Common Genetic Syndrome Research Articles

Young children with Noonan syndrome: evaluation of feeding problems

Noonan syndrome (NS) is a common genetic syndrome with a high variety in phenotype. Even though genetic testing is possible, NS is still a clinical diagnosis. Feeding problems are often present in infancy. We investigated the feeding status of 108 patients with clinically and genetically confirmed NS. Only patients with a documented feeding status before the age of 6 were included. A distinction was made between patients with early onset feeding problems (< 1 year) and children with late onset feeding problems (> 1 year). Seventy-one of 108 patients had feeding problems, of which 40 patients required tube feeding. Children with a genetic mutation other than PTPN11 and SOS1 had significantly more feeding problems in the first year. Fifty-two of all 108 patients experienced early onset feeding problems, of which 33 required tube feeding. A strong decrease in prevalence of feeding problems was found after the first year of life. Fifteen children developed feeding problems later in life, of which 7 required tube feeding.Conclusion: Feeding problems occur frequently in children with NS, especially in children with NS based on genetic mutations other than PTPN11 and SOS1. Feeding problems develop most often in infancy and decrease with age.What is Known:• Young children with Noonan syndrome may have transient feeding problems.• Most of them will need tube feeding.What is New:• This is the first study of feeding problems in patients with clinically and genetically proven Noonan syndrome.• Feeding problems most often develop in infancy and resolve between the age of 1 and 2.

New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors.

Neurofibromatosis Type 1 (NF1) is a common genetic disorder and cancer predisposition syndrome (1:3000 births) caused by mutations in the tumor suppressor gene NF1. NF1 encodes neurofibromin, a negative regulator of the Ras signaling pathway. Individuals with NF1 often develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage, some of which progress further to malignant peripheral nerve sheath tumors (MPNSTs). Treatment options for neurofibromas and MPNSTs are extremely limited, relying largely on surgical resection and cytotoxic chemotherapy. Identification of novel therapeutic targets in both benign neurofibromas and MPNSTs is critical for improved patient outcomes and quality of life. Recent clinical trials conducted in patients with NF1 for the treatment of symptomatic plexiform neurofibromas using inhibitors of the mitogen-activated protein kinase (MEK) have shown very promising results. However, MEK inhibitors do not work in all patients and have significant side effects. In addition, preliminary evidence suggests single agent use of MEK inhibitors for MPNST treatment will fail. Here, we describe the preclinical efforts that led to the identification of MEK inhibitors as promising therapeutics for the treatment of NF1-related neoplasia and possible reasons they lack single agent efficacy in the treatment of MPNSTs. In addition, we describe work to find targets other than MEK for treatment of MPNST. These have come from studies of RAS biochemistry, in vitro drug screening, forward genetic screens for Schwann cell tumors, and synthetic lethal screens in cells with oncogenic RAS gene mutations. Lastly, we discuss new approaches to exploit drug screening and synthetic lethality with NF1 loss of function mutations in human Schwann cells using CRISPR/Cas9 technology.

Immune Dysregulation in Children With Down Syndrome.

Down syndrome (DS) is the most common genetic syndrome associated with immune defects. The extent of immune dysregulation in DS is substantial, spanning the innate and adaptive systems and including anomalies in: T and B cells, monocytes, neutrophil chemotaxis, circulating cytokines, and suboptimal antibody responses which all contribute to an increased risk of infections, poorer clinical outcomes and chronic inflammation in this vulnerable cohort. Other aspects of innate immunity may also be abnormal and contribute to the increased morbidity and warrant further interrogation such as: gamma delta T cell function, the inflammasome, Toll-like receptors and their pathways. Pharmacotherapies such as pavilizumab, pneumococcal and influenza immunizations, as well as potential immunoprophylactic agents such as pidotimod, azithromycin and Broncho-Vaxom may help alleviate the infectious consequences. Children with DS need to be managed with a heightened sense of awareness and urgency in the setting of sepsis and signs of chronic inflammation need regular screening and appropriate follow up.

