Clinical, radiological, and genetic characterization of SLC13A5 variants in Saudi families: Genotype phenotype correlation and brief review of the literature.

Background: SLC13A5 (solute carrier family 13, member 5) encodes sodium/citrate cotransporter, which mainly localizes in cellular plasma membranes in the frontal cortex, retina, and liver. Pathogenic variants of the gene cause an autosomal recessive syndrome known as "developmental and epileptic encephalopathy 25 with amelogenesis imperfecta." Results: Here, we have investigated six patients from three different consanguineous Saudi families. The affected individuals presented with neonatal seizures, developmental delay, and significant defects in tooth development. Some patients showed other clinical features such as muscle weakness, motor difficulties, intellectual disability, microcephaly, and speech problems in addition to additional abnormalities revealed by electroencephalography (EEGs) and magnetic resonance imaging (MRI). One of the MRI findings was related to cortical thickening in the frontal lobe. To diagnose and study the genetic defects of the patients, whole exome sequencing (WES) coupled with confirmatory Sanger sequencing was utilized. Iterative filtering identified two variants of SLC13A5, one of which is novel, in the families. Families 1 and 2 had the same insertion (a previously reported mutation), leading to a frameshift and premature stop codon. The third family had a novel splice site variant. Confirmatory Sanger sequencing corroborated WES results and indicated full segregation of the variants in the corresponding families. The patients' conditions were poorly controlled by multiple antiepileptics as they needed constant care. Conclusion: Considering that recessive mutations are common in the Arab population, SLC13A5 screening should be prioritized in future patients harboring similar symptoms including defects in molar development.

Incidence of newborn screening disorders among 56632 infants in Central Saudi Arabia. A 6-year study.

OBJECTIVES: To determine the incidence of newborn screening (NBS) disorders and to study the key performance indicators of the program. METHODS: This retrospective single-center study enrolled all infants who underwent NBS from January 2012 to December 2017 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. We screened 17 NBS disorders. Blood samples were collected 24 hours after birth. If the initial result was positive, a second sample was collected. True positive cases were immediately referred for medical management. Data were extracted from laboratory computerized and non-computerized records using case report forms. RESULTS: During the study period, 56632 infants underwent NBS with a coverage rate of 100%. Thirty-eight cases were confirmed. The incidence of congenital hypothyroidism was 1:3775. The positive predictive value for the detection of congenital hypothyroidism was 11.8%. Propionic aciduria was the most common metabolic disorder, with an incidence of 1:14158. Very long-chain acyl CoA dehydrogenase deficiency and glutaric aciduria type 1 had an incidence of 1:18877 each. Phenylketonuria, biotinidase deficiency, maple syrup urine disease, and citrullinemia had an incidence of 1:28316 each. However, galactosemia and 3-methyl crotonyl carboxylase deficiency had the lowest incidence of 1:56632. CONCLUSION: The NBS coverage rate at our facility was 100%. Congenital hypothyroidism was the most frequently detected disorder with an incidence that matches worldwide figures. The incidence of other inherited disorders was consistent with regional figures.

First report of two successive deletions on chromosome 15q13 cytogenetic bands in a boy and girl: additional data to 15q13.3 syndrome with a report of high IQ patient.

15q13.3 syndrome is associated with a wide spectrum of neurological disorders. Among a cohort of 150 neurodevelopmental cases, we identified two patients with two close proximity interstitial hemizygous deletions on chromosome 15q13. Using high-density microarrays, we characterized these deletions and their approximate breakpoints. The second deletion in both patients overlaps in a small area containing CHRNA7 where the gene is partially deleted. The CHRNA7 is considered a strong candidate for the 15q13.3 deletion syndrome's pathogenicity. Patient 1 has cognitive impairment, learning disabilities, hyperactivity and subtle dysmorphic features whereas patient 2 has mild language impairment with speech difficulty, mild dysmorphia, heart defect and interestingly a high IQ that has not been reported in 15q13.3 syndrome patients before. Our study presents first report of such two successive deletions in 15q13.3 syndrome patients and a high IQ in a 15q13.3 syndrome patient. Our study expands the breakpoints and phenotypic features related to 15q13.3 syndrome.

The Prevalence of Phenylketonuria in Arab Countries, Turkey, and Iran: A Systematic Review.

BACKGROUND/OBJECTIVES: This paper seeks to identify the prevalence of Phenylketonuria (PKU) in Arab countries, Turkey, and Iran. The study reviewed the existence of comprehensive national newborn screening programs and reported consanguinity rates. METHODS: A computer based literature search was conducted using relevant keywords to retrieve studies conducted on PKU. A total of 34 articles were included. Prevalence was categorized based on the type of screening method used for PKU diagnoses. RESULTS: The prevalence of classical PKU diagnosed through a comprehensive national newborn screening program ranged from 0.005% to 0.0167%. The highest prevalence was reported in Turkey at 0.0167%, whereas the lowest prevalence was reported in the UAE, 0.005%. CONCLUSION: The findings of this review emphasize the need for the establishment of more efficient reporting systems in these countries that would help measure Disability-Adjusted Life Year (DALY) in order to estimate the overall societal burden of PKU.

A Novel Homozygous Mutation in SPTBN2 Leads to Spinocerebellar Ataxia in a Consanguineous Family: Report of a New Infantile-Onset Case and Brief Review of the Literature.

