and Ala446Thr mutations exhibited identical primary open-angle glaucomaphenotypic features in both cases and controls. In the remaining 17 cases and 12 controls the phenotype were still the same. The clinical profile in Thr474Thr mutation was statistically significant for female gender, younger age group (&lt;40 years), older age group (≥ 65 years), positive family history, poor visual acuity, severe visual field changes, diffuse retinal nerve fibre layer defects, peripapillary atrophy surrounding the optic nerve head and high cup disc ratio between 0.8 and 1.0 Conclusions: The silent myocilin mutations, Thr474Thr, break their silence in a Zambian population. The silent mutation Thr474Thr found was associated with primary open-angle glaucoma phenotype and appeared to be a glaucoma-causing.

ATAD3A: A Key Regulator of Mitochondria-Associated Diseases.

Mitochondrial membrane protein ATAD3A is a member of the AAA-domain-containing ATPases superfamily. It is important for the maintenance of mitochondrial DNA, structure, and function. In recent years, an increasing number of ATAD3A mutations have been identified in patients with neurological symptoms. Many of these mutations disrupt mitochondrial structure, function, and dynamics and are lethal to patients at a young age. Here, we summarize the current understanding of the relationship between ATAD3A and mitochondria, including the interaction of ATAD3A with mitochondrial DNA and mitochondrial/ER proteins, the regulation of ATAD3A in cholesterol mitochondrial trafficking, and the effect of known ATAD3A mutations on mitochondrial function. In the current review, we revealed that the oligomerization and interaction of ATAD3A with other mitochondrial/ER proteins are vital for its various functions. Despite affecting different domains of the protein, nearly all documented mutations observed in ATAD3A exhibit either loss-of-function or dominant-negative effects, potentially leading to disruption in the dimerization of ATAD3A; autophagy; mitophagy; alteration in mitochondrial number, size, and cristae morphology; and diminished activity of mitochondrial respiratory chain complexes I, IV, and V. These findings imply that ATAD3A plays a critical role in mitochondrial dynamics, which can be readily perturbed by ATAD3A mutation variants.

Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations

IntroductionLorlatinib, a third-generation ALK tyrosine kinase inhibitor, improved outcomes compared with crizotinib in patients with previously untreated ALK-positive advanced NSCLC in the phase 3 CROWN study. Here, we investigated response correlates using plasma circulating tumor DNA (ctDNA) and tumor tissue profiling. MethodsALK fusions and ALK with or without TP53 mutations were assessed by next-generation sequencing. End points included objective response rate (ORR), duration of response, and progression-free survival (PFS) by blinded independent central review on the basis of EML4::ALK variants and ALK with or without TP53 or other mutation status. ResultsALK fusions were detected in the ctDNA of 62 patients in the lorlatinib arm and 64 patients in the crizotinib arm. ORRs were numerically higher with lorlatinib versus crizotinib for EML4::ALK variant 1 (v1; 80.0% versus 50.0%) and variant 2 (v2; 85.7% versus 50.0%) but were similar between the arms for variant 3 (v3; 72.2% versus 73.9%). Median PFS in the lorlatinib arm was not reached for EML4::ALK v1 and v2 and was 33.3 months for v3; in the crizotinib arm, median PFS was 7.4 months, not reached, and 5.5 months, respectively. ORRs and PFS were improved with lorlatinib versus crizotinib regardless of TP53 mutation status and in patients harboring preexisting bypass pathway resistance alterations. In the lorlatinib arm, PFS was lower in patients who had a co-occurring TP53 mutation. Results from ctDNA analysis were similar to those observed with tumor tissue samples. ConclusionsPatients with untreated ALK-positive advanced NSCLC derived greater clinical benefits, with higher ORRs and potentially longer PFS, when treated with lorlatinib compared with crizotinib, independent of EML4::ALK variant or ALK mutations, TP53 mutations, or bypass resistance alterations.