Abnormal Genetic Testing Research Articles

Fetal and neonatal outcomes of posterior fossa anomalies: a retrospective cohort study

The primary aim of this study was to estimate the incidence of posterior fossa anomalies (PFA) and assess the associated outcomes in King Abdulaziz Medical City (KAMC), Riyadh. All fetuses diagnosed by prenatal ultrasound with PFA from 2017 to 2021 in KAMC were analyzed retrospectively. PFA included Dandy–Walker malformation (DWM), mega cisterna magna (MCM), Blake's pouch cyst (BPC), and isolated vermian hypoplasia (VH). The 65 cases of PFA were 41.5% DWM, 46.2% MCM, 10.8% VH, and 1.5% BPC. The annual incidence rates were 2.48, 2.64, 4.41, 8.75, and 1.71 per 1000 anatomy scans for 2017, 2018, 2019, 2020, and 2021, respectively. Infants with DWM appeared to have a higher proportion of associated central nervous system (CNS) abnormalities (70.4% vs. 39.5%; p-value = 0.014) and seizures than others (45% vs. 17.9%; p-value = 0.041). Ten patients with abnormal genetic testing showed a single gene mutation causing CNS abnormalities, including a pathogenic variant in MPL, C5orf42, ISPD, PDHA1, PNPLA8, JAM3, COL18A1, and a variant of uncertain significance in the PNPLA8 gene. Our result showed that the most common PFA is DWM and MCM. The autosomal recessive pathogenic mutation is the major cause of genetic disease in Saudi patients diagnosed with PFA.

Genetic Profile and Clinical Characteristics of Brugada Syndrome in the Chinese Population.

Brugada syndrome (BrS) is an inheritable arrhythmia syndrome that can lead to sudden cardiac death in patients while the heart structure is normal. However, the genetic background of more than 65% of BrS probands remains unclear. The purpose of this study is to report the variant spectrum in a Chinese cohort with suspected BrS and to analyze their distinct clinical and electrocardiographic features. Patients with suspected BrS from Tongji Hospital between 2008 and 2021 were analyzed retrospectively. A total of 79 probands were included in this study. Patients with type 1 BrS electrocardiogram (ECG) had a prolonged QRS duration compared to patients with type 2/3 BrS ECG. Of them, 59 probands underwent genetic testing. Twenty-five patients (42.37%) showed abnormal genetic testing results, and eight of them (13.56%) carried pathogenic/likely pathogenic (P/LP) mutations. Mutation carriers presented much more prominent depolarization and repolarization abnormalities than non-carriers, including a prolonged P-wave duration, QRS duration, QTc interval, decreased QRS amplitude, and deviation of the electrocardiographic axes (T-wave axis and R-wave axis). Furthermore, our study identified four novel P/LP mutations: Q3508X in TTN, A990G in KCNH2, G1220E, and D372H (in a representative pedigree) in SCN5A. Our study showed the variant spectrum of a suspected Chinese BrS cohort, and we identified four novel P/LP mutations in TTN, KCNH2, and SCN5A.

Abnormal Genetic Testing in Males With Concomitant Neurodevelopmental Disabilities and Genital Malformation

BackgroundNeurodevelopmental disorders (NDDs) affect 1:6 children in the United States and are often linked to genetic disorders. Because many genes are enriched in brain and testicular tissue, genital malformations identified early may be a predictor of genetic disorders in children with NDDs. However, few studies have evaluated the specific effects of genital malformations. This study assesses the association between genital malformations and abnormal genetic testing among male patients with NDD. MethodsA retrospective chart review was performed of 447 male patients seen at Children's Health Dallas (2009 to 2019) with concomitant genital malformations and NDDs. We assessed the strength of factors associated with obtaining a genetic test and having abnormal results. ResultsWe identified 447 patients with concomitant genital malformations and NDD. Fifty-six percent (251 of 447) received genetic testing, of which 68.5% (172 of 251) had abnormal results. Patients with mixed genitourinary malformations, global developmental delay (GDD), intellectual delay, or autism spectrum disorder were more likely to have a genetic test. Patients with bilateral testicular involvement, GDD, severe language delay, wheelchair dependence, or abnormal magnetic resonance imaging findings were more likely to have abnormal results. ConclusionThe diagnostic yield of 68.5% in our cohort of male patients with genital malformations was higher than previous reports of 5% to 35% in NDD populations. More severe phenotypic features may be associated with increased yield. Identification of genital malformations during infancy may guide clinical surveillance, and copresentations with NDDs may support genetic testing.

