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Article: A Novel Heterozygous

Arbide, Daniel / Elkhateeb, Nour / Goljan, Ewa / Gonzalez, Carolina Perez / Maw, Anna / Park, Soo-Mi

2024 Volume 2024, Page(s) 5906936

Abstract: Microrchidia CW-type zinc finger protein 2 (MORC2) is an ATPase-containing nuclear protein which regulates transcription through chromatin remodelling and epigenetic silencing. ...

Abstract	Microrchidia CW-type zinc finger protein 2 (MORC2) is an ATPase-containing nuclear protein which regulates transcription through chromatin remodelling and epigenetic silencing.
Language	English
Publishing date	2024-01-02
Publishing country	United States
Document type	Case Reports
ZDB-ID	2664417-4
ISSN	2090-6552 ; 2090-6544
ISSN (online)	2090-6552
ISSN	2090-6544
DOI	10.1155/2024/5906936
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Article ; Online: Large-scale next generation sequencing based analysis of SLCO1B1 pharmacogenetics variants in the Saudi population.

Goljan, Ewa / Abouelhoda, Mohammed / Tahir, Asma / ElKalioby, Mohamed / Meyer, Brian / Monies, Dorota

Human genomics

2024 Volume 18, Issue 1, Page(s) 30

Abstract: Background: SLCO1B1 plays an important role in mediating hepatic clearance of many different drugs including statins, angiotensin-converting enzyme inhibitors, chemotherapeutic agents and antibiotics. Several variants in SLCO1B1 have been shown to have ... ...

Abstract	Background: SLCO1B1 plays an important role in mediating hepatic clearance of many different drugs including statins, angiotensin-converting enzyme inhibitors, chemotherapeutic agents and antibiotics. Several variants in SLCO1B1 have been shown to have a clinically significant impact, in relation to efficacy of these medications. This study provides a comprehensive overview of SLCO1B1 variation in Saudi individuals, one of the largest Arab populations in the Middle East. Methods: The dataset of 11,889 (9,961 exomes and 1,928 pharmacogenetic gene panel) Saudi nationals, was used to determine the presence and frequencies of SLCO1B1 variants, as described by the Clinical Pharmacogenetic Implementation Consortium (CPIC). Results: We identified 141 previously described SNPs, of which rs2306283 (50%) and rs4149056 (28%), were the most common. In addition, we observed six alleles [15 (24.7%) followed by 20 (8.04%), 14 (5.86%), 5 (3.84%), 31 (0.21%) and 9 (0.03%)] predicted to be clinically actionable. Allele diplotype to phenotype conversion revealed 41 OATP1B1 diplotypes. We estimated the burden of rare, and novel predicted deleterious variants, resulting from 17 such alterations. Conclusions: The data we present, from one of the largest Arab cohorts studied to date, provides the most comprehensive overview of SLCO1B1 variants, and the subsequent OATP1B1 activity of this ethnic group, which thus far remains relatively underrepresented in available international genomic databases. We believe that the presented data provides a basis for further clinical investigations and the application of personalized statin drug therapy guidance in Arabs.
MeSH term(s)	Humans ; Pharmacogenetics ; High-Throughput Nucleotide Sequencing ; Saudi Arabia ; Liver-Specific Organic Anion Transporter 1/genetics ; Polymorphism, Single Nucleotide/genetics
Chemical Substances	Liver-Specific Organic Anion Transporter 1 ; SLCO1B1 protein, human
Language	English
Publishing date	2024-03-25
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	2147618-4
ISSN	1479-7364 ; 1479-7364
ISSN (online)	1479-7364
ISSN	1479-7364
DOI	10.1186/s40246-024-00594-9
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Article ; Online: Identification of pharmacogenetic variants from large scale next generation sequencing data in the Saudi population.