Neurocognitive abilities in individuals with Down syndrome-a narrative review

Down syndrome (DS), or trisomy 21, is the most common genetic syndrome associated with intellectual disability. Despite the variability in expression, there is a distinct developmental phenotype characterized by deficits in learning/memory, executive functions, and language skills accompanying the psychomotor delay. The severity of intellectual impairment has the dominant effect on functioning, other influences such as parental and societal attitudes, supports available and social opportunities also play a role in the attainment of skills.

Genetics and the Gynecologic Patient.

Background: The field of hereditary cancer syndromes and genetic testing for patients and families is a rapidly evolving discipline, with an emphasis on cancer prevention.Methods: We review the literature regarding the most common genetic syndromes associated with gynecologic malignancies and discuss the management of these conditions. We also examine the logistic process surrounding cancer genetic testing and identify some perceived barriers.Results: Five genetic syndromes are known to be associated with gynecologic malignancies: hereditary breast and ovarian cancer, Lynch, Cowden, Peutz-Jeghers, and Li-Fraumeni. Each is associated with varying risks of breast, ovarian, and uterine malignancies. The National Comprehensive Cancer Network guidelines regarding the management of these syndromes are focused primarily on reducing the risk of developing gynecologic malignancies. However, great complexity is involved with genetic testing for patients and their families, and barriers exist for the widespread use and implementation of such testing.Conclusion: Genetic testing is fundamental to primary cancer prevention and to oncologic care. Physicians, payers, and institutions must work collaboratively to maximize genetic testing with the goals of primary cancer prevention and treatment.

Ketotifen Modulates Mast Cell Chemotaxis to Kit-Ligand, but Does Not Impact Mast Cell Numbers, Degranulation, or Tumor Behavior in Neurofibromas of Nf1-Deficient Mice.

Neurofibromatosis Type 1 (NF1) is one of the most common genetic tumor predisposition syndromes in humans. Mutant NF1 results in dysregulated RAS allowing neoplasms throughout the neuroaxis. Plexiform neurofibromas (pNF) afflict up to 50% of patients with NF1. They are complex tumors of the peripheral nerve that cause major morbidity via nerve dysregulation and mortality via conversion to malignant sarcoma. Genetically engineered mouse models (GEMM) of NF1 provide valuable insights for the identification of therapies that have utility in people with pNF. Preclinical studies in GEMMs implicate mast cells and the c-Kit/Kit ligand pathway in pNF tumorigenesis. Kit ligand is a potent chemokine secreted by tumorigenic, Nf1-deficient Schwann cells. Ketotifen is an FDA-approved drug for the treatment of allergic conjunctivitis and asthma that promotes mast cell stabilization and has been used in prior case studies to treat or prevent pNFs. This study investigated the effect of ketotifen on mast cell infiltration and degranulation in the presence and absence of Kit ligand provocation and the effect of ketotifen on shrinking or preventing pNF formation in the Nf1flox/flox ;PostnCre + GEMM. Ketotifen decreased mast cell infiltration in response to exogenous Kit ligand administration, but did not affect mast cell degranulation. Importantly, ketotifen did not reduce mast cells numbers or activity in pNF and did not prevent pNF formation or decrease the volume of established pNF despite administration of pharmacologically active doses. These findings suggest that ketotifen has limited use as monotherapy to prevent or reduce pNF burden in the setting of Nf1 mutations.

Characteristics and etiologies of short stature in children: Experience of an endocrine clinic in a Tunisian tertiary care hospital.

BackgroundShort stature is a common reason for referral to pediatric endocrinology clinics. It may be a manifestation of a pathological condition requiring early treatment. The aim of this study was to describe the characteristics and etiologies of short stature among children referred to the pediatric endocrinology clinic of the main pediatric tertiary care center in Tunisia.MethodsRetrospective and descriptive study in the endocrinology unit of children referred for short stature between January 2012 and December 2016. Data on the patients' medical history, physical findings, laboratory tests, bone age and chromosomal analysis were collected.Results470 children (266 males and 204 females) were referred during that period. 214 (45.5%) had normal height, and 80.8% of them were referred by general practitioners. The other 256 children (54.5%) had a confirmed short stature (mean age :7.2 years, mean height: -2.77 SDS). Endocrinological causes were the most common(43% GHD, 4% hypothyroidism) followed by intrauterine growth retardation IUGR (24%), genetic syndromes (8.4%), chronic pediatric diseases (7.8%), skeletal dysplasia (6.2%), normal variant of short stature (5%), and psychosocial deprivation (1.2%). Among non-endocrine causes, Turner syndrome was the most common genetic syndrome (4.4%), achondroplasia the main skeletal dysplasia (4%) and celiac disease the main chronic disease (3.4%).ConclusionsST is largely overestimated in our country. Therefore, it is important to insist on adequate measurement and analysis of growth parameters to avoid unnecessary investigations. GHD and IUGR were the most common causes. Celiac disease, though frequent in Tunisia, is not a common cause of short stature.