Comparing the attitudes of physicians and non-physicians toward communicating a patient's BRCA1 mutation to a first-degree relative against a patient's wishes.

Although genetic testing can be vastly informative, it creates a dilemma if a patient does not want to disclose an abnormal genetic test to at-risk relatives. A sample of 200 participants from Nevada (100 physicians, 100 non-physicians) completed an 11-item questionnaire asking demographic information, familiarity with genetics and genetic testing, and opinions about a physician's role in a hypothetical case in which a patient does not wish to communicate her BRCA1 mutation to her sister. Although most respondents did not think the physician should notify the sister against the patient's wishes, more non-physicians (40%) than physicians (23%) contended that the physician should do so (p = 0.0119). Most respondents from both groups agreed that the physician should not have the legal duty to notify the sister, would not be morally justified in sharing genetic test results with the sister, but should have the right to notify a patient's relatives if the disease is "serious, preventable, and treatable." More non-physicians than physicians agreed that physicians should have an educational requirement on how to communicate genetic test results to patients and their family (88% vs 65%, p = 0.0002). Most physicians (70%) reported a familiarity/strong familiarity with genetic testing compared to non-physicians (33%; p < 0.0001). Future qualitative research should assess physicians' understanding of issues surrounding familial communication of genetic test results. Educational interventions to facilitate effective communication to patients and families are needed and welcomed by most physicians. Discrepancies between the attitudes of physicians and patients or the public need to be better understood and addressed.

Extended genetic testing in fetuses with sonographic skeletal system abnormalities.

To analyze genetic causes of skeletal system abnormalities diagnosed by prenatal sonography and to establish a diagnostic protocol with regard to extended genetic testing in this group of patients. This prospective observational cohort study included all singleton pregnancies with a sonographic abnormality of the skeletal system evaluated in a single ultrasound department during a 1-year period (2019). Fetuses underwent routine genetic testing by chromosomal microarray analysis (CMA) supplemented with polyploidy testing, and those with either a normal result or an abnormal result not consistent with the observed phenotype underwent exome sequencing (ES). Interpretation of variants was discussed by a panel of specialists to identify pathogenic/likely pathogenic variants. The study group comprised 55 fetuses. A chromosomal abnormality consistent with the observed phenotype was detected in 24 (43.6%) cases. After exclusions, 26 (47.3%) cases underwent further molecular testing by ES, of which 18 (69.2%) were classified as having abnormal ES results, thus increasing the diagnostic yield by a further 18 (32.7%) cases and giving an abnormal genetic test result in 42/55 (76.4%) fetuses overall. Pathogenic or likely pathogenic sequence variants in 14 different genes were detected across 18 fetuses. Seven genes are already listed in the International Skeletal Dysplasia Society Nosology and seven are not typically found to be causal for skeletal dysplasias and are not listed in the Nosology. In fetuses with skeletal system anomalies, chromosomal abnormality was the most common genetic diagnosis. Exome sequencing increased the diagnostic yield over that of CMA and polyploidy testing. Fetuses with skeletal abnormalities should undergo extended genetic testing following routine testing, as many genetic anomalies responsible for skeletal defects may otherwise be missed. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Improved universal tumor screening program with paired testing: Experience at a large community-based teaching hospital.

