Search

Background The optimal amount and timing of protein intake in critically ill patients are unknown. REPLENISH (Replacing Protein via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial evaluates whether supplemental enteral protein added to standard enteral nutrition to achieve a high amount of enteral protein given from ICU day five until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve a moderate amount of enteral protein would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients. Methods In this multicenter randomized trial, critically ill patients will be randomized to receive supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition to achieve a high amount of enteral protein (range of 2-2.4 g/kg/day) or no supplemental enteral protein to achieve a moderate amount of enteral protein (0.8–1.2 g/kg/day). The primary outcome is 90-day all-cause mortality, and other outcomes include functional and health-related quality-of-life assessments at 90 days. The study sample size of 2502 patients will have 80% power to detect a 5% absolute risk reduction in 90-day mortality from 30–25%. Consistent with international guidelines, this statistical analysis plan specifies the methods for evaluating primary and secondary outcomes and subgroups. Applying this statistical analysis plan to the REPLENISH trial will facilitate unbiased analyses of clinical data. Conclusion Ethics approval was obtained from the King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia (RC19/414/R ). Approvals were also obtained from the institutional review boards of each participating institution. Our findings will be disseminated in an international peer-reviewed journal and presented at relevant conferences and meetings Trial registration: ClinicalTrials.gov Identifier: NCT04475666. Registered on July 17, 2020 https://clinicaltrials.gov/ct2/show/NCT04475666

Geroderma osteodysplasticum (GO; MIM 231070) is characterized by a typical progeroid facial appearance, wrinkled, lax skin, joint laxity, skeletal abnormalities with variable degree of osteopenia, frequent fractures, scoliosis, bowed long bones, vertebral collapse, and hyperextensible fingers. The disorder results from mutations in the GORAB—golgin, RAB6 interacting. This gene encodes a member of the golgin family, a group of coiled-coil proteins on golgin that maps to chromosome 1q24. The encoded protein has a function in the secretory pathway, was identified by terminal kinase-like protein, and thus, it may function in mitosis. Mutations in this gene have been associated with GO. Herein, we describe the clinical presentation of one young male patient from related Saudi parents. Mutations, a homozygous frameshift mutation (c.306dup p.(pro 103 Thrfs*20)). Interestingly, phenotypic variability was observed in this patient with GO features that were more atypical than the cases reported in the literature as he looks tall stature where most of the cases reported were short and arachnodactyly fingers which mimic other syndromes.

Human disorders of the enteric nervous system (ENS), e.g., Hirschsprung's disease, are rarely associated with major central nervous system involvement. We describe two families each segregating a different homozygous truncating variant in KIF26A with a unique constellation of severe megacolon that resembles Hirschsprung's disease but lacks aganglionosis as well as brain malformations that range from severe to mild. The intestinal phenotype bears a striking resemblance to that observed in Kif26a

Objective: Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare genetic disorder of ketone utilization and isoleucine catabolism caused by mutations in the OXCT1 gene, Case: A Saudi girl case of SCOT deficiency confirmed by genetic analysis has been reported in this study. A 5-year-old girl presented to the emergency with the first episode of severe metabolic ketoacidosis after a febrile illness. On admission, she was drowsy lethargic, and severely dehydrated needs to admit in a highly dependent area. Initial investigations were done during the crisis showed refractory severe metabolic acidosis (pH of 7.18, HCO3- of 7.4 mmol/L), normal ammonia, lactic acidosis, and urine organic acid profile revealed elevations in 3-hydroxybutyrate and acetoacetate. Genetic analysis was done by CentoMito Comprehensive (Large extended screening panel), sequencing of OXCT1 gene revealed that the proband is homozygous for the missense likely pathogenic variant c.1402C>T p.(Arg468Cys) confirming the diagnosis of SCOT deficiency. Conclusion: This is the first Saudi child with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency case report as searched in the literature. This case highlights the importance of suspecting SCOT deficiency in the differential diagnosis of pediatric metabolic ketoacidosis in preventing life-threatening of severe Metabolic ketoacidosis

Congenital myopathies include a wide range of genetically determined disorders characterized by muscle weakness that usually manifest shortly after birth. To date, two different homozygous loss-of-function variants in the HACD1 gene have been reported to cause congenital myopathy. We identified three patients manifesting with neonatal-onset generalized muscle weakness and motor delay that carried three novel homozygous likely pathogenic HACD1 variants. The two of these changes (c.373_375+2delGAGGT and c.785-1G>T) were predicted to introduce splice site alterations, while one is a nonsense change (c.458G>A). The clinical presentation of our and the previously reported patients was comparable, including the temporally progressive improvement that seems to be characteristic of HACD1-related myopathy. Our findings conclusively confirm the implication of HACD1 in the pathogenesis of congenital myopathies, corroborate the main phenotypic features, and further define the genotypic spectrum of this genetic form of myopathy. Importantly, the genetic diagnosis of HACD1-related myopathy bears impactful prognostic value.

