Year 2019, Volume 2 - Issue 2

Precision genetics for precision medicine approach in the epilepsies is facilitating: first, find the genetic cause; second, establish a therapy addressing the pathophysiology mechanism revealed; and finally avoidance of adverse reactions of antiepileptic medications.

Background: We developed a novel method for measuring the concentrations of tricarboxylic acid (TCA) cycle intermediates in dried blood spots (DBS) using liquid chromatography-tandem mass spectrometry (LC-MS/ MS). Analytes were derivatized before analysis using 4-[2-(N,N-dimethylamino) ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxa-diazole (DAABD-AE), a reagent that imparts powerful chromatographic and mass spectrometric properties onto carboxyl group-containing analytes. Methodology: Extraction and derivatization of TCA cycle intermediates were achieved in a single step by incubating a 3.2 mm circle of the DBS samples with DAABD-AE for 1 hour at 65 C. From the resultant mixture, 1.0 µl was injected into the LC-MS/MS. Results: Total analytical run time to separate target analytes from other interfering components in the sample was 8 minutes. The peaks corresponding to malic, fumaric, citric, succinic, and 2-ketoglutaric acid appeared at 3.55, 3.62, 3.64, 3.67, and 3.68 minutes, respectively. The method was adequately reproducible with a coefficient of variation for intraday (n = 15) and inter-day (n = 13) studies of 5.2%-18.4%. Reference intervals in DBS from controls (n = 125) were as follow (µmol/l): citric (36.6-126.4), 2-ketoglutaric (9.1-42.1), succinic (1.2-2.4), fumaric (2.4-9.0), and malic acid (15.9-39.3). Compared to controls, the levels of citric, succinic, and malic acids were statistically different in patients (n = 7) with a p-value of< 0.05. No statistically significant difference was detected in concentrations of 2-ketoglutaric and fumaric acids. Conclusion: We describe a simple, quick, and sensitive method to measure TCA cycle intermediates in DBS samples. That TCA cycle plays a central role in cellular metabolism; this method should be useful in studying these metabolites in health and disease.

Background: Prenatal diagnosis (PND) is an effective method for early detection of genetics and hereditary diseases during pregnancy in order to help the couple to take the proper decision regarding affected fetus. The current study aimed at assessing the attitude of Saudi couple regarding prenatal diagnosis and termination of pregnancy (TOP) for fetal abnormalities. Methodology: A descriptive cross-sectional was carried out; 100 couples attended Genetic Clinics in King Abdullah Specialized Children’s Hospital in Riyadh, who were interviewed using an questionnaire consisting of four parts covering socio-demographic data of participants, family & obstetric history, knowledge, and attitude of couples regarding PND and TOP. Descriptive statistics and chi-square tests were used for data analysis. Results: The results of the study showed that the mean age of fathers were 38.8± 8.1 years, while the mean age of mothers were 33.9 ± 6.9 and most of the couples (93%) lived in the urban area. Among them, 47% of couples had a positive family history of genetic diseases; 16% of mothers performed PND in their previous pregnancies. Among them, 62% and 76% of fathers and mothers, respectively, had satisfactory knowledge about PND and TOP with a statistically significant difference between them. Conclusion: A comprehensive genetic counselling service offered to the couples may influence the decision on TOP. The awareness about PND and TOP is crucial to obtain good understanding and positive future strategies.