e22505 Background: Lynch syndrome (LS) is the most common cause of hereditary predisposition to colon, endometrial, and other cancers. The universal tumor screening program for LS at Beaumont Health (BH) utilizes immunohistochemistry (IHC) of the mismatch repair (MMR) proteins to identify patients for genetics evaluation. We present the 8-year experience of the program at a large community-based teaching hospital. Methods: The MMR IHC results for all colorectal cancer (CRC) resection specimens screened from August 2012 to September 2020 were reviewed. Specimens with absent MLH1 and PMS2 were evaluated for MLH1 promoter hypermethylation with reflex to BRAF V600E mutation analysis. All abnormal results were referred for cancer genetics evaluation. The distribution of abnormal MMR and germline genetic testing results was analyzed. Results: Specimens from 2361 CRC resections were screened, and 511 specimens had abnormal MMR IHC (22%). Most cases of absent MLH1 and PMS2 were explained by hypermethylation or BRAF analysis (n = 338, 66% of all abnormal, 89% of MLH1 and PMS2). Of the remaining cases showing MMR deficiency (n = 173), the most common result was absence of MSH2 and MSH6 (n = 67), followed by absence of MLH1 and PMS2 (n=41, see table). Germline genetic testing of 83 individuals with abnormal MMR IHC revealed 49 cases of Lynch syndrome [MLH1 (n=9), MSH2 (n= 25), MSH6 (n=7), PMS2 (n=7), EPCAM (n=1)]. A significant proportion of cases (n=34, 40%) had negative germline testing, and had unexplained MMR deficiency. Paired germline/tumor testing was implemented in 2017, and 14 patients had this analysis. Using this approach, 5 individuals were identified to have somatic mutations explaining their result, and the proportion of unexplained cases was reduced to 29% (n = 4). Conclusions: Recent advances in cancer screening and therapeutics have underscored the importance of analyzing tumors for mismatch repair deficiency (dMMR), with known challenges to implementation and interpretation of results. The BH cancer genetics program has demonstrated successful growth of a universal tumor screening program over 8 years. This has led to the identification of a large number of dMMR tumors (22% of all CRC resections) and LS cases (2% of all CRC resections), which impacts management for patients and their families. Recent implementation of paired germline/tumor testing has improved the testing algorithm, and resulted in more accurate interpretation of a greater proportion of abnormal IHC results. This combined approach allows for focused high-risk screening for LS patients, access to novel therapeutic interventions including immune therapies for patients with dMMR tumors, and future precision oncology approaches.[Table: see text]

Factors associated with test failure in pregnant women undergoing cell-free DNA-based testing for fetal trisomy.

To investigate the factors associated with cell-free DNA test failure, and the optimal subsequent management of these pregnancies. This was a retrospective study of 27,363 singleton pregnancies undergoing cell-free DNA testing. Women with cell-free DNA test failure were divided into a high-risk group and a low-risk group according to their indications. The subsequent management and pregnancy outcomes of these women were followed up. The rate of cell-free DNA test failure at the first sampling was 1.49%, and 78.4% of failures were due to a low fetal fraction. Of the 66 women who refused any subsequent management, an adverse pregnancy outcome was seen in 5 cases, all belonging to the high-risk group. Of the 13 low-risk women who chose second-trimester maternal serum screening, all obtained a low-risk maternal serum screening result and an unaffected pregnancy outcome. A redraw was chosen by 171 women, which yielded a result in 75.4% and their pregnancy outcomes were unaffected; 42 women had an uninformative result again and received an amniocentesis. As 158 women had an amniocentesis after the first sampling, this procedure was offered in 200 cases altogether. Abnormal genetic testing results were shown in six (3%, 6/200) cases, all in the high-risk group. High-risk pregnant women with cell-free DNA test failure are at increased risk of adverse pregnancy outcomes. A second sampling for cell-free DNA test or maternal serum screening might be suggested to low-risk women. Invasive prenatal diagnosis should be offered to the high-risk patients, especially those with a second cell-free DNA test failure.

Abstract OT-11-01: The informed genetics annotated patient registry: The iGAP registry

Abstract Background Interest and knowledge about the genetics and biology of inherited risk of and progression of disease is growing. Physicians are increasingly using tests and technology, including germline genetic, genomic, and biomarker testing, to provide insight into a healthy individual's risk and an affected individual's disease characteristics, in order to provide personalized clinical management. However, many barriers to adoption of precision medicine still exist in the clinical setting, including rapid advances in technology and research, complex guidelines for eligibility, variable quality and cost, and adequate understanding of appropriate implementation by medical professionals. Methods The iGAP Registry uses an innovative digital platform to collect genetic, genomic, biomarker data and correlates it with clinical, pathologic and outcome data to inform providers of an individual’s risk of developing cancer, guide them to appropriate clinical grade testing and provide clinical decision support to providers for prevention and management strategies over time. The iGAP Registry’s digital platform minimizes technological barriers to longitudinal research participation and is available in mobile and desktop formats, allowing for easy implementation in a wide variety of clinic and hospital settings. The risk tool uses predictive analytics to identify and curate patients at risk who are eligible for initial and further testing. The tool additionally can generate letters of medical necessity, each individualized by personal and family history, for eligibility for genetic testing (based on national guidelines) and additional imaging (based on validated cancer risk calculators). The insights tool provides physicians with decision support on how to interpret and manage abnormal genetic testing results on an individual level and supports improved understanding across lab terminology through variant classification. The insights tool also supplies letters of medical necessity and supporting evidence across many specialties. The platform connects the information stored in the risk and insights tools to a unique participant record and automatically feeds the data into a digital case report form for the research registry. Additional clinical data is entered for patients who consent to be a part of the Registry. This allows for seamless longitudinal data collection over time without disrupting typical clinical workflows, and is further enriched by emailed patient-reported outcomes and physician decision impact questionnaires. Follow-up occurs over 5 years after initial data entry for the 10,000 expected subjects in the Registry (Table 1). Conclusion The iGAP Registry is a multi-center longitudinal, observational research database with an integrated platform of clinically-useful tools designed to address gaps for providers specifically for identifying individuals at elevated risk based on clinical and pathologic factors, guiding them to appropriate genetic, genomic, and biomarker testing and providing clinical insights on actionable results for personalized management and prevention for the individual and their family members over time. The iGAP Registry is currently enrolling and accepting new sites at www.igapregistry.org or https://clinicaltrials.gov/ct2/show/NCT04419896. Table 1: Eligibility CriteriaRetrospective18 years or older;Is/was a patient at participating practice previously tested with germline, genomic, or biomarker tests;For germline patients, have a diagnosis of cancer or P/LP result.Prospective18 years or older;§Presents consecutively to a participating practice and who has previously been screened and tested;Receives/has received germline, genomic, or other biomarker testing, either through a prior provider or a participating practice;Consents to be a part of the registry. Citation Format: Rakesh Patel, Peter Beitsch, Pat Whitworth, Chloe Wernecke, Mary Kay Hardwick. The informed genetics annotated patient registry: The iGAP registry [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-11-01.