The objective of this study was the identification of likely genes and mutations associated with an autosomal recessive (AR) rare spinocerebellar ataxia (SCA) phenotype in two patients with infantile onset, from a consanguineous family. Using genome-wide SNP screening, autozygosity mapping, targeted Sanger sequencing and nextgen sequencing, family segregation analysis, and comprehensive neuropanel, we discovered a novel mutation in SPTBN2. Next, we utilized multiple sequence alignment of amino acids from various species as well as crystal structures provided by protein data bank (PDB# 1WYQ and 1WJM) to model the mutation site and its effect on ß-III-spectrin. Finally, we used various bioinformatic classifiers to determine pathogenicity of the missense variant. A comprehensive clinical and diagnostic workup including radiological exams were performed on the patients as part of routine patient care. The homozygous missense variant (c.1572C>T; p.R414C) detected in exon 2 was fully segregated in the family and absent in a large ethnic cohort as well as publicly available data sets. Our comprehensive targeted sequencing approaches did not reveal any other likely candidate variants or mutations in both patients. The two male siblings presented with delayed motor milestones and cognitive and learning disability. Brain MRI revealed isolated cerebellar atrophy more marked in midline inferior vermis at ages of 3 and 6.5 years. Sequence alignments of the amino acids for ß-III-spectrin indicated that the arginine at 414 is highly conserved among various species and located towards the end of first spectrin repeat domain. Inclusive bioinformatic analysis predicted that the variant is to be damaging and disease causing. In addition to the novel mutation, a brief literature review of the previously reported mutations as well as clinical comparison of the cases were also presented. Our study reviews the previously reported SPTBN2 mutations and cases. Moreover, the novel mutation, p.R414C, adds up to the literature for the infantile-onset form of autosomal recessive ataxia associated with SPTBN2. Previously, few SPTBN2 recessive mutations have been reported in humans. Animal models especially the ß-III-/- mouse model provided insights into early coordination and gait deficit suggestive of loss-of-function. It is expected to see more recessive SPTBN2 mutations appearing in the literature during the upcoming years.

Tysnd1 deficiency in mice interferes with the peroxisomal localization of PTS2 enzymes, causing lipid metabolic abnormalities and male infertility.

Peroxisomes are subcellular organelles involved in lipid metabolic processes, including those of very-long-chain fatty acids and branched-chain fatty acids, among others. Peroxisome matrix proteins are synthesized in the cytoplasm. Targeting signals (PTS or peroxisomal targeting signal) at the C-terminus (PTS1) or N-terminus (PTS2) of peroxisomal matrix proteins mediate their import into the organelle. In the case of PTS2-containing proteins, the PTS2 signal is cleaved from the protein when transported into peroxisomes. The functional mechanism of PTS2 processing, however, is poorly understood. Previously we identified Tysnd1 (Trypsin domain containing 1) and biochemically characterized it as a peroxisomal cysteine endopeptidase that directly processes PTS2-containing prethiolase Acaa1 and PTS1-containing Acox1, Hsd17b4, and ScpX. The latter three enzymes are crucial components of the very-long-chain fatty acids ß-oxidation pathway. To clarify the in vivo functions and physiological role of Tysnd1, we analyzed the phenotype of Tysnd1(-/-) mice. Male Tysnd1(-/-) mice are infertile, and the epididymal sperms lack the acrosomal cap. These phenotypic features are most likely the result of changes in the molecular species composition of choline and ethanolamine plasmalogens. Tysnd1(-/-) mice also developed liver dysfunctions when the phytanic acid precursor phytol was orally administered. Phyh and Agps are known PTS2-containing proteins, but were identified as novel Tysnd1 substrates. Loss of Tysnd1 interferes with the peroxisomal localization of Acaa1, Phyh, and Agps, which might cause the mild Zellweger syndrome spectrum-resembling phenotypes. Our data established that peroxisomal processing protease Tysnd1 is necessary to mediate the physiological functions of PTS2-containing substrates.

Molecular genotyping of hemophilia A in Saudi Arabia: report of 2 novel mutations.

Different types of mutations have been reported in patients with hemophilia A. Although about half of all severe factor VIII deficiencies are caused by gene rearrangements (inversions) involving intron 22 in F8, other mutations such as point mutation, large deletions and insertions had been reported. We report the result of the first molecular testing for or F8 mutations from Saudi Arabia. A cohort of 22 men with hemophilia A was studied for F8 mutations. All patients were tested for factor VIII coagulant activity and inhibitors. Peripheral blood samples were used for DNA extraction followed by PCR detection of intron 22 inversion and all samples tested negative were screened for other F8 mutations. The patient's age ranged between 4 and 37 years. All patients except two siblings had severe hemophilia A. Only two patients out of 22 developed inhibitors with no obvious relation to the genotype. F8 Intron 22 inversion was detected in 10 patients (50%) of severe cases. Additionally, five point mutations and one deletion/insertion involving different exons were detected. All identified mutations were associated with severe phenotype except for one, which was associated with mild phenotype of hemophilia. This is the first report of molecular genotype of hemophilia A in the Saudi population and one of the few for Arab population. We had confirmed the incidence of Inversion 22 in severe hemophilia. We are reporting two novel mutations in F8, which can be used for carrier detection and prenatal genetic diagnosis (PGD).