Year 2018, Volume 1 - Issue 2

No abstract available

Background The 48,XXXY syndrome is a rare sex chromosome aneuploidy, presenting characteristic features such as prominent facial and skeletal malformations, intrauterine growth retardation, and psychomotor retardation. Psychological, endocrinological, auxological issues and orthopedic disorders constitute the major problems in this syndrome, which require long term clinical and biochemical follow-up. Materials and Methods In the present investigation, chromosomal analysis (standard chromosomal karyotyping) and fluorescence in situ hybridization (FISH) was performed according to the standard protocols. Results Here, we report a single affected individual (boy) having Saudi origin, suffering from rare sex chromosomal aneuploidy. The main presenting complaint is the obvious dysmorphic features associated with developmental delay, epicanthal folds, short nose, prominent philtrum, low seated ears, and overlapping toes. Chromosomal analysis and fluorescence in situ hybridization (FISH) revealed an extra two X chromosomes thus causing the 48,XXXY syndrome. Conclusion Patients with facial dysmorphism, developmental delay, unexplained hypotonia and accompanying behavioral disturbances must be tested for sex chromosome aneuploidies. Management and proper diagnosis require a multidisciplinary approach involving pediatric endocrinology, pediatric surgery, orthopedics, psychiatry, and clinical genetic evaluations. Considering 48,XXXY syndrome as a highly severe disorder, cytogenetic tests should be performed as the first diagnostic approach.

Type 2 Diabetes (T2D) is a polygenic and multi-factorial complex disease. The significant challenge of finding genetic markers that could be used to predict T2D risk remains unresolved. Saudi Arabia is one of several ethnicities with a high prevalence rate of T2D. A large number of studies have been performed that explored genetic factors associated with T2D risk. In this work, we conducted a systematic review of published studies on T2D genetic markers in the Saudi population. Multiple databases were employed in the literature review, which focused on studies that either reported the association or non-association of a genetic marker with T2D risk. Using appropriate search terms, we collected, analyzed, and selected 428 articles published between the years of 2000-2018, Of these, 18 articles reported a total of 67 polymorphisms in 46 genes that are strongly linked to T2D in the Saudi population. Most of the relevant studies used genotyping as the primary methodology to identify genetic markers of T2D. Most of these studies were published between the years of 2012-2017. A total of 23 polymorphisms in 17 genes were found to be associated with T2D risk in the Saudi population: KCNJ11, PPARG2, IRS1, VDE, WFS1, JAZF1, CDKN2A/B, TCF7L2, KCNQ1, HNF4A, DUSP9, APOE, HNF1A, SLC30A8, APOC3, SNAP25, and ACE.

Frontonasal dysplasia (FND) is a rare complex genetic facial malformation, mostly characterized by affecting the face and head regions of the body. Craniofacial defects can have a severe impact, revealing different types of clinical phenotypes, which are broadly grouped as frontonasal dysplasias (FNDs). FNDs have been classified along with selected disorders on the genetic and molecular basis. FND is clinically diagnosed on the basis of at least two features including median facial cleft, broad nasal bridge, ocular hypertelorism, widened philtrum, median cleft upper lip, widow's peak frontal hairline and missing or underdeveloped nasal tip. The three types of FNDs are caused by the ALX genes (ALX1, ALX3, ALX4). Genes and pathways related to facial development are associated with direct or indirect expression of the FGF8, the SHH, and the BMP4. The present review provides a detail literature review on the FND phenotypes and mutation update of different genes involved that will help in proper classification, genetic counseling, and diagnosis of the affected families.

Background: Dilated cardiomyopathy (DCM) is a progressive, lethal disorder that has heterogeneous genetic background. It has been linked to mutations in Nebulin-related-anchoring protein (NRAP) gene. NRAP expressed mainly in striated and cardiac muscles, and it plays substantial role in the sarcomeric contraction cycle and myofibrillogenesis. Case Presentation: A 17-month-old baby girl presented at the age of 13 months with symptoms of heart failure. She was diagnosed as a case of dilated cardiomyopathy. Using whole exome sequencing, diagnosis is confirmed due to homozygous NRAP variant c.400-407 del p.(Cys134 Serfs*12), which create premature stop codon. Conclusion: This case report supports preceding reports that biallelic deletion mutations in NRAP gene cause an autosomal recessive DCM with low penetrance genetic risk factor. However, the age of presentation can vary from early infancy up to adulthood.