148 Discordant congenital heart defects in monochorionic twins: risk factors and proposed pathophysiology

There is a six-fold increase in congenital heart defects (CHD) among monochorionic (MC) twins compared to singleton or dichorionic twin pregnancies. Though MC twins share a genotype, discordant phenotypes related to CHD have been described. Our objective was to characterize the spectrum of CHD in MC twins in the context of genetic results and clinical demographics for a modern cohort to provide insight into risk factors and pathophysiology of discordant CHD in MC twins. Retrospective analysis of all twins receiving prenatal fetal echocardiography at a single institution from January 2010 – March 2020 (N=163) yielded 24 MC twin pairs (48 neonates) with CHD (n=6 concordant CHD, n=18 discordant CHD). Descriptive analysis including frequencies, means, and standard deviations were conducted for all maternal, CHD diagnoses, and neonatal variables. Continuous variables were analyzed using the Student t-test and categorical variables were analyzed using the Fisher Exact test. The most common lesions were septal defects (50% and 45% in concordant and discordant cohort) and right heart lesions (33% and 18% in concordant and discordant cohort). Diagnostic genetic testing was abnormal for 17% of the concordant and 6% of the discordant pairs, with no difference between the groups (p=0.45). Six (25%) twin pairs, 2 concordant and 4 discordant, were complicated by twin-to-twin transfusion syndrome, with all recipient twins acquiring diagnosis of CHD and no twins with abnormal genetic testing. No significant association was found between clinical risk factors and development of discordant CHD (p>0.05). This data supports environmental and epigenetic influences versus genotypic factors in the development of discordant CHD, pertinent for early diagnosis and postnatal prognosis. This is illustrated by the higher rates of discordant (75%) versus concordant (25%) CHD in MC twin pairs in this population, low incidence of family history of CHD, and the low incidence of genetic abnormalities (8.3%) in our MC cohort with CHD.

Newborn Screening for Pompe Disease: Pennsylvania Experience

Pennsylvania started newborn screening for Pompe disease in February 2016. Between February 2016 and December 2019, 531,139 newborns were screened. Alpha-Glucosidase (GAA) enzyme activity is measured by flow-injection tandem mass spectrometry (FIA/MS/MS) and full sequencing of the GAA gene is performed as a second-tier test in all newborns with low GAA enzyme activity [<2.10 micromole/L/h]. A total of 115 newborns had low GAA enzyme activity and abnormal genetic testing and were referred to metabolic centers. Two newborns were diagnosed with Infantile Onset Pompe Disease (IOPD), and 31 newborns were confirmed to have Late Onset Pompe Disease (LOPD). The incidence of IOPD + LOPD was 1:16,095. A total of 30 patients were compound heterozygous for one pathogenic and one variant of unknown significance (VUS) mutation or two VUS mutations and were defined as suspected LOPD. The incidence of IOPD + LOPD + suspected LOPD was 1: 8431 in PA. We also found 35 carriers, 15 pseudodeficiency carriers, and 2 false positive newborns.