Goljan, Ewa / Abouelhoda, Mohammed / ElKalioby, Mohamed M / Jabaan, Amjad / Alghithi, Nada / Meyer, Brian F / Monies, Dorota

PloS one

2022 Volume 17, Issue 1, Page(s) e0263137

Abstract: It is well documented that drug responses are related to Absorption, Distribution, Metabolism, and Excretion (ADME) characteristics of individual patients. Several studies have identified genetic variability in pharmacogenes, that are either directly ... ...

Abstract	It is well documented that drug responses are related to Absorption, Distribution, Metabolism, and Excretion (ADME) characteristics of individual patients. Several studies have identified genetic variability in pharmacogenes, that are either directly responsible for or are associated with ADME, giving rise to individualized treatments. Our objective was to provide a comprehensive overview of pharmacogenetic variation in the Saudi population. We mined next generation sequencing (NGS) data from 11,889 unrelated Saudi nationals, to determine the presence and frequencies of known functional SNP variants in 8 clinically relevant pharmacogenes (CYP2C9, CYP2C19, CYP3A5, CYP4F2, VKORC1, DPYD, TPMT and NUDT15), recommended by the Clinical Pharmacogenetics Implementation Consortium (CPIC), and collectively identified 82 such star alleles. Functionally significant pharmacogenetic variants were prevalent especially in CYP genes (excluding CYP3A5), with 10-44.4% of variants predicted to be inactive or to have decreased activity. In CYP3A5, inactive alleles (87.5%) were the most common. Only 1.8%, 0.7% and 0.7% of NUDT15, TPMT and DPYD variants respectively, were predicted to affect gene activity. In contrast, VKORC1 was found functionally, to be highly polymorphic with 53.7% of Saudi individuals harboring variants predicted to result in decreased activity and 31.3% having variants leading to increased metabolic activity. Furthermore, among the 8 pharmacogenes studied, we detected six rare variants with an aggregated frequency of 1.1%, that among several other ethnicities, were uniquely found in Saudi population. Similarly, within our cohort, the 8 pharmacogenes yielded forty-six novel variants predicted to be deleterious. Based upon our findings, 99.2% of individuals from the Saudi population carry at least one actionable pharmacogenetic variant.
MeSH term(s)	Female ; Gene Frequency ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Pharmacogenetics ; Pharmacogenomic Testing ; Pharmacogenomic Variants ; Polymorphism, Single Nucleotide ; Saudi Arabia
Language	English
Publishing date	2022-01-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0263137
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Article ; Online: The clinical utility of rapid exome sequencing in a consanguineous population.

Monies, Dorota / Goljan, Ewa / Assoum, Mirna / Albreacan, Muna / Binhumaid, Faisal / Subhani, Shazia / Boureggah, Abdulmlik / Hashem, Mais / Abdulwahab, Firdous / Abuyousef, Omar / Temsah, Mohamad H / Alsohime, Fahad / Kelaher, James / Abouelhoda, Mohamed / Meyer, Brian F / Alkuraya, Fowzan S

Genome medicine

2023 Volume 15, Issue 1, Page(s) 44

Abstract: Background: The clinical utility of exome sequencing is now well documented. Rapid exome sequencing (RES) is more resource-intensive than regular exome sequencing and is typically employed in specialized clinical settings wherein urgent molecular ... ...

Abstract	Background: The clinical utility of exome sequencing is now well documented. Rapid exome sequencing (RES) is more resource-intensive than regular exome sequencing and is typically employed in specialized clinical settings wherein urgent molecular diagnosis is thought to influence acute management. Studies on the clinical utility of RES have been largely limited to outbred populations. Methods: Here, we describe our experience with rapid exome sequencing (RES) in a highly consanguineous population. Clinical settings included intensive care units, prenatal cases approaching the legal cutoff for termination, and urgent transplant decisions. Results: A positive molecular finding (a pathogenic or likely pathogenic variant that explains the phenotype) was observed in 80 of 189 cases (42%), while 15 (8%) and 94 (50%) received ambiguous (variant of uncertain significance (VUS)) and negative results, respectively. The consanguineous nature of the study population gave us an opportunity to observe highly unusual and severe phenotypic expressions of previously reported genes. Clinical utility was observed in nearly all (79/80) cases with positive molecular findings and included management decisions, prognostication, and reproductive counseling. Reproductive counseling is a particularly important utility in this population where the overwhelming majority (86%) of identified variants are autosomal recessive, which are more actionable in this regard than the de novo variants typically reported by RES elsewhere. Indeed, our cost-effectiveness analysis shows compelling cost savings in the study population. Conclusions: This work expands the diversity of environments in which RES has a demonstrable clinical utility.
MeSH term(s)	Pregnancy ; Female ; Humans ; Consanguinity ; Exome Sequencing ; Phenotype
Language	English
Publishing date	2023-06-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-023-01192-5
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Article ; Online: Genetic Alterations in Pediatric Thyroid Cancer Using a Comprehensive Childhood Cancer Gene Panel.

