Year 2021, Volume 4 - Issue 2

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Background: Inborn errors of metabolism (IEM) are prevalent autosomal recessive disorders in Saudi Arabia. Socio-economic factors, such as consanguineous marriages, play a role in the high rate of diseases. The government of Saudi Arabia created a newborn screening program (NBS) for the most prevalent disorders to facilitate early intervention and the prevention of severe complications. The study aimed to determine the carried pathogenic allele of the diseases included in the NBS and the most frequently carried phenotype in the Saudi population. Methodology: We performed targeted genetic screening for the genes associated with the IEM in the NBS. We used the results of the whole exome sequencing of 1,314 affected and unaffected individuals from 650 families. The results constitute the King Abdullah International Medical Research Center Genomic Database. Results: According to the data set, four diseases occurred most frequently in the Saudi population: adrenal hyperplasia, propionic acidemia, phenylketonuria, and maple syrup urine disease. In total, 12 pathogenic variants occurred frequently. Conclusion: This study generated an updated list of the most pathogenic variants in the Saudi population, based on the National Guard Hospital dataset. Additional research with larger data sets from the different regions will provide valuable information about the allele distribution in the Saudi population, creating a carrier screening program.

Background: Cystic fibrosis (CF) is a genetic disease that affects the transmembrane conductance regulator gene responsible for modulating chloride ion transportation in the cell membrane. Hypovitaminosis D is frequently observed among fibrocystic disease patients. Therefore, this study was aimed to evaluate the effect of vitamin D3 supplementation in patients with CF concerning their metabolic and deoxyribonucleic acid (DNA) methylation profiles. Methodology: A clinical trial involving 12 CF patients was carried out in Joao Pessoa. After assessment of hypovitaminosis D prevalence in the studied population, four patients with vitamin D3 insufficiency/deficiency were administered cholecalciferol megadose supplementation in addition to biochemical examinations and analysis of inflammatory and epigenetic indicators. The DNA methylation profile of the studied genes' promoter regions was determined through a qualitative methylation restriction enzyme technique. Data were analyzed using the Statistical Package for the Social Sciences 25.0 software for T-tests, Mann-Whitney, and Wilcoxon test calculations. Results: Hypovitaminosis D was observed in 58%, 33% of the studied individuals. Patients with hypovitaminosis D reported blood sugar, glutamic-pyruvic transaminase (ALT), and uric acid levels significantly higher (p = 0.02; p = 0.05; p = 0.02, respectively) compared to individuals with sufficient 25-hydroxyvitamin D (25(OH)D), as well as elevated inflammatory values. Supplementation did not influence epigenetic nor metabolic parameters significantly, although the mean 25(OH)D serum concentration value increased from 18.3 ng/dl to 34.1 ng/dl (p = 0.06). Conclusion: Cholecalciferol megadose elevated 25(OH)D serum levels, although it did not alter inflammatory, glycemic, or epigenetic parameters. This encourages future studies on the matter since significant differences were found in blood sugar, uric acid, and ALT serum levels for the vitamin D3 insufficiency/deficiency group despite this study’s small sample size.

Background: Genetic diseases result from gene mutations that disrupt the function of body systems, and most of them cannot be treated. Genetic diseases are a serious issue responsible for severe economic, emotional, and health impacts on patients and their families. In Saudi Arabia, consanguineous marriage is common, leading to an increased prevalence of genetic diseases. Therefore, Saudi Arabia has endeavored to reduce the frequency of genetic diseases by implementing the premarital screening program, which is mandatory and accessible for people planning to get married, and the genetic counseling program. Methods: In this study, we investigated the awareness and knowledge of genetic diseases among residents of the western region of Saudi Arabia, and we conducted a cross-sectional survey focusing on the level of awareness and knowledge of genetic diseases and available health care. Results: We found that the residents of the western region had good knowledge about genetic diseases, but 96.10% lacked the awareness of health services provided for this type of disease. Furthermore, 91.90% of them had a positive attitude toward genetic testing. Conclusion: The present study found that Saudi society had a good attitude toward genetic testing, such as prenatal and preimplantation genetic diagnosis. Many of the study participants were not aware, where to access genetic tests for their families, and most considered health services for patients with genetic diseases to be rudimentary, thus pointing out a lack of awareness and knowledge toward health services.

Background: The endoplasmic reticulum membrane protein complex 1 (EMC1) gene encodes a subunit of the EMC with multiple alternatively spliced transcripts encoding different isoforms. Monoallelic and biallelic mutations of the EMC1 gene have been reported for cerebellar atrophy, visual impairment, psychomotor retardation, lipoid proteinosis of Urbach and Wiethe, and Alkuraya-Kucinskas syndrome. Objectives: Herein, we present whole exome sequencing results of eight Saudi pediatric patients with distinctive clinical features which revealed both monoallelic and biallelic variants in the EMC1 gene (CHR1 exon4:19568918, NM_001271429.2, c.364G>A; p.A122T), including two previously reported siblings (CHR1 exon21:19547328, NM_015047.3, c.2602G>A; p.G868R). Results: The patients presented with the neurological and extra-neurological clinical spectrum that included seizures, spastic diplegia, cognitive impairment, axial and appendicular hypotonia, dysmorphic features, joint hyper-flexibility, attention deficit hyperactivity disorder, skeletal dysplasia in addition to generalized global developmental delay, failure to thrive, speech delay, intellectual disability, and visual impairments. Furthermore, brain Magnetic resonance imaging findings were consistent with variable clinical features and revealed brain atrophy, thinning of corpus callosum, semi-lobar holoprosencephaly, white matter abnormality, diffuse paucity of the myelin within the brain parenchyma, and reduction of white matter arborization in the temporal lobes. Conclusion: In conclusion, these clinical cases highlight the importance of the EMC1 gene in disease phenotype and add up to the expanded EMC1-related phenotype.