Thermal energy storage technology is an important topic, as it enables renewable energy technology to be available 24/7 and under different weather conditions. Phase changing materials (PCM) are key players in thermal energy storage, being the most economic among those available with adjustable thermal properties. Paraffin wax (PW) is one of the best materials used in industrial processes to enhance thermal storage. However, the low thermal conductivity of PW prevents its thermal application. In this study, we successfully modified PW based on multi-walled carbon nanotubes (MWCNT) with different concentrations of TiO

Background: Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory condition resulting from altered crosstalk between innate and adaptive immune responses. Familial HLH is caused by mutations in several genes whereas the acquired form is associated with infections, rheumatic diseases, malignancies, and inherited metabolic disorders. Case Presentation: We report an infant boy who developed HLH and the potential involvement of mitochondrial DNA in pathogenicity. This patient was with evidence of mitochondrial disease based on neonatal-onset lactic acidosis, elevated lactate in cerebrospinal fluid, a significant lactate peak on magnetic resonance spectroscopy, and generalized reduction of multiple respiratory chain enzyme complex activities. In addition, full mitochondrial genome sequencing only revealed the identification of the homoplasmic m.4325A>G mutation. Subsequently, he presented with a febrile illness complicated by HLH. Conclusion: Elevated levels of lactic acidosis and mitochondrial dysfunction strengthen the involvement of mitochondria in causing secondary HLH in our patient.

Osteogenesis imperfecta is a clinically and genetically group of heterogeneous disorders associated with decreased bone density, brittle bones, bone deformity, recurrent fractures, and growth retardation. Osteogenesis imperfecta is commonly associated with mutations of the genes encoding for type I collagen (COL1A1/COL1A2). Mutations in other genes, some associated with type I collagen post-translational processing, have also been identified as the cause of osteogenesis imperfecta. Mutations in the transmembrane protein 38B (TMEM38B) gene have been reported in a rare autosomal recessive form of osteogenesis imperfecta. TMEM38B encodes TRIC-B - a trimeric intracellular cation channel type B which is essential to modulate intracellular calcium signaling. In this study, we are reporting a case of osteogenesis imperfecta type XIV from a Saudi consanguineous family. Our patient was an eight-month-old child with short limbs, club feet, and lower limb deformities with developmental delay. Radiological findings were consistent with the evidence of osteogenesis imperfecta. There was no evidence of impaired hearing or blue sclera and based on the clinical assessment, we classified our patient as a non-syndromic osteogenesis imperfecta. A pathogenic deletion in the chromosome 9q31.2 region, partially encompassing the TMEM38B gene, was detected using chromosomal microarray analysis. This study expands our knowledge about the rare type of osteogenesis imperfecta in our consanguineous population. Besides, it emphasizes the use of genomic medicine in clinical practices to formulate early interventions to clinically improve the patient’s condition.

SLC25A42 gene encodes an inner mitochondrial membrane protein that imports Coenzyme A into the mitochondrial matrix. A mutation in this gene was recently reported in a subject born to consanguineous parents who presented with mitochondrial myopathy with muscle weakness and lactic acidosis. In this report, we present 12 additional individuals with the same founder mutation who presented with variable manifestations ranging from asymptomatic lactic acidosis to a severe phenotype characterized by developmental regression and epilepsy. Our report confirms the link between SLC25A42 and mitochondrial disease in humans, and suggests that pathogenic variants in SLC25A42 should be interpreted with the understanding that the associated phenotype may be highly variable.

An addressable packing parameter approach was developed for reversibly tuning the self-assembly of oligo(aniline)-based supra-amphiphiles., We present a newly developed approach to non-covalently address the packing parameter of an electroactive amphiphile. The pH-responsive reversible switching of a tetra(aniline)-based cationic amphiphile, TANI-pentyl trimethylammonium bromide (TANI-PTAB), between self-assembled vesicles and nanowires by acid/base chemistry in aqueous solution is used to exemplify this approach. Trifluoroacetic acid (TFA) was selected as a prototypical acid to form emeraldine salt (ES) state (TANI(TFA)2-PTAB) vesicles for this new class of small-molecule supramolecular amphiphiles. UV-vis-NIR spectroscopy, transmission electron microscopy (TEM), tapping-mode atomic force microscopy (AFM), and fluorescence spectroscopy were used to investigate the reversible structural transformation from vesicles to nanowires. We show that utilising different protonic acid-dopants for TANI-PTAB can regulate the packing parameter, and thus the final self-assembled structures, in a predictable fashion. We envisage potential application of this concept as smart and switchable delivery systems.