Current and Emerging Imaging Techniques in Patients with GeneticAortic Syndromes.

Patients with genetic aortic syndromes such as Marfan or Loeys-Dietz syndrome have a decreased life expectancy due to the risk of aortic dissection and rupture. Imaging plays an important role in the acute setting but also in the initial diagnosis and image-based monitoring. In this article, we provide an overview of the most common genetic aortic syndromes and recommended imaging strategies. Furthermore, we highlight modern imaging methods allowing for the quantification of hemodynamic changes in aortic disease. This is a narrative review article on genetic aortic syndromes and recommended imaging strategies, where we take into account expert opinions and standard-of-care practices from our own center. Radiological imaging plays a key role in the initial diagnosis and surveillance of patients with genetic aortic syndromes. Radiologists contribute significantly to the multi-disciplinary setting of genetic aortic syndromes with knowledge of special features and recommended imaging methods. Accurate measurement of the aorta is crucial, particularly in terms of diameter-based surgical treatment algorithms. Modern imaging methods like 4D-flow MRI and pulse wave velocity have a potential to further improve individualized risk stratification in patients with genetic aortic syndromes. · The risk for cardiovascular complications such as acute aortic syndrome is increased in patients with genetic aortic syndromes.. · Recommended time intervals between image-based monitoring depend on the underlying aortic disease.. · CT-angiography should be used only in the acute setting.. · Non-contrast MR-angiography is adequate for screening and image-based monitoring of patients with genetic aortic syndromes.. · Weinrich JM, Lenz A, Girdauskas E et al. Current and Emerging Imaging Techniques in Patients with Genetic Aortic Syndromes. Fortschr Röntgenstr 2020; 192: 50 - 58.

Impact of noonan syndrome on admissions for pediatric cardiac surgery

Noonan Syndrome is the second most common genetic syndrome associated with congenital heart disease. Many patients with Noonan Syndrome will require a cardiac intervention. This study aimed to characterize the difference in cardiac surgery admissions in patients with and without Noonan Syndrome. Data regarding hospital admissions was collected using the Kids' Inpatient Database from 1997 to 2012. A cross-sectional study was conducted comparing baseline characteristics, cardiac morphology, cardiac surgery, and other comorbidities between those with and without Noonan Syndrome. Regression analysis was conducted to determine factors related to Noonan Syndrome and risk factors for increased length of hospitalization, need for ECMO, and inpatient mortality using Noonan Syndrome as the independent variable. A total of 46,169 admissions with cardiac surgery under 18 years of age were included in the final analyses. Of these 778 (1.6%) had Noonan Syndrome. Pulmonary stenosis, coronary anomalies, and valvuloplasty without valve replacement were independently associated with Noonan Syndrome. Those with Noonan Syndrome were 90% more likely to have chylothorax. Pediatric cardiac surgery admissions tended to be 4.5 days longer and cost $54,296 more in total charges with Noonan Syndrome. Inpatient mortality is also increased by Noonan Syndrome. Noonan Syndrome is present in a relatively small proportion of pediatric cardiac surgery admissions. Noonan Syndrome is independently associated with increased length and cost of such admissions as well as inpatient mortality.