Background: Mutations in the collagen VI genes (COL6A1, COL6A2, and COL6A3) cause Ullrich congenital muscular dystrophy (UCMD) (UCMD; Mendelian Inheritance in Man [MIM] 254090), Bethlem myopathy (BM) (BM; MIM 158810) and phenotypes between BM and UCMD. Both of UCMD and BM are inherited as autosomal dominant and autosomal recessive. Case Presentation: A 4-year-old patient presented to the clinical genetic department with complaints of mental motor retardation, epilepsy and joint contractures. The patient's physical examination, biochemical test results, magnetic resonance image, echocardiography were lead us suspected from congenital muscular dystrophy. Then WES analysis was performed. As a result of WES analysis, homozygous mutation was detected in COL6A2 gene. Conclusion: WES analysis is a good method for diseases with recessive inheritance. In addition, detailed and holistic assessment of patients is important.

Background: Denys-Drash syndrome (DDS) is a very rare genetic disease. Wilms' tumor, genital abnormalities, and congenital glomerulopathy are the main features of DDS which resulted from a heterozygous mutation in the WT1 gene. Case Presentation: First case of DDS has been diagnosed in Saudi Arabia in four months newborn who admitted to nephrology department with ambiguous bilateral undescended testis, and nephropathy. On admission, he had normal vital signs except high blood pressure. His kidney function tests showed abnormal kidney function. Ultrasonography and MRI were done to figure out his nephropathy and undescended testis, respectively. Both Abdominal ultrasonography and kidney histopathology confirmed diffuse mesangial sclerosis (DMS). MRI graph located the un-identical ectopic testis. The autosomal dominant inherited pathogenic missense mutation in exon 9 of WT1 gene (c.1181G>A (p.Arg394GLu)) was confirmed by DNA direct sequencing analysis. At his 4th year of age, his nephropathy developed to End Stage Renal Disease (ESRD). Conclusion: DDS should be considered in new born baby with nephrotic syndrome and ambiguous gonads. DNA direct sequencing analysis for WT1 gene is very helpful for confirmation of DDS.

Background: Mitchell-Riley Syndrome (OMIM # 615710) is a rare autosomal recessive disorder, characterized by a genetic mutation in the RFX6 gene. Clinically it is presented with triad of neonatal diabetes, gall bladder agenesis/hypoplasia and intestinal atresia. Case presentation: We reported a female Saudi twin of consanguineous parents presented with neonatal diabetes, gall bladder agenesis/hypoplasia and intestinal atresia since birth who deceased at 5 months of age due to sepsis. Molecular genetics testing of RFX6 gene showed novel homozygous missense mutation; NM_173560.3: (c.983A>T; p.Asp328Val). We compared current patient to previously reported cases Conclusion: We alert the clinicians to consider this syndrome in any neonate presenting with diabetes, gallbladder agenesis, and intestinal atresia.

Background: This report provides a molecular cytogenetic characterization of an Omani girl with 19p13.12 microdeletion and compares her clinical features of global developmental delay (GDD) and multiple congenital anomalies with the gene mutations and disorders associated with this locus. Case Presentation: The 4-year-old Omani girl presented to the National Genetic Center with the following clinical features: GDD, hypotonia, multiple congenital anomalies, facial dysmorphism, and skeletal anomalies. Array comparative genomic hybridization (CGH) identified a 1.913 Mb de novo microdeletion in the patient within 19p13.12. The deletion includes 53 genes, of which 35 are Online Mendelian Inheritance in Man (OMIM) genes. The deleted region includes NFIX (OMIM #164005), CACNA1A (OMIM # 601011) and NACC1 (OMIM # 610672) genes which are previously reported to be associated with the presented clinical features. Conclusion: 19p13.12 microdeletion syndrome is a rare condition for which only one prenatal and 5 postnatal cases have been reported previously. This case of 19p13.12 microdeletion syndrome is the first case to be reported in Oman as well as in the Gulf Cooperation Council countries (GCC) and in the Middle East and North Africa (MENA).

Introduction: Iron-Sulfur Cluster (ISC) biogenesis is a vital cellular process in the mitochondria. It is required to produce various ISC-containing proteins which are present in the nucleus, mitochondria, and cytosol. ISC proteins are responsible for essential functions such as glycine cleavage and the formation of lipoic acid. ISCA2 encodes an A-type ISC protein involved in the assembly of mitochondrial iron-sulfur cluster (4Fe- 4S) which is important for electron transfer and mitochondrial function. ISCA2 related Mitochondrial Disorder (IRMD) is a severe disorder of systemic energy metabolism, characterized by weakness, respiratory failure, lack of neurological development, lactic acidosis, hyperglycinemia and early death. ISCA2 gene is located on Chromosome 14q24.3 and has autosomal recessive inheritance. Objective: In this report, we present the clinical and radiological features a subject homozygous for the common founder pathogenic variant; c.229G>A; p.Gly77Ser. Conclusion: IRMD presents with infantile onset triad of progressive neurodevelopmental regression, nystagmus and optic atrophy. It is a rapidly progressive condition with death usually in first two years of life. It should be considered in infantile onset leukodystrophy. Future studies are needed to understand the role of ISCA2 gene, the effect of its mutation, and any targets for future treatment strategies.