Prenatally detected isolated ventricular septum defects and the association with chromosomal aberrations-A nationwide register-based study from Denmark.

To evaluate the association between prenatally detected isolated ventricular septum defects (VSDs) and chromosomal aberrations in a nationwide study in Denmark. Nationwide, register-based study with prospectively collected data including all singleton pregnancies from 2014-2018. From the Danish Fetal Medicine Database, we retrieved data on maternal characteristics, first-trimester biomarkers, pre- and postnatal diagnoses, genetic test results, and pregnancy outcomes. VSDs were considered isolated in the absence of other malformations or soft markers, and with a low first-trimester risk assessment for trisomies 21, 18 and 13. All cases of an isolated VSD with a chromosomal anomaly were audited. The genetic tests included karyotyping and chromosomal microarray. We retrieved data on 292 108 singleton pregnancies; 323 registered with a prenatally detected VSD and 697 with a VSD detected postnatally (incidence of 0.35%). Only 1/153 (0.7%, 95% CI 0.02;3.6%) of the isolated prenatally detected VSDs had an abnormal genetic test result (del (8)(q23.1)). Moreover, they had a lower free β-hCG MoM (0.9 MoM vs 0.99 MoM, P = 0.02), and were more likely born small for gestational age (SGA), defined as birthweight 2 or more SD below the mean, compared with the control population (5.2% vs 2.5%, P = 0.03). We found a prevalence of chromosomal aberrations of 0.7% in fetuses with a prenatally detected isolated VSD. Moreover, we found an association between isolated VSDs and a larger proportion being born SGA.

Comparison of growth and feeding method in infants with and without genetic abnormalities after neonatal cardiac surgery.

Congenital heart disease (CHD) is multifactorial in origin, resulting from an interaction between environmental and genetic factors. Multifactorial growth delay is common in infants with CHD. The impact of a genetic abnormality and CHD on the growth of an infant is lacking in the literature. The aim of this study is to compare the growth and method of feeding following neonatal cardiac surgery in infants with normal versus abnormal genetic testing. A retrospective chart review of neonates who underwent a Risk Adjustment in Congenital Heart Surgery IV-VI procedure between 1 January, 2006 and 22 September, 2016 was performed at our institution. Weight, length, head circumference measurements, and feeding method were collected at birth, time of neonatal surgery, and monthly up to 6 months of age. A total of 53 infants met inclusion criteria, of which 22 had abnormal genetic testing. Approximately 90% of infants were discharged following neonatal cardiac surgery with supplemental tube feeds. At each monthly follow-up visit, more infants were exclusively fed orally: 80% of infants with normal genetics at 5 months post-operative follow-up versus 60% of infants with abnormal genetic testing, although statistically insignificant. Growth was not different among the two groups. Infants with critical CHD with or without genetic abnormalities are at risk for growth delays and many need supplemental tube feeds post-operatively and throughout follow-up. Infants with genetic abnormalities are slower to achieve oral feeds and more likely to require tube feedings. It is important to have a systematic protocol for managing these high-risk infants.

Identification of Novel SCN5A Single Nucleotide Variants in Brugada Syndrome: A Territory-Wide Study From Hong Kong.

BackgroundThe aim of this study is to report on the genetic composition of Brugada syndrome (BrS) patients undergoing genetic testing in Hong Kong.MethodsPatients with suspected BrS who presented to the Hospital Authority of Hong Kong between 1997 and 2019, and underwent genetic testing, were analyzed retrospectively.ResultsA total of 65 subjects were included (n = 65, 88% male, median presenting age 42 [30–54] years old, 58% type 1 pattern). Twenty-two subjects (34%) showed abnormal genetic test results, identifying the following six novel, pathogenic or likely pathogenic mutations in SCN5A: c.674G > A, c.2024-11T > A, c.2042A > C, c.4279G > T, c.5689C > T, c.429del. Twenty subjects (31%) in the cohort suffered from spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) and 18 (28%) had incident VT/VF over a median follow-up of 83 [Q1–Q3: 52–112] months. Univariate Cox regression demonstrated that syncope (hazard ratio [HR]: 4.27 [0.95–19.30]; P = 0.059), prior VT/VF (HR: 21.34 [5.74–79.31; P < 0.0001) and T-wave axis (HR: 0.970 [0.944–0.998]; P = 0.036) achieved P < 0.10 for predicting incident VT/VF. After multivariate adjustment, only prior VT/VF remained a significant predictor (HR: 12.39 [2.97–51.67], P = 0.001).ConclusionThis study identified novel mutations in SCN5A in a Chinese cohort of BrS patients.

