Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.

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2,200 previously unpublished Saudi families as a first-tier test.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.

SARS-COV-2 Triggers the Development of Class I and Class II HLA Antibodies in Recovered Convalescent Plasma Donors.

Various studies have shown that SARS-CoV-2 is a highly immunogenic virus. It is known that different types of immunogenic viral pathogens could trigger the formation of HLA antibodies. Therefore, there is a concern that the SARS-CoV-2 could also induce the development of HLA antibodies in volunteers, who donate convalescent plasma after their recovery from COVID-19. HLA antibodies have been identified as the main cause for transfusion-related acute lung injury (TRALI), a well-documented life-threatening complication of transfusions. The TRALI risk could be high in COVID-19 patients who need convalescent plasma, as such patients usually have already an impaired respiratory system affected by the SARS-CoV-2 infection. In this study, we screened 34 convalescent plasma donors on the presence of antibodies against HLA class I and II antigens. All included donors have no any history of sensitization events such as blood transfusions, pregnancy, or previous transplants. We found a high rate of HLA antibody formation in convalescent plasma donors. The frequency of positivity for HLA antibodies for class I, class II, class I and II, and the overall reactivity was 23%, 31%, 46%, and 76%, respectively. The presented data suggest a closed correlation between SARS-CoV-2 virus infection and the development of HLA antibodies in recovered convalescent plasma donors. This finding might have the potential to reduce the risk of TRALI and mortality rate in COVID-19 patients by implementing HLA diagnostic strategies before the administration of convalescent plasma.

Serum Based miRNA as a Diagnostic Biomarker for Multiple Sclerosis: a Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aimed to identify deferentially expressed serum miRNAs in multiple sclerosis patients and to evaluate their diagnostic value in multiple sclerosis diagnosis. Studies were identified on PubMed, Google scholar and Saudi digital library up to 30 September 2019. Articles that examined miRNA expression level in MS patients compared to healthy control group were included in the review and the data were extracted by three independent author. The comprehensive Meta-Analysis version 3 software was used for meta-analysis and heterogeneity of studies was identified according to I2 value. Our literatures search identified 9 eligible articles concerning the serum miRNA as a diagnostic biomarker for multiple sclerosis in comparison to healthy control group. 19 serum miRNAs differentially expressed in MS patients were identified (8 downregulated, 11 upregulated and 1 with discordant result). In publications that provided information on specific miRNA diagnostic value, the pooled AUC was 72% (95% CI 0.65-0.78, p-value 0.00) for the overall multiple sclerosis patients and primary progressive MS (PPMS) (95% CI 0.66-0.78 p-value 0.00). A miRNA panel of four miRNAs showed high sensitivity (73%) and specificity (68%) in distinguishing multiple sclerosis from control groups. When using single miRNA (miR-145), the sensitivity increased to 79% and the specificity to 87%. The available data from the literature and this meta-analysis suggests the potential use of serum miRNA as biomarkers for early diagnosis of MS with high sensitivity and specificity in distinguishing multiple sclerosis subtypes from healthy controls.Abbreviation: MS: Multiple sclerosis; IDD: inflammatory demyelinating diseases; RRMS: relapsing-remitting Multiple sclerosis; PPMS: primary progressive Multiple sclerosis; SPMS: secondary progressive Multiple sclerosis; NMO: Neuromyelitis optica; miRNA: microRNA; ECmiRNA: extracellular microRNA; AUC: Area Under the Curve; ROC: Receiver Operator Characteristic.

Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.