Increased brain age in adults with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is the most common genetic obesity syndrome, with associated learning difficulties, neuroendocrine deficits, and behavioural and psychiatric problems. As the life expectancy of individuals with PWS increases, there is concern that alterations in brain structure associated with the syndrome, as a direct result of absent expression of PWS genes, and its metabolic complications and hormonal deficits, might cause early onset of physiological and brain aging.In this study, a machine learning approach was used to predict brain age based on grey matter (GM) and white matter (WM) maps derived from structural neuroimaging data using T1-weighted magnetic resonance imaging (MRI) scans. Brain-predicted age difference (brain-PAD) scores, calculated as the difference between chronological age and brain-predicted age, are designed to reflect deviations from healthy brain aging, with higher brain-PAD scores indicating premature aging.Two separate adult cohorts underwent brain-predicted age calculation. The main cohort consisted of adults with PWS (n = 20; age mean 23.1 years, range 19.8–27.7; 70.0% male; body mass index (BMI) mean 30.1 kg/m2, 21.5–47.7; n = 19 paternal chromosome 15q11–13 deletion) and age- and sex-matched controls (n = 40; age 22.9 years, 19.6–29.0; 65.0% male; BMI 24.1 kg/m2, 19.2–34.2) adults (BMI PWS vs. control P = .002). Brain-PAD was significantly greater in PWS than controls (effect size mean ± SEM +7.24 ± 2.20 years [95% CI 2.83, 11.63], P = .002). Brain-PAD remained significantly greater in PWS than controls when restricting analysis to a sub-cohort matched for BMI consisting of n = 15 with PWS with BMI range 21.5–33.7 kg/m2, and n = 29 controls with BMI 21.7–34.2 kg/m2 (effect size +5.51 ± 2.56 years [95% CI 3.44, 10.38], P = .037). In the PWS group, brain-PAD scores were not associated with intelligence quotient (IQ), use of hormonal and psychotropic medications, nor severity of repetitive or disruptive behaviours. A 24.5 year old man (BMI 36.9 kg/m2) with PWS from a SNORD116 microdeletion also had increased brain PAD of 12.87 years, compared to 0.84 ± 6.52 years in a second control adult cohort (n = 95; age mean 34.0 years, range 19.9–55.5; 38.9% male; BMI 28.7 kg/m2, 19.1–43.1).This increase in brain-PAD in adults with PWS indicates abnormal brain structure that may reflect premature brain aging or abnormal brain development. The similar finding in a rare patient with a SNORD116 microdeletion implicates a potential causative role for this PWS region gene cluster in the structural brain abnormalities associated primarily with the syndrome and/or its complications. Further longitudinal neuroimaging studies are needed to clarify the natural history of this increase in brain age in PWS, its relationship with obesity, and whether similar findings are seen in those with PWS from maternal uniparental disomy.

Hearing reduction in patients with genetic diseases

Hearing reduction and hearing loss in children and adults represent severe medico-social disorders leading to patient disability. During the recent several years, there have been numerous publications dealing with various aspects of the genetics of hereditary diseases and syndromes causing a considerable hearing reduction and even hearing loss. One bears in mind the large-scale genome investigations as well as the trials of genetic polymorphisms and gene mutations in hearing impairment. In these patients, one observes autosomal recessive and autosomal dominant inheritance as well as an X-linked one. In the present papers, some novelties in this interdisciplinary field such as genetic research and common genetic syndromes with hearing impairment are concisely presented.

USING QF-PCR ASSAY IN DETECTION OF COMMON GENETIC CAUSES IN INFERTILE MALES

At present, quantitative fluorescent - polymerase chain reaction (QF-PCR) technology is widely being used in prenatal diagnosis of some common genetic syndromes such as Down syndrome, Patau syndrome and Edwards syndrome. The advantages of this technique are its high accuracy, rapid test results and wide applicability. It has used this technique to detect AZF (Azoospermia factor) micro-deletions by Devyser's kit at Tu Du Hospital, Ho Chi Minh City. The novelty of the study was to create a kit with 14 genetic markers and to develop a QF-PCR protocol to detect some common genetic causes in men seeking medical for their infertility with the sperm concentration of ≤ 5 million/ml. We conducted an evaluation in reliability in order to confirm whether the QF-PCR results from the set-up protocol were accurate and reliable. We developed the research on the application of QF-PCR to test for the DNA samples of patients. They were 10 normal reproductive men, 2 patients with Klinefelter syndrome, 4 patients with AZFc micro-deletions, 1 female with normal reproduction. Cordially, we used a sample of water to control the experiment. The results have shown that the kit with 14 genetic markers and the built-in QF-PCR protocol for detecting some common genetic causes in men seeking medical care for their infertility were accurate 100% compared to multiplex-PCR and peripheral blood lymphocyte cultures. The study results are important for identifying some common genetic causes in men seeking medical care for their infertility and helping doctors build the most inferior treatment regimens for their patients.