A Comprehensive Clinical Genetics Approach to Critical Congenital Heart Disease in Infancy

To investigate the frequency of genetic diagnoses among infants with critical congenital heart disease (CHD) using a comprehensive cardiovascular genetics approach and to identify genotype-phenotype correlations. A retrospective chart review of patients evaluated by cardiovascular genetics in a pediatric cardiac intensive care unit from 2010 to 2015 was performed. Infants with CHD who were <1month of age were included. CHD was classified using structured phenotype definitions. Cardiac and noncardiac phenotypes were tested for associations with abnormal genetic testing using χ1 and Fisher exact tests. Genetic evaluation was completed in 293 infants with CHD, of whom 213 had isolated congenital heart disease (iCHD) and 80 had multiple congenital anomalies. Overall, the yield of abnormal genetic testing was 26%. The multiple congenital anomalies cohort had a greater yield of genetic testing (39%) than the iCHD cohort (20%) (OR 2.7). Using a non-hierarchical CHD classification and excluding 22q11.2 deletion and common aneuploidies, right ventricular obstructive defects were associated with abnormal genetic testing (P=.0005). Extracardiac features associated with abnormal genetic testing included ear, nose, and throat (P=.003) and brain (P=.0001) abnormalities. A diagnosis of small for gestational age or intrauterine growth retardation also was associated with abnormal genetic testing (P=.0061), as was presence of dysmorphic features (P=.0033, OR 3.5). Infants without dysmorphia with iCHD or multiple congenital anomalies had similar frequencies of abnormal genetic testing. The present study provides evidence to support a comprehensive cardiovascular genetics approach in evaluating infants with critical CHD while also identifying important genotype-phenotype considerations.

Novel mutations in the CYBB gene causing X-linked chronic granulomatous disease: a case report of 2 patients

Introduction: Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency caused by mutations in the NADPH complex characterized by recurrent infections, inflammation and autoimmunity. While autosomal recessive forms exist, X-linked CGD makes up the majority of cases, which is caused by mutations in the CYBB gene. Patients are at high risk for infections with catalase positive bacteria and fungi. The prognosis has improved significantly with improvements in disease detection and management, including prophylactic antibiotic and antifungal therapy. Hematopoietic stem cell transplantation (HSCT) is a curative option for patients with a suitable donor. Aim: To report the clinical presentation, immune features and genetic mutations in 2 patients with novel mutations in the CYBB gene causing X-linked CGD who underwent HSCT. Results: Case 1: Patient 1 is a 14-year-old patient who initially presented with disseminated aspergillosis at the age of 3. He was noted to have an abnormal neutrophil oxidative burst index (NOBI) and genetic testing revealed a mutation in the CYBB gene (c.883_87dupGTGGT) consistent with CGD. He successfully underwent HSCT at age 4. At age 10 he developed a primary intracranial rhabdomyosarcoma in the posterior cranial fossa. Case 2: Patient 2 is a 4-year-old male who was worked up for CGD after developing a perianal abscess at 1 month of age followed by Moraxella bacteremia at 2 months of age. He had 2 abnormal NOBIs and genetic testing identified a novel mutation in the CYBB gene that was thought to explain his phenotype (c.941delA). He underwent an HSCT (10/10 HLA matched unrelated donor). Both patients have had normalization of their NOBI post-transplant and remain free of significant infections. Discussion: We report the clinical presentation, immune features and genetic mutations in 2 patients with novel mutations in the CYBB gene causing X-linked CGD. Identifying pathogenic mutations causing CGD is important for a better understanding of genotype–phenotype associations and disease course in this patient population. Statement of novelty: We describe 2 pediatric patients diagnosed with X-linked chronic granulomatous disease due to novel mutations in the CYBB gene.

Increased Sylvian fissure angle as early sonographic sign of malformation of cortical development.