Background: To evaluate knowledge and attitude toward cancer genetic tests (CGT) and cancer genetic counseling for improving underdeveloped CGT services and to achieve a better understanding of how cancer genetic services are being perceived in the Saudi society. Methodology: An electronic survey was conducted targeting three different types of subjects; physicians, cancer patients, and public participants. Characteristics of the study population were summarized as frequencies, means, and standard deviations. The association between two categorical variables was evaluated by the Chisquare test and cross-tabulation. Multiple logistic regression analyses, using a backward stepwise elimination procedure, were performed to examine the potential impact of the variables. All the explanatory variables were calculated using the Statistical Package for Social Sciences (16.0) software program. Continuous variables were grouped into ordinal categories to facilitate inclusion in the multiple logistic regression analysis. Analysis of variance was used to measure knowledge scores with different independent variables. Results: The public cohort showed a higher knowledge score than the patient cohort. A willingness to undergo CGT correlated with high knowledge in the public cohort [r (n = 1,083) = 0.12, p < 0.001), but with positive family history in the patient cohort [r (n= 100) = 0.29, p < 0.01]. Attitudes toward CGT were not correlated with a fear of stigma or privacy in the public cohort. The majority of physicians reported an increase in the number of patients seeking CGT and agreed that testing should not be performed without counseling as they would refer to appropriate patients accordingly. Physicians self-reported significant levels of uncertainty regarding CGT, such as qualifications, attitudes toward CGT, and confounding factors. Conclusion: There is an overall positive attitude toward CGT in Saudi society. Public health actions are needed to enhance cancer genetic services for high-risk families.

Background: In Middle East countries, including Saudi Arabia, 60%–70% of all marriages occur between first cousins, leading to uniquely common genetic disorders compared to Western countries. The primary objective of this study is to investigate differences between the attitudes of genetics professionals and patients toward incidental findings identified through whole-genome sequencing (WGS)/whole exome sequencing (WES). Methodology: A mixed qualitative and quantitative cross-sectional study was done to assess the ethical dilemmas and challenges faced in providing genetic information to Saudi patients attending a genetics clinic. A webbased survey was used to interview the participants. A total of 50 subjects were enrolled in this cross-sectional study, including 20 genetics professionals (MG: medical geneticists and GC: genetic counselors) and 30 patients who were interviewed before and after Next-Generation Sequencing tests. Results: Among the total, 55% of genetic professionals disagreed on patients being provided with their genetic results and raw data, and they preferred focusing on actionable results that yield benefits such as medical treatment and disease prevention. However, the majority of patients (73.3%) were interested in receiving all the raw genomic data for themselves and their children, while 26.7% felt opposite. Conclusion: This study identified differences in the attitudes of genetics professionals and patients toward the reporting of incidental findings from WES/WGS. Overall, the results suggested that GCand MGshould be aware of variations in individual preferences and should respect the beliefs and preferences of their patients.

Autism spectrum disorder (ASD) or (OMIM #209850), which is a devastating neurodevelopmental disorder (NDD), is a severe childhood-onset disorder characterized by insufficiencies in social communication, verbal, and nonverbal communication and restricted or repetitive behavior or interests and/or activities. Until recently, the etiology of ASD has remained unclear. Over the last decade, a pivotal role for de novo germ line mutations has been established, conclusively. Such mutations have led to the discovery of a lot of ASD risk loci and genes. Autism belongs to a spectrum of disorders that share core symptoms; however, show considerable variation in severity. ASD affects approximately 0.6%–0.7% of children worldwide, inducing a substantial public health burden and a cause of suffering for the affected families. Despite having a very high heritability, ASD has shown remarkable genetic heterogeneity, which has complicated the identification of risk variants and left the etiology mostly unknown. Last, we have observed an extraordinary and unprecedented revolution in the understanding of ASD’s biology, genetics, and intervention. However, the increases in ASD incidence highlight the need for persistent efforts to identify novel ASD findings that may help in the development of effective medical interventions for all individuals with ASD. In this paper, we aim to highlight some significant studies of the genetic basis of ASD from genomic architecture, genome-wide, and single-candidate genes. Furthermore, we presented future research directions that might accelerate the pace of scientific discovery and eventually translate into empirically supported interventions for those affected with ASD.