Klippel-Feil syndrome 4 (KFS4; MIM# 616549) is an autosomal recessive disorder caused by biallelic pathogenic variants in MYO18B and comprises, in addition to Klippel-Feil anomaly (KFA), nemaline myopathy, facial dysmorphism, and short stature. We aim to outline the natural history of KFS4 and provide an updated description of its clinical, radiological, laboratory, and molecular findings. We comprehensively analyzed the medical records of 6 Saudi and 1 American patients (including 5 previously unpublished cases) with a molecularly confirmed diagnosis of KFS4. All patients had myopathy of varying severity that followed a slowly progressive or non-progressive course, affecting primarily the proximal musculature of the lower limb although hand involvement with distal arthrogryposis and abnormal interphalangeal creases was also observed. KFA and characteristic dysmorphic features, including ptosis and bulbous nose, were observed in all but two patients. The causal MYO18B variants were a founder NM_032608.5:c.6905C>A; p.(Ser2302*) variant in the Saudi patients (P1-P6) and a novel MYO18B homozygous variant (c.6660_6670del;p.[Arg2220Serfs*74]) in the American Caucasian patient (P7). We report the phenotypic and genetic findings in seven patients with KFS4. We describe the natural history of this disease, confirm myopathy as a universal feature and describe its pattern and progression, and note interesting differences between the phenotypes observed in patients with KFA and those without.

The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.

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.

Diagnosis and treatment of late-onset Pompe disease in the Middle East and North Africa region: consensus recommendations from an expert group.

BACKGROUND: Pompe disease is a rare autosomal recessive disorder caused by a deficiency of the lysosomal enzyme alpha-glucosidase responsible for degrading glycogen. Late-onset Pompe disease has a complex multisystem phenotype characterized by a range of symptoms. METHODS: An expert panel from the Middle East and North Africa (MENA) region met to create consensus-based guidelines for the diagnosis and treatment of late-onset Pompe disease for the MENA region, where the relative prevalence of Pompe disease is thought to be high but there is a lack of awareness and diagnostic facilities. RESULTS: These guidelines set out practical recommendations and include algorithms for the diagnosis and treatment of late-onset Pompe disease. They detail the ideal diagnostic workup, indicate the patients in whom enzyme replacement therapy should be initiated, and provide guidance on appropriate patient monitoring. CONCLUSIONS: These guidelines will serve to increase awareness of the condition, optimize patient diagnosis and treatment, reduce disease burden, and improve patient outcomes.

Adherence to subcutaneous interferon beta-1a treatment among patients with relapsing multiple sclerosis: the MAIN-MS study.

Introduction and background: Adherence is a critical factor for optimal clinical outcomes in multiple sclerosis (MS) treatment. This study investigated the adherence and clinical outcomes of MS patients treated with subcutaneous (sc) interferon (IFN) (ß)-1a, an established immunomodulatory treatment for relapsing MS. The benefits of a patient support programme (PSP) were also studied. Methods: This phase-IV prospective, observational multicentre study enrolled patients with relapsing MS who were treated with sc IFN ß-1a for 24 months was conducted at 53 centres across 17 countries. The primary endpoint was adherence to sc IFN ß-1a treatment, as assessed using Morisky Green Levine Medication Adherence Scale (MGLS) scores at 24 months. The MGLS is a self-reported diagnostic tool to address medication non-adherence, with a score ranging from 0 to 4, with 0 representing high adherence, 1-2 representing medium adherence, and 3-4 representing low adherence. Other endpoints included time to study and treatment discontinuation over 24 months, the proportion of relapse-free patients, and Expanded Disability Status Scale (EDSS) progression (defined as ≥1.0 point increase sustained for 3 months) at 24 months. A subgroup analysis was performed for endpoints based on patients assigned to PSP (yes/no-PSP versus non-PSP subgroup). Results: Of the 577 patients enrolled, 408 had evaluable MGLS scores at 24 months. A total of 336 (58.2%; 95% confidence interval [CI]: 54.1-62.3%) patients reported high adherence, 57 (9.9%; 95% CIs: 7.6-12.7%) reported medium adherence, and 15 (2.6%; 95% CI: 1.5-4.3%) reported low adherence at 24 months. The PSP subgroup reported higher adherence (n = 206; 65.8%) than the non-PSP subgroup (n = 130; 56.5%). By 24 months, 52.2% of the patients were relapse-free and 17.2% patients experienced ≥1 relapse. Expanded Disability Status Scale progression was observed in 12.3% of patients. Over the 24-month period, 30.8% of the patients discontinued treatment, and the most common reasons for treatment discontinuation were adverse events (AEs, 10.4%), being lost to followup (7.1%), and a lack of efficacy (5.5%). Overall, 39.6% patients experienced ≥1 AE, which ranged from mild to moderate. Conclusion: The study demonstrated high adherence to sc IFN ß-1a treatment with an added benefit of PSP participation. More than half of the patients remained relapse-free over a 24-month period. No new safety concerns to sc IFN ß-1a treatment were observed. Clinical trial registration: https://clinicaltrials.gov/study/NCT02921035, NCT02921035.