ABSTRACTObjectiveTo evaluate Sylvian fissure development by assessing Sylvian fissure angles in fetuses with malformation of cortical development (MCD).MethodsThis was a retrospective study of 22 fetuses with MCD. Cases with a stored three‐dimensional (3D) brain volume acquired at 18 + 0 to 30 + 6 weeks of gestation at an ultrasound‐based research clinic between January 2010 and December 2017 were identified through a database. Of the 22 fetuses, seven had an extracranial abnormality, such as cardiac, renal, gastrointestinal and/or digital anomalies, and five had a minor abnormality such as micrognathia, low‐set ears and/or single umbilical artery. To confirm the final clinical diagnosis of brain abnormality, postmortem histological findings or prenatal or postnatal magnetic resonance images were used. For measurement of Sylvian fissure angle, an anterior coronal plane of the fetal brain on transvaginal 3D volume multiplanar imaging was visualized as a single image from the three orthogonal views. The right and left Sylvian fissure angles were measured between a horizontal reference line (0°) and a line drawn along the upper side of the respective Sylvian fissure. The Sylvian fissure angle on both sides was plotted on the graphs of the reference ranges for gestational age in weeks.ResultsIn 21 (95.5%; 95% CI, 86.8–100.0%) of 22 fetuses with MCD, the Sylvian fissure angle on one or both sides was larger than the 90th percentile of the normal reference. There was one case with apparent focal MCD in the parietal lobe, but the Sylvian fissure angles were normal. A case with apparent unilateral cortical dysplasia and one with apparent unilateral schizencephaly had conspicuous discrepancies between the left and right Sylvian fissure angles. Abnormal genetic test results were obtained in six cases, including four cases with a mutation in a single gene.ConclusionsThis study has shown that the Sylvian fissures, as defined by the Sylvian fissure angle, have delayed development in most MCD cases prior to the diagnosis of the condition. The Sylvian fissure angle may potentially be a strong indicator for the subsequent development of cortical malformation, before the time point at which the gyri and sulci become obvious on the fetal brain surface. Further research is required to validate these findings. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

A Rare Case of Wilson Disease in a 72-Year-Old Patient.

ABSTRACTWilson disease is an autosomal recessive disorder of abnormal copper metabolism that is prevalent in the younger population, rarely presenting in patients older than 40 years. Clinical presentation may be variable, and diagnosis is often aided by clinical and biochemical tests. We report the case of a 72-year-old woman who presented with acute liver failure initially of unclear etiology. Our patient was initially managed for presumed drug-induced liver injury but ultimately diagnosed with Wilson disease on the basis of clinical presentation, laboratory testing, liver biopsy, quantitative hepatic copper, and abnormal genetic testing.

Use of Genetic Testing after Abnormal Screening Ultrasound: A Descriptive Cohort Study

Background/Aims: The study aimed to characterize the use of genetic testing after abnormal screening ultrasound. Methods: We performed a retrospective review of patients undergoing genetic testing after abnormal ultrasound. Genetic evaluation consisted of noninvasive prenatal screening (NIPS) or amniocentesis. Classification of ultrasound findings, type of genetic testing, and results were collected. Results: A total of 139 subjects underwent genetic evaluation after abnormal screening ultrasound. Screening via NIPS was pursued by 61 (44%) patients while 78 (56%) proceeded directly to amniocentesis. Patients electing for amniocentesis had more cardiac, neurologic, and gastrointestinal malformations while soft markers for aneuploidy prompted more NIPS screening. Results were negative in 85% of the NIPS group compared to 60% of the amniocentesis group. Only 8% of patients who underwent NIPS proceeded to diagnostic testing. Conclusion: Patients pursuing NIPS after abnormal ultrasound had more soft markers of aneuploidy. Patients pursuing diagnostic testing were more likely to have major structural malformations and more total abnormalities identified. Patients who proceeded directly to amniocentesis were more likely to have abnormal genetic testing.

Outcome after prenatal and postnatal diagnosis of complex congenital heart defects and the influence of genetic anomalies.

Determine prenatal detection rate, mortality and association with genetic abnormalities in patients with severe CHD. Single center retrospective study in patients with severe CHD diagnosed prenatally or postnatally (2006 to 2014). A total of 567 patients were included, 176 (31%) after prenatal diagnosis, with large differences in prenatal detection rate among CHD types. Coarctation (24%), tetralogy of Fallot (21%) and univentricular heart (19%) were the most prevalent CHD. Overall mortality rate was 30% with important contributions of prenatal mortality including termination of pregnancy (40%) and postnatal compassionate care (15%). In the group requiring surgery, mortality rate was 12%. Genetic testing was available in 70%. A genetic cause was present in 140/394 patients tested (36%; 25% in the total group). Mortality was higher in the group with abnormal genetic testing compared with those with normal or no genetic testing (57/141 vs 112/423; p=0,002). Only one third of severe CHD are detected; overall mortality remains high (30%) with major contributions of termination of pregnancy and compassionate care. A genetic cause was found in 36% and was associated with a decreased survival. Counseling must include the possibility of associated genetic pathology and its impact on survival. © 2017 John Wiley & Sons, Ltd.

