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2,200 previously unpublished Saudi families as a first-tier test.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

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder. Around 490 mutations in ITGA2B and ITGB3 genes were reported. We aimed to use targeted next-generation sequencing (NGS) to identify variants in patients with GT. We screened 72 individuals (including unaffected family members) using a panel of 393 genes (SHGP heme panel). Validation was done by Sanger sequencing and pathogenicity was predicted using multiple tools. In 83.5% of our cohort, 17 mutations were identified in ITGA2B and ITGB3 (including 6 that were not previously reported). In addition to variants in the two known genes, we found variants in ITGA2, VWF and F8. The SHGP heme panel can be used as a high-throughput molecular diagnostic assay to screen for mutations and variants in GT cases and carriers. Our findings expand the molecular landscape of GT and emphasize the robustness and usefulness of this panel.

Decision making in the public healthcare system is heavily invested in screening and preventative medicine in addition to the translation of national initiatives that help in implementing precision medicine. Molecular testing for cancers and inherited disorders helps families, patients and healthcare providers in disease management. Different genome programs and genetics initiatives around the world are contributing and providing data to help decision makers, pharmaceutical companies and other health related commercial entities to tailor diagnosis and treatment in a healthcare era that honors molecular individuality and population differences. The Saudi Human Genome Program (SHGP) is a national program committed to sequencing 100,000 genomes. In its early stages, it focused on understanding monogenic disorders. The data output was then expanded to allow researchers to interrogate the genetics of complex disorders and understand the molecular landscape of this highly inbred population. The results of the first phase of this program (consisting 35000 WES and gene panels and 2000 WGS) was translated into the establishment of a knowledge database of population specific mutations and single nucleotide variants (SNVs) that is used for molecular diagnosis. This was translated to a definitive molecular diagnosis in nearly half of ~2500 cases with Mendelian monogenic disorders using 13 targeted gene panels. To date; the SHGP knowledge database contains more than 2000 disease causing mutations and more that 4 million SNVs. In the Kingdom, there are two established national screening programs, premarital and newborn. These programs are extremely powerful at serving patients and carriers/family members equally, and will further benefit from the availability of population specific molecular databases. As we soar towards the mid-phase of the program, it has become obviously a valuable platform to inform clinical decision and policy making. The presumed presentation of carriers and family members in light of autosomal recessive inheritance is indicative of possible missed diagnosis when they are asymptomatic or present with milder clinical features, creating heavier burdens on the healthcare system. As further evidence emerges, genomics will continue to change practice in other healthcare areas including cancer and chronic diseases. In this study, we present rare genetic variants in common and rare bleeding disorders, where we have looked at data from the SHGP with both disease stratification and blindly to redefine and classify the rarity of pathogenic genetic variants in associated genes. We assessed an initial set of 1400 individuals using a targeted gene panel consisting of 393 genes implicated in nonmalignant blood related disorders (SHGP heme panel). We looked for variants and mutations to reclassify bleeding disorders based on the incidence of carriers and affected individuals. We then used a replication set of ~5000 WES to validate pathogenicity and assess allele frequencies. Our data will help impact decision making for effective screening and prevention of common blood related disorders and will aid in increasing the diagnostic yield, identifying predisposition markers and implementing better genetic counseling programs. Table Disclosures No relevant conflicts of interest to declare.