Alzahrani, Ali S / Alswailem, Meshael / Alswailem, Anwar Ali / Al-Hindi, Hindi / Goljan, Ewa / Alsudairy, Nourah / Abouelhoda, Mohamed

The Journal of clinical endocrinology and metabolism

2020 Volume 105, Issue 10

Abstract: Context: Pediatric differentiated thyroid cancer (DTC) differs from adult DTC in its underlying genetics and clinicopathological features. In this report, we studied these aspects in 48 cases of pediatric DTC.: Patients and methods: We used the ... ...

Abstract	Context: Pediatric differentiated thyroid cancer (DTC) differs from adult DTC in its underlying genetics and clinicopathological features. In this report, we studied these aspects in 48 cases of pediatric DTC. Patients and methods: We used the comprehensive Oncomine Childhood Cancer Gene panel on Ion Torrent next-generation sequencing platform. We included 48 patients (37 girls and 11 boys) with pediatric DTC (median age 17 years; range, 5-18 years) and studied the association between these genetic alterations and the clinicopathological features and outcome. Results: Of 48 tumors, 33 (69%) had somatic genetic alterations that were mutually exclusive except in one tumor. BRAFV600E and RET-PTC1 were the most common, occurring in 9 different tumors (19%) each. RET-PTC3 and ETV6-NTRK3 were the next most common, with each occurring in 4 different tumors (8%). Other genetic alterations including EML4-NTRK1, EML4-ALK, NRAS, KRAS, PTEN, and CREBBP occurred once each. There were no differences between those who had mutations and those without mutations with respect to age, sex, tumor multifocality, extrathyroidal extension, vascular invasion, lymph node or distant metastasis, and American Thyroid Association response to therapy status at the last follow-up visits. Similarly, none of these factors was different between those with fusion genes vs single-point mutations vs no mutations. Conclusions: In pediatric DTC, fusion genes are more common than single-point mutations. The most common genetic alterations are RET-PTC1, BRAFV600E, RET-PTC3, and ETV6-NTRK3. Other alterations occur rarely. Genetic alterations do not correlate with the clinicopathological features or the outcome.
MeSH term(s)	Adolescent ; Biomarkers, Tumor/genetics ; Child ; Child, Preschool ; DNA Mutational Analysis ; Disease-Free Survival ; Female ; Follow-Up Studies ; High-Throughput Nucleotide Sequencing ; Humans ; Iodine Radioisotopes/therapeutic use ; Kaplan-Meier Estimate ; Male ; Oncogene Proteins, Fusion/genetics ; Point Mutation ; Saudi Arabia/epidemiology ; Thyroid Gland/pathology ; Thyroid Gland/surgery ; Thyroid Neoplasms/genetics ; Thyroid Neoplasms/mortality ; Thyroid Neoplasms/pathology ; Thyroid Neoplasms/therapy ; Thyroidectomy
Chemical Substances	Biomarkers, Tumor ; Iodine Radioisotopes ; Iodine-131 ; Oncogene Proteins, Fusion
Language	English
Publishing date	2020-06-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgaa389
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Article ; Online: Correction to: Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism.