Normative Values of Intracranial Translucency (IT) Thickness as an Ultrasonographic Marker for Neural Tube Defect (NTD) Screening in the Iranian Singleton Pregnancies

Background: Neural tube defects are the second most common congenital anomalies following congenital heart defects. Once NTD is detected prenatally, different options are available including pregnancy termination, and intrauterine fetal surgery. Considering these facts, prenatal screening for NTDs is becoming a part of routine fetal care. Several ultrasonographic markers have been suggested for detection of NTD during pregnancy. Intracranial translucency (IT) is a relatively new ultrasonographic marker for NTD screening during first-trimester. It actually represents the fourth cerebral ventricle, seen as an anechoic structure in the mid-sagittal plane of the fetal face posterior to the brainstem. Its absence or obliteration can be an indirect sign of open spina bifida, which is caused secondary to the caudal displacement of brain in these fetuses. In this study, we aimed to determine the normative values of this marker in the Iranian population. Objectives: To determine the normative values of intracranial translucency (IT) thickness in the Iranian singleton pregnancies. Methods: 230 consecutive singleton pregnancies between 11 weeks and 13 weeks+6 days of gestation were included in the study during 9 months (June 2015 to February 2016) prospectively in Mahdieh and Sarem womens hospital, Tehran, Iran. Crown-rump length (CRL), nuchal translucency (NT) thickness, fetal heart rate, and nasal bone status were evaluated by ultrasound as parts of the routine first-trimester screening for aneuploidies. Precise gestational age was determined by the fetal CRL as well. In addition, IT thickness was measured in the mid-sagittal view of the fetal head between two echogenic horizontal lines: posterior border of the brainstem anteriorly and anterior aspect of the fourth ventricle choroid plexus posteriorly (figure 1). All the measurements were performed by a radiologist with four years of experience in fetal imaging. Ethnicities other than Iranian, multiple gestation pregnancies, and pregnancies conceived by assisted reproductive technology (ART) were not included in the study initially. Other exclusion criteria were any obvious anatomic fetal anomaly in the ultrasound examination, abnormal genetic or maternal serum biomarker test result, increased NT, and presence of open NTD in the post-partum follow-up. Results: : Of the 230 included singleton pregnancies, all of them resulted in healthy live births, except for two pregnancies terminated at 19 and 17 weeks of gestation due to severe skeletal dysplasia and an abnormal genetic test result compatible with Down syndrome, respectively. None of born babies had open NTD on post-partum follow-up. Five pregnancies were excluded from the final analysis, including a fetus with increased NT, two pregnancies with abnormal maternal serum biomarker test result (one of which confirmed to be trisomy 21), poor visualization due to maternal severe obesity in one case, and skeletal dysplasia diagnosed at 19 weeks of gestation in one of pregnancies. The median maternal age was 29 (range, 16 - 49) years. Median gestational age was 12 weeks + 5 days (range, 11 weeks + 2 days-13 weeks + 6 days). There were 68 cases per gestational week between 11 and 11 + 6 weeks, 84 cases between 12 and 12 + 6 weeks, and 73 cases between 13 and 13 + 6 weeks. Mean IT thickness was 1.94 - 0.73 mm (95% CI, 1.84 - 2.04) in all included pregnancies. This measurement was 1.57 - 0.34 mm (95% CI, 1.49 - 1.65) for fetuses between 11 and 11 + 6 weeks, 1.86 - 0.29 mm (95% CI, 1.80 - 1.92) for fetuses between 12 and 12 + 6 weeks, and 2.12 - 0.41 mm (95% CI, 2.02 - 2.22) for fetuses between 13 and 13 + 6 weeks. Kolmogorov-Smirnov analysis demonstrated normality of IT thickness distribution in the included cases (P > 0.10). Linear regression analysis demonstrated that there was a statistically significant positive linear association between IT thickness and gestational age (rs = 0.92, P = 0.021). Conclusions: We determined the normative values of IT thickness for the Iranian fetuses in a pilot study, which may be considered for NTD screening during the first-trimester in the national and international guidelines. It is important to determine normal measurements of different ultrasonographic and biochemistry markers nationally, since there are significant differences among various ethnicities. One should expect that IT thickness increases in a linear manner during first-trimester, and in case of its obliteration or absence open NTDs should be strongly suspected.