Background: Wolman disease (WD) severe lysosomal acid lipase is a rare, autosomal recessive lysosomal storage disease caused by the absence or deficiency of lysosomal acid lipase enzyme. This deficiency leads to the accumulation of cholesterol esters and triglycerides in multiple organs of the body. Jazan Region is the second smallest region of Saudi Arabia. It stretches 300 km (190 mi) along the southern Red Sea coast, just north of Yemen. It covers an area of 11,671 km² and has a population of 1,567,547 at the 2017 census. The region has the highest population density in the Kingdom and a high consanguinity marriage rate. Case Presentation: We report a rare case of WD, misdiagnosed by a surgeon to be pyloric stenosis, treated for a while as renal tubular acidosis, found to have typical WD presentation of malabsorption, hepatosplenomegaly, and adrenal calcification. Conclusion: This case report is the first report that described the existence of WD in the Jazan region up to date.

Background: The congenital muscular dystrophies (CMD) are a group of heterogeneous diseases, manifested with a wide variety of clinical findings. Dystroglycanopathy is regarded as a subgroup among the CMD group of diseases. POMT1 mutations that cause alpha-dystroglycan hypoglycolization are reported to cause CMD diseases with autosomal recessive inheritance pattern. Case Presentation: A 14-year-old girl patient was referred with classical symptoms for CMDs. Whole exome sequencing (WES) analysis revealed a mutation in the POMT1 gene after the differential diagnosis of the patient. A homozygous mutation detected in the patient diagnosed muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 1 (OMIM 613155). Conclusion: Different mutations in the POMT1 gene have been found to cause three different types of diseases (CMDs). The differential diagnosis for these diseases clinically remains difficult, as a result, detailed clinical evaluation of patients becomes mandatory. Also, a multidisciplinary and collaborative approach involving complete clinical information and anamnesis is essential for the interpretation of genetic test results for such complex disorders.

Background: Niemann–Pick (NP) disease is a genetically heterogeneous metabolic disorder caused by bi-allelic variants in NPC1, NPC2, or SMPD1, with initial symptoms and age at onset varying widely. The interpretation of variants in NP disease genes is challenging when these alterations have never been observed before, and when parental samples are not available. Case Presentation: We clinically, genetically, and biochemically characterized an infant with a complex presentation and a negative family history. Clinical and paraclinical observations were consistent with NP disease. Genetic screening identified two previously unreported SMPD1 missense variants, which were initially classified as variants of unknown significance. Based on strongly increased plasma levels of lysosphingomyelin-509, both variants could be re-classified as likely pathogenic, thus establishing a diagnosis of NP disease type A/B. Conclusion: A combination of genetics with biochemical approaches facilitates conclusive diagnosis of metabolic disorders including NP disease. Blood-based biomarkers are particularly promising in this respect.

Background: Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolically inherited disorder, caused by an abnormal function of the branched-chain α-keto acid dehydrogenase complex in the mitochondria. Case Presentation: The proband was born after a full-term pregnancy and normal vaginal delivery, with a good Apgar score (8, 9 at 1 and 5 minutes) and the birth weight of 2.5 kg with ambiguous genitalia in the form of phallus-like structure (3 cm), the fusion of labio-scrotal folds and urogenital sinus. The third day after birth, the proband was lethargic and developed hyperkalemia and hyponatremia, which required intravenous fluid therapy and hormonal replacement with hydrocortisone and fludrocortisone. The treatment was based on the positive family history of congenital adrenal hyperplasia in an older male sibling. Laboratory tests, cytogenetic study, tandem mass spectroscopy, and surgery were performed for the affected individual (II-8) using standard procedures. The laboratory and the treatment revealed significant improvements. Follow-up tandem mass spectroscopy results were observed in the normal range. The affected individual was treated with prednisone (2.5 mg bid) and Florinef (Fludrocortisone) (0.1 mg OD). The subject had regular menses, while acne and hirsutism were not observed. Conclusion: We are reporting the first case of MSUD associated with CAH, 21-hydroxylase deficiency salt-losing type and suggest that glucocorticoids might have an important role in treating MSUD cases.