Background: The genetics domain is witnessing great advances in diagnosing and predicting genetic diseases. In a clinical setting, autosomal recessive genetic disorders are frequently observed as a result of the high rate of consanguinity. The advances in genomic technologies and methods in recent years have facilitated new tools for gene discovery in humans. There is a debate over the ethical dilemmas and challenges behind providing families with the genetic test results and incidental findings. Thus, this vast source of information can have a multitude of ethical, social, legal, and political implications. Objectives: In this study, we aimed to study how families of affected children respond when they receive incidental findings. Also, we aimed to identify how healthcare professionals descriptively abide by their role and the information-sharing procedures. Methods: This study was a qualitative study conducted at King Faisal Specialist Hospital and Research Centre in Riyadh. It included a total of 14 participants and a total of 14 healthcare providers. Results and conclusion: Six strong themes emerged in this study. This study explored the experiences of parents of children affected with genetic diseases and the experiences of healthcare providers attending these families; their observations and the ethical challenges they faced during their practice.

Background: Non-immune hydrops fetalis (NIHF) is the abnormal accumulation of serous fluid in more than two fetal or neonatal interstitial spaces due to non-immune causes. It is a serious condition that requires extensive medical care as it indicates severe fetal compromise. Severe anemia, infections, heart or lung defects, and liver disease are all possible causes. Less common causes of NIHF include single gene defects and chromosomal abnormalities. Case Presentation: We report a 2-month-old girl born at 32 weeks of gestation and found to have polyhydramnios and massive congenital ascites. Whole exome sequencing (WES) identified a biallelic pathogenic variant c.617G>A p. (Cys206Tyr) in the thrombospondin 1 domain-containing protein 1 (THSD1) gene. She was misdiagnosed to have ascites secondary to liver dysfunction. Conclusion: Rare causes of fetal hydrops like THSD1 mutation need to be excluded in cases of recurrent non-immune hydrops with no obvious etiology.

Background: Peroxisomes are cells' organelles that responsible for the metabolism of branched-chain and very-long-chain fatty acids (VLCFA), polyamines, and amino acids. Peroxisomal biogenesis factor 6 (PEX6) is one of the factors required for the import of the proteins into peroxisomes. Mutation in any one of PEX genes will result in Zellweger syndrome (ZS), one of the peroxisome biogenesis disorder. Case Presentation: A 11-year-old girl referred was with central hypotonia and global developmental delay and feeding problems. She has an open and flat fontanel. Liver function tests and thyroid-stimulating hormone were elevated. Plasma VLCFA C26, VLCFA C24/C22, and VLCFA C26/C22 were elevated. Cerebrospinal fluid flow artifact and posterior displacement of the basilar artery findings raised the possibility of increased intracranial pressure. X-ray showed mild irregularity in the end plates of the lumbar vertebrae, bilateral coxa valga, irregularity in the articular surfaces of the ossified epiphysis of the upper and lower limbs, and generalized osteopenia. The audiological assessment profound hearing loss in both ears. Inborn error of metabolism, next-generation sequencing gene panel analysis, and whole exome sequencing showed that no pathogenic or likely pathogenic variants explaining the phenotypes. The single nucleotide polymorphisms testing showed a deletion in PEX6 gene (homozygous variant of uncertain significance). Conclusion: We report a case of ZS associated with a new PEX6 mutation that has not been previously reported in the literature.

Background: Alpha-mannosidosis [Online Mendelian Inheritance in Man (OMIM): 248500] is an autosomal recessive disorder due to a deficiency of the lysosomal enzyme alpha-mannosidase. It is an ultra-orphan disease. In this paper, we report a case of alpha-mannosidosis in a Saudi boy of consanguineous parents, who was referred to our hospital to be worked up for possible mucopolysaccharidosis. Case Presentation: The patient was presented with dysmorphic features, global developmental delay, hearing defect, and recurrent respiratory tract infections. On examination, he had short stature, a short neck, cataracts, hearing impairment, chest deformity, hepatomegaly, umbilical hernia, right inguinal hernia, and two Mongolian spots in the back. He had normal peripheral blood smear: urinary oligosaccharide and dry blood spot for mucopolysaccharide enzyme assay founded to be negative. Definitive diagnosis was performed by directly sequencing the MAN2B1 gene of the peripheral blood leukocytes. It showed a homozygous variant c.1065delC; p.Ala356fs*7 (NM_001173498.1) as likely pathogenic. Conclusion: We report a novel variant mutation in MAN2B1 gene mutation. Also, to the best of authors' knowledge, this is the first reported case of alpha-mannosidosis in a Saudi patient.

Background: ATP6V1B2 gene mutation is associated with Zimmermann-Laband syndrome 2 (ZLS2), which is a rare developmental disorder characterized by nail hypoplasia and hereditary deafness. Case Presentation: We report a new phenotypic mutation of ATP6V1B2 associated with ZLS 2. The patient has atresia of the left pulmonary artery (LPA) and features of hearing loss and nail hypoplasia. The other interesting part is that the child had two types of mutations inherited from father and mother. He is carrier for GJB2 mutation (inherited from father) and diseased with ATP6V1B2 mutation (inherited from mother). Conclusion: The association of ZLS features with absent LPA was not reported previously in the literature. This finding will add new information to the database of previously reported ATP6V1B2 rare mutations.