A Case of Chromosome 22q11.2 Deletion Syndrome with White Matter Abnormalities and Hypernasal Speech: Importance of Extracardiac Symptoms for Earlier Diagnosis

AbstractChromosome 22q11.2 deletion syndrome (22q11.2DS) is one of the most common genetic syndromes. The varying presentation and severity of this syndrome result in diagnostic delays, especially in patients without cardiac malformation or characteristic features. We report a noncardiac case of 22q11.2DS with white matter abnormalities and velopharyngeal insufficiency. The recognition of white matter abnormalities as a feature of 22q11.2DS contributed to early diagnosis. Diagnostic delay could lead to inappropriate management and unfavorable outcomes. Increased awareness of the various minor features of 22q11.2DS may enable clinicians to diagnose this syndrome earlier and provide appropriate medical management.

Effects of human sex chromosome dosage on spatial chromosome organization.

Sex chromosome aneuploidies (SCAs) are common genetic syndromes characterized by the presence of an aberrant number of X and Y chromosomes due to meiotic defects. These conditions impact the structure and function of diverse tissues, but the proximal effects of SCAs on genome organization are unknown. Here, to determine the consequences of SCAs on global genome organization, we have analyzed multiple architectural features of chromosome organization in a comprehensive set of primary cells from SCA patients with various ratios of X and Y chromosomes by use of imaging-based high-throughput chromosome territory mapping (HiCTMap). We find that X chromosome supernumeracy does not affect the size, volume, or nuclear position of the Y chromosome or an autosomal chromosome. In contrast, the active X chromosome undergoes architectural changes as a function of increasing X copy number as measured by a decrease in size and an increase in circularity, which is indicative of chromatin compaction. In Y chromosome supernumeracy, Y chromosome size is reduced suggesting higher chromatin condensation. The radial positioning of chromosomes is unaffected in SCA karyotypes. Taken together, these observations document changes in genome architecture in response to alterations in sex chromosome numbers and point to trans-effects of dosage compensation on chromosome organization.

Current clinical topics of Lynch syndrome.

Lynch syndrome (LS) is one of the most common genetic cancer syndromes, occurring at a rate of 1 per 250-1000 in the general population. This autosomal dominant disease is caused by a germline variant in one of the four mismatch repair genes, MSH2, MLH1, MSH6, PMS2, or the EPCAM gene. LS develops at early ages in colorectal cancer (CRC), endometrial cancer, and various other associated tumors. Accurate diagnosis of LS and utilization of various risk-reduction strategies such as surveillance, prophylactic surgery, and chemoprevention could improve clinical outcomes. The efficacy of surveillance has only been proven for CRC; however, specialists have proposed surveillance for other LS associated tumors. Universal screening for tumor tissue using microsatellite instability testing or the mismatch repair protein immunochemistry in all CRC or endometrial cancers is recommended not only as a diagnostic tool for LS, but also as a predictive, prognostic, and therapeutic marker. Next-generation sequencing methods have revealed several conditions with phenotypes similar to LS, such as Lynch-like syndrome, constitutional mismatch repair deficiency syndrome, and polymerase proofreading-associated polyposis. Distinguishing LS from these similar conditions is clinically important, since clinical management for patients differs according to the conditions. Recently, immune checkpoint inhibitors have been shown to be a promising treatment against mismatch repair-deficient (dMMR) solid tumors. The efficacy of immune-checkpoint inhibitors in LS-associated tumors has been shown to be similar to that in sporadic dMMR tumors. This review discusses current clinical topics related to LS screening, diagnosis, surveillance, and therapy.

Gastro-oesophageal reflux - an important causative factor of severe tooth wear in Prader-Willi syndrome?