Mitochondrial diseases are a clinically heterogeneous group of multisystem disorders caused by mitochondrial dysfunction. Hepatic involvement is a common feature in neonatal mitochondrial hepatopathies, which may manifest as acute liver failure, hepatic steatohepatitis, cholestasis, or even as chronic liver failure of insidious onset. Mitochondrial diseases are usually severe and rapidly progressive conditions and eventually fatal. However, some of the rare forms show remarkable spontaneous recoveries. The diagnostic process is complex, requiring clinical, biochemical, histological, and genetic investigations. Mutations in several mitochondrial DNA (mt-DNA) and nuclear genes involved in mt-DNA stability and mitochondrial protein synthesis machinery have been associated with mitochondrial disorders. Recently, mutations of TRMU gene encoding mitochondrial tRNA-specific 2-thiouridylase defines the pathomechanism of mitochondrial protein translation defect in the neonatal period presenting with early-onset, reversible liver disease. Here, we report the clinical, biochemical, and genetic findings from one Arab Yamani child presenting with hepatopathy, hyperlactatemia and respiratory chain defect associated with hemophagocytic lymphohistiocytosis, a feature which has not been described in previously reported cases. The aim was to have a prompt definitive genetic diagnosis to provide timely clinical management, decrease morbidity, and improve the survival of the patient. Utilizing next-generation sequencing techniques we identified the pathogenic biallelic mutation c.835G>A (p.Val279Met) in TRMU gene by whole exome sequencing. Since spontaneous recovery is a rare feature in mitochondrial liver disorders, early identification of underlying TRMU mutation can influence clinical management decisions. Our results add to the repertoire of a small number of cases with TRMU mutations reported in mitochondrial liver diseases, for further elaboration of genotype-phenotype correlation.

Polycystic kidney disease (PKD) is one of the most common genetic renal diseases and may be inherited in an autosomal dominant or autosomal recessive pattern. Pathogenic variants in two major genes, PKD1 and PKD2, and two rarer genes, GANAB and DNAJB11, cause autosomal dominant PKD (ADPKD). Early onset and severe PKD can occur with PKD1 and PKD2 pathogenic variants and such phenotypes may be modified by second alleles inherited in trans. Homozygous or compound heterozygous hypomorphic PKD1 variants may also cause a moderate to severe disease PKD phenotype. Targeted renal gene panel followed by Sanger sequencing of PKD1 gene were employed to investigate molecular causes in early onset PKD patients. In this study, we report four consanguineous Saudi Arabian families with early onset PKD which were associated with biallelic variants in PKD1 gene. Our findings confirm that PKD1 alleles may combine to produce severe paediatric onset PKD mimicking the more severe autosomal recessive ciliopathy syndromes associated with PKD. Screening of parents of such children may also reveal subclinical PKD phenotypes.

Purpose Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases. Methods Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines. Results We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders. Conclusions Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.

Temtamy syndrome is a syndromic form of intellectual disability characterized by ocular involvement, epilepsy and dysgenesis of the corpus callosum. After we initially mapped the disease to C12orf57, we noted a high carrier frequency of an ancient startloss founder mutation [c.1A>G; p.M1?] in our population, and variable phenotypic expressivity in newly identified cases. This study aims to combine 33 previously published patients with 23 who are described here for the first time to further delineate the phenotype of this syndrome. In addition to the known p.M1? founder, we describe four novel homozygous variants, thus increasing the number of Temtamy syndrome-related C12orf57 variants to seven, all but one predicted to be loss of function. While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable: 73.2% (41/56) had epilepsy, 63% (34/54) had corpus callosal abnormalities, 14.5% (8/55) had coloboma, and 16.4% (9/55) had microphthalmia. Our analysis also revealed a high frequency of less recognized features such as congenital heart disease (51.4%), and brain white matter abnormalities (38%, 19/50). We conclude that C12orf57 variants should be considered in the etiology of developmental delay/intellectual disability, even when typical syndromic features are lacking, especially in those who trace their ancestry to Saudi Arabia where a founder C12orf57 mutation is among the most common recessive causes of intellectual disability.

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016–December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most “negative” clinical exome tests are unsolved due to interpretation rather than technical limitations. Electronic supplementary material The online version of this article (doi:10.1007/s00439-017-1821-8) contains supplementary material, which is available to authorized users.

We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort’s genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.