Consensus treatment recommendations for late-onset Pompe disease.

INTRODUCTION: Pompe disease is a rare, autosomal recessive disorder caused by deficiency of the glycogen-degrading lysosomal enzyme acid alpha-glucosidase. Late-onset Pompe disease is a multisystem condition, with a heterogeneous clinical presentation that mimics other neuromuscular disorders. METHODS: Objective is to propose consensus-based treatment and management recommendations for late-onset Pompe disease. METHODS: A systematic review of the literature by a panel of specialists with expertise in Pompe disease was undertaken. CONCLUSIONS: A multidisciplinary team should be involved to properly treat the pulmonary, neuromuscular, orthopedic, and gastrointestinal elements of late-onset Pompe disease. Presymptomatic patients with subtle objective signs of Pompe disease (and patients symptomatic at diagnosis) should begin treatment with enzyme replacement therapy (ERT) immediately; presymptomatic patients without symptoms or signs should be observed without use of ERT. After 1 year of ERT, patients' condition should be reevaluated to determine whether ERT should be continued.

The disease course of multiple sclerosis before and during COVID-19 pandemic: A retrospective five-year study.

INTRODUCTION: COVID-19 pandemic is thought to influence the natural history of immune disorders, yet the knowledge on its effect on multiple sclerosis (MS) is unknown and not fully understood for which we conducted this retrospective study. METHODS AND MATERIALS: We included all patients with MS seen in King Faisal Specialist Hospital and Research Centre in Jeddah, Saudi Arabia, between January 2017 and October 20201. We determined clinical and radiological evidence of disease activities in all patients by the end of the study period, and we compared the disease patterns before and during the pandemic. We also identified patients with COVID-19 since March 2020, who had at least 3 months of follow-up following the infection. RESULTS: We studied 301 patients; 216 (72%) were women, the mean age was 38 years (range; 16, 73 years), the mean disease duration was 10 years (range; 1, 36 years), and the median EDSS score was 0.5 (range; 0, 8). RRMS accounted for most of the cases (270 patients). MS disease activities were 25% less prevalent during the pandemic compared to the preceding 3 years (26 vs. 51%, respectively, p < 0.01). Bivariate analysis showed significant higher disease activities in patients younger than 35 years (73 vs 27%), on DMT (68 vs 32%), and complaint to therapy (69 vs 31%). Multiple logistic regression analysis showed that the likelihood of MS disease activities were 3 times more during the pre-pandemic era (adjusted OR = 3.1, p value < 0.05, 95% CI; 1.4, 7.1). Thirty patients (10%) were infected with COVID-19. All patients reported mild symptoms, and none required hospitalization. COVID-19 was prevalent among younger patients with RRMS, with low EDSS scores, irrespective of DMTs they received. COVID-19 infection was not associated with clinical relapses or MRI changes. Disease activities were dependent on DMT use and not COVID-19 status. Multivariate analyses also confirmed no effect of COVID-19 on disease activities (p = 0.3 and 0.4, for clinical and MRI changes, respectively). CONCLUSIONS: MS disease activities did not increase during the pandemic, yet the apparent decrease in the disease activities is probably due to under reporting and not a real decrease in disease activities because of the pandemic. The COVID-19 infection in our MS patients showed a benign disease course, yet standard precautions to reduce the risk of COVID-19 transmission should be applied accordingly.