BackgroundPrader-Willi syndrome (PWS) is the most common genetic human obesity syndrome and is characterized by hypotonia, endocrine disturbances, hyperphagia, obesity and mild mental retardation. Oral abnormalities, such as decreased salivary flow rates and extreme tooth wear, have also been described. Studies have shown a significant increase in reflux symptoms in individuals with obstuctive sleep apnoea syndrome and increased BMI, both of which are typical findings in PWS. Gastro-oesophageal reflux disease (GORD) has been identified in some individuals with PWS and is a significant intrinsic factor in dental tooth wear. The aim of this study was therefore to estimate the prevalence of GORD in adults and children and to evaluate a possible correlation between GORD and tooth wear in adults with PWS. They were all registered at the TAKO-centre.ResultsTwenty-nine individuals, 17 adults with a mean age of 32.6 years (range 18–48) and 12 children with a mean age of 8.8 years (range 3–17), agreed to undergo 24-hour oesophageal pH monitoring, and 90% of those enrolled managed to complete the examination. Four children and eleven adults were diagnosed with pathological gastro-oesophageal reflux, which is defined as acid exposure (pH less than 4) more than 3.6 or 4.3 percent of the time, respectively. Manometry performed in the adult group showed a pathologically high lower oesophageal sphincter pressure in four of the five individuals who had normal oesophageal pH values (pH under 4 less than 4.3% of the time). The two groups (reflux and non-reflux) were well balanced according to BMI, genotype, tooth grinding and hyposalivation. However, twice as many individuals in the reflux group as in the non-reflux group reported high consumption of acidic foods and drinks. Increased tooth wear was significantly correlated with GORD in the two groups (reflux n=6 and non-reflux n=6).ConclusionsThe prevalence of gastro-oesophageal reflux is high in individuals with PWS. Tooth wear was strongly associated with GORD and acidic drinks, and both may be important aetiological factors underlying the extreme tooth wear in this group. Our data suggest a need for routine screening for GORD and dental wear in young individuals with Prader-Willi syndrome.

Attentional functioning in individuals with 22q11 deletion syndrome: insight from ERPs.

The 22q11 deletion syndrome (22q11DS), or DiGeorge syndrome (DG), is one of the most common genetic deletion syndromes. DG also carries a high risk for psychiatric disorders, with learning disabilities frequently being reported. Impairments in specific cognitive domains, such as executive functioning and attention, have also been described. The aim of this study was to investigate attentional functioning in a group of subjects with DG using ERPs, and in particular the P300 and CNV components. We studied ten patients with DG and ten healthy subjects that performed a P300 Novelty task and a CNV motor task. P3b amplitude was significantly lower in patients than in controls, while P3b latency was comparable in patients and controls. The P3a parameters were similar in both groups. All CNV amplitudes were significantly lower in DG patients than in controls. DG patients displayed slower reaction times in the CNV motor task than healthy subjects. These results point to a cognitive dysfunction related above all to executive attentional processing in DG patients. In particular, a specific difficulty emerged in selective attention and in the ability to orient and to sustain the anticipatory attention required for an executive motor response.

The interaction between neurocognitive functioning, subthreshold psychotic symptoms and pharmacotherapy in 22q11.2 deletion syndrome: A longitudinal comparative study

BackgroundThe 22q11.2 deletion syndrome (22q11DS) is the most common genetic syndrome associated with schizophrenia. The goal of this study was to evaluate longitudinally the interaction between neurocognitive functioning, the presence of subthreshold psychotic symptoms (SPS) and conversion to psychosis in individuals with 22q11DS. In addition, we attempted to identify the specific neurocognitive domains that predict the longitudinal evolution of positive and negative SPS, as well as the effect of psychiatric medications on 22q11DS psychiatric and cognitive developmental trajectories. MethodsForty-four participants with 22q11DS, 19 with Williams syndrome (WS) and 30 typically developing (TD) controls, age range 12–35years, were assessed at two time points (15.2±2.1months apart). Evaluation included the Structured Interview for Prodromal Symptoms (SIPS), structured psychiatric evaluation and the Penn Computerized Neurocognitive Battery (CNB). Results22q11DS individuals with SPS had a yearly conversion rate to psychotic disorders of 8.8%, compared to none in both WS and TD controls. Baseline levels of negative SPS were associated with global neurocognitive performance (GNP), executive function and social cognition deficits, in individuals with 22q11DS, but not in WS. Deficits in GNP predicted negative SPS in 22q11DS and the emergence or persistence of negative SPS. 22q11DS individuals treated with psychiatric medications showed significant improvement in GNP score between baseline and follow-up assessments, an improvement that was not seen in untreated 22q11DS. ConclusionsOur results highlight the time-dependent interplay among positive and negative SPS symptoms, neurocognition and pharmacotherapy in the prediction of the evolution of psychosis in 22q11DS.

