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Alkuraya F.S.,King Faisal Specialist Hospital And Research Center | Alkuraya F.S.,Alfaisal University
Trends in Genetics | Year: 2015

Although numerous approaches have been pursued to understand the function of human genes, Mendelian genetics has by far provided the most compelling and medically actionable dataset. Biallelic loss-of-function (LOF) mutations are observed in the majority of autosomal recessive Mendelian disorders, representing natural human knockouts and offering a unique opportunity to study the physiological and developmental context of these genes. The restriction of such context to 'disease' states is artificial, however, and the recent ability to survey entire human genomes for biallelic LOF mutations has revealed a surprising landscape of knockout events in 'healthy' individuals, sparking interest in their role in phenotypic diversity beyond disease causation. As I discuss in this review, the potentially wide implications of human knockout research warrant increased investment and multidisciplinary collaborations to overcome existing challenges and reap its benefits. © 2014 Elsevier Ltd.

Alkuraya F.S.,King Faisal Specialist Hospital And Research Center | Alkuraya F.S.,Alfaisal University
Human Genetics | Year: 2013

Autozygosity, or the inheritance of two copies of an ancestral allele, has the potential to not only reveal phenotypes caused by biallelic mutations in autosomal recessive genes, but to also facilitate the mapping of such mutations by flagging the surrounding haplotypes as tractable runs of homozygosity (ROH), a process known as autozygosity mapping. Since SNPs replaced microsatellites as markers for the purpose of genomewide identification of ROH, autozygosity mapping of Mendelian genes has witnessed a significant acceleration. Historically, successful mapping traditionally required favorable family structure that permits the identification of an autozygous interval that is amenable to candidate gene selection and confirmation by Sanger sequencing. This requirement presented a major bottleneck that hindered the utilization of simplex cases and many multiplex families with autosomal recessive phenotypes. However, the advent of next-generation sequencing that enables massively parallel sequencing of DNA has largely bypassed this bottleneck and thus ushered in an era of unprecedented pace of Mendelian disease gene discovery. The ability to identify a single causal mutation among a massive number of variants that are uncovered by next-generation sequencing can be challenging, but applying autozygosity as a filter can greatly enhance the enrichment process and its throughput. This review will discuss the power of combining the best of both techniques in the mapping of recessive disease genes and offer some tips to troubleshoot potential limitations. © 2013 Springer-Verlag Berlin Heidelberg.

Khalaf H.,King Faisal Specialist Hospital And Research Center
Transplantation Proceedings | Year: 2010

Introduction Vascular complications (VC) after liver transplantation (OLT) are one of the most feared problems that frequently result in graft and patient loss. Herein we have reported our experience with VC after either deceased donor liver transplantation (DDLT) or living donor liver transplantation (LDLT). Patients and Methods Between April 2001 and September 2009, we performed 224 OLT: 155 DDLT and 69 LDLT. The overall male/female ratio was 136/88 and the adult/pediatric ratio was 208/16. We retrospectively identified and analyzed vascular complications in both groups. Results In the DDLT group, 11/155 recipients (7%) suffered vascular complications; hepatic artery thrombosis (HAT; n = 5; 3.2%), portal vein thrombosis occurred (n = 4; 2.6%); hepatic vein stenosis (n = 1; 0.6%), and severe postoperative bleeding due to a slipped splenic artery ligature (n = 1, 0.6%). In the DDLT group, 4/11 (36.4%) patients died as a direct result of the vascular complications. In the LDLT group, 9/69 recipients (13%) suffered vascular complications: HAT (n = 3; 4.3%), portal vein problems (n = 5; 7.2%), and hepatic vein stenosis (n = 1; 1.5%). Among LDLT, 3/9 (33.3%) patients died as a direct result of the vascular complications. In both groups vascular complications were associated with poorer patient and graft survival. Conclusions In our experience, the incidence of vascular complications was significantly higher among the LDLT group compared with the DDLT group. Vascular complications were associated with poorer graft and patient survival rates in both groups. © 2010 Elsevier Inc.

Anazi S.,King Faisal Specialist Hospital And Research Center
Molecular Psychiatry | Year: 2016

Intellectual disability (ID) is a measurable phenotypic consequence of genetic and environmental factors. In this study, we prospectively assessed the diagnostic yield of genomic tools (molecular karyotyping, multi-gene panel and exome sequencing) in a cohort of 337 ID subjects as a first-tier test and compared it with a standard clinical evaluation performed in parallel. Standard clinical evaluation suggested a diagnosis in 16% of cases (54/337) but only 70% of these (38/54) were subsequently confirmed. On the other hand, the genomic approach revealed a likely diagnosis in 58% (n=196). These included copy number variants in 14% (n=54, 15% are novel), and point mutations revealed by multi-gene panel and exome sequencing in the remaining 43% (1% were found to have Fragile-X). The identified point mutations were mostly recessive (n=117, 81%), consistent with the high consanguinity of the study cohort, but also X-linked (n=8, 6%) and de novo dominant (n=19, 13%). When applied directly on all cases with negative molecular karyotyping, the diagnostic yield of exome sequencing was 60% (77/129). Exome sequencing also identified likely pathogenic variants in three novel candidate genes (DENND5A, NEMF and DNHD1) each of which harbored independent homozygous mutations in patients with overlapping phenotypes. In addition, exome sequencing revealed de novo and recessive variants in 32 genes (MAMDC2, TUBAL3, CPNE6, KLHL24, USP2, PIP5K1A, UBE4A, TP53TG5, ATOH1, C16ORF90, SLC39A14, TRERF1, RGL1, CDH11, SYDE2, HIRA, FEZF2, PROCA1, PIANP, PLK2, QRFPR, AP3B2, NUDT2, UFC1, BTN3A2, TADA1, ARFGEF3, FAM160B1, ZMYM5, SLC45A1, ARHGAP33 and CAPS2), which we highlight as potential candidates on the basis of several lines of evidence, and one of these genes (SLC39A14) was biallelically inactivated in a potentially treatable form of hypermanganesemia and neurodegeneration. Finally, likely causal variants in previously published candidate genes were identified (ASTN1, HELZ, THOC6, WDR45B, ADRA2B and CLIP1), thus supporting their involvement in ID pathogenesis. Our results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.Molecular Psychiatry advance online publication, 19 July 2016; doi:10.1038/mp.2016.113. © 2016 Macmillan Publishers Limited

Aboussekhra A.,King Faisal Specialist Hospital And Research Center
International Journal of Developmental Biology | Year: 2011

Since Paget's "Seed and Soil" hypothesis in 1889 on cancer growth and metastasis, several studies on various solid tumors have confirmed the active role of the tumor milieu on the onset, growth and spread of neoplastic cells. Fibroblasts constitute the major components of the tumor microenvironment (stroma), and are therefore the most studied cell type. Therefore, a large amount of data has emerged showing the cancer-promoting function of these cells through paracrine effects that escort tumor cells through all the carcinogenesis steps. This involves many signaling proteins that transmit the message in both directions, allowing cooperative crosstalk between cancer cells and their stroma. This prompted several researchers to investigate the potential use of the molecular and cellular features of active stromal fibroblasts to generate specific tools for prevention, prognosis and treatment of cancer. Herein, I review the cellular and molecular features of active cancer-associated fibroblasts and their origin. Additionally, I summarize our current understanding of the procarcinogenic actions of these cells and their potential prognostic value for breast cancer patients. © 2011 UBC Press.

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