Abstract A37: Synthetic lethality as a tool to reveal novel vulnerabilities in NF1-associated tumorigenesis

Abstract Neurofibromatosis Type 1 (NF1) is a common (1:2500 births) genetic disorder and cancer predisposition syndrome, caused by mutations in the tumor suppressor gene NF1. One of the known functions of the protein encoded by NF1 (neurofibromin) is that of a negative regulator of Ras pathway signaling, through its Ras-GAP activity. Among other symptoms, individuals with NF1 often develop benign tumors of the peripheral nervous system (called dermal or plexiform neurofibromas), originating from the Schwann cell linage or their precursors. While these benign tumors can cause significant pain and mobility problems, some (~10%) progress further to malignant peripheral nerve sheath tumors (MPNSTs) and are a leading cause of death among NF1 patients. Both plexiform neurofibromas and MPNSTs arise following loss of the remaining WT NF1 allele within the Schwann cell linage (or their precursors). It is believed the majority of NF1-associated MPNSTs originate from preexisting plexiform neurofibromas. Treatment options for the benign plexiform neurofibromas and MPNSTs are extremely limited, mostly relying on surgical resection and broad-spectrum chemotherapy. Finding new molecular targets for therapeutics effective against both benign tumors and MPNSTs are critical for improved patient outcomes and quality of life. The genetic basis of NF1 syndrome make it a top candidate for using synthetic lethal genetic and therapeutic approaches to uncover unique variabilities in NF1 deficient cells. We have developed a drug discovery pipeline to identify targeted therapeutics for treatment NF1-related neoplasia, including MPNSTs. Using CRISPR/Cas9, we have created an immortalized human Schwann cell line that is deficient for the NF1 gene, which when paired with its isogenic wild-type parent is an outstanding research tool for identifying synthetic lethal interactions. The NF1 deficient cells exhibit increased oncogenic phenotypes, including increased anchorage independent growth under low serum conditions, higher basal levels of Ras-GTP, and a tendency to form tumors in athymic nude mice. These isogenic cell lines are currently being utilized for a number of synthetic lethal screens to identify therapeutics and targets specific to cells lacking NF1. These include: 1. A large-scale screen (~24,000 compounds from focused libraries) for drugs that preferentially kill the NF1 deficient cells. This could identify new targeted therapies for potential use in the clinic. 2. Synthetic lethal genetic screens using genome-wide RNAi and CRISPR/Cas9 approaches to knockdown/out expression of additional genes. The design of our system incorporates two key components that we believe provide the best chance of success. First, our studies utilize the correct, tumor specific, human cell type (Schwann cells). Secondly, we have created isogenic pairs of these cells, differing only in their NF1 status, in which to conduct our synthetic lethal screens. NF1 dependent vulnerabilities identified from this study might also have wider reaching implications and uses, as NF1 is often somatically altered in other cancers. The convergence of genome editing technologies with high throughput drug and synthetic lethal genetic screening provide an exciting opportunity for investigation of NF1 and other genetic cancer predisposition syndromes. Citation Format: Kyle B. Williams, Rory L. Williams, Sue K. Rathe, Jon Hawkinson, David A. Largaespada. Synthetic lethality as a tool to reveal novel vulnerabilities in NF1-associated tumorigenesis [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A37.

Integrating surgery and genetic testing for the modern surgeon.

The field of cancer genetics is rapidly evolving and several genetic mutations have been identified in hereditary cancer syndromes. These mutations can be diagnosed via routine genetic testing allowing prompt intervention. This is especially true for certain variants of colorectal, breast, and thyroid cancers where genetic testing may guide surgical therapy. Ultimately, surgical intervention may drastically diminish disease manifestation or progression in individuals deemed as high-risk based on their genetic makeup. Understanding the concepts of gene-based testing and integrating into current surgical practice is crucial. This review addresses common genetic syndromes, tests, and interventions salient to the current surgeon.