Alsemari, Abdulaziz / Al-Younes, Banan / Goljan, Ewa / Jaroudi, Dyala / BinHumaid, Faisal / Meyer, Brian F / Arold, Stefan T / Monies, Dorota

Human genomics

2017 Volume 11, Issue 1, Page(s) 33

Abstract: Correction: After publication of the article [1], it has been brought to our attention that there is a nomenclature issue with this article. At the time of acceptance, the VARS2 mutation was considered equivalent to the VARS2 mutation. However, this has ...

Abstract	Correction: After publication of the article [1], it has been brought to our attention that there is a nomenclature issue with this article. At the time of acceptance, the VARS2 mutation was considered equivalent to the VARS2 mutation. However, this has changed so that VARS now only refers to shorter mitochondrial sequence of valyl-tRNA synthesase containing 1093 amino acids. "Therefore, in the context of this article, every usage of "VARS2" should be replaced with "VARS" when referring to the causative variant".
Language	English
Publishing date	2017--08
Publishing country	England
Document type	Journal Article ; Published Erratum
ISSN	1479-7364
ISSN (online)	1479-7364
DOI	10.1186/s40246-017-0130-6
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Article ; Online: Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism.

Alsemari, Abdulaziz / Al-Younes, Banan / Goljan, Ewa / Jaroudi, Dyala / BinHumaid, Faisal / Meyer, Brian F / Arold, Stefan T / Monies, Dorota

Human genomics

2017 Volume 11, Issue 1, Page(s) 28

Abstract: Background: Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes ... ...

Abstract	Background: Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency. Results: A G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic. Conclusions: These findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.
MeSH term(s)	Body Height/genetics ; Chromosome Mapping ; Epilepsy/genetics ; Exome ; Female ; Genes, Recessive ; Growth Disorders/genetics ; HLA Antigens/genetics ; HLA Antigens/metabolism ; Human Growth Hormone/deficiency ; Human Growth Hormone/genetics ; Humans ; Hypogonadism/genetics ; Intellectual Disability/genetics ; Male ; Pedigree ; Pregnancy ; Syndrome ; Valine-tRNA Ligase/genetics ; Valine-tRNA Ligase/metabolism ; Young Adult
Chemical Substances	HLA Antigens ; Human Growth Hormone (12629-01-5) ; VARS2 protein, human (144515-61-7) ; Valine-tRNA Ligase (EC 6.1.1.9)
Language	English
Publishing date	2017-11-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2147618-4
ISSN	1479-7364 ; 1473-9542
ISSN (online)	1479-7364
ISSN	1473-9542
DOI	10.1186/s40246-017-0124-4
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Article ; Online: Integrated Analysis of Whole Exome Sequencing and Copy Number Evaluation in Parkinson's Disease.

Yemni, Eman Al / Monies, Dorota / Alkhairallah, Thamer / Bohlega, Saeed / Abouelhoda, Mohamed / Magrashi, Amna / Mustafa, Abeer / AlAbdulaziz, Basma / Alhamed, Mohamed / Baz, Batoul / Goljan, Ewa / Albar, Renad / Jabaan, Amjad / Faquih, Tariq / Subhani, Shazia / Ali, Wafa / Shinwari, Jameela / Al-Mubarak, Bashayer / Al-Tassan, Nada

Scientific reports

2019 Volume 9, Issue 1, Page(s) 3344

Abstract: Genetic studies of the familial forms of Parkinson's disease (PD) have identified a number of causative genes with an established role in its pathogenesis. These genes only explain a fraction of the diagnosed cases. The emergence of Next Generation ... ...

Abstract	Genetic studies of the familial forms of Parkinson's disease (PD) have identified a number of causative genes with an established role in its pathogenesis. These genes only explain a fraction of the diagnosed cases. The emergence of Next Generation Sequencing (NGS) expanded the scope of rare variants identification in novel PD related genes. In this study we describe whole exome sequencing (WES) genetic findings of 60 PD patients with 125 variants validated in 51 of these cases. We used strict criteria for variant categorization that generated a list of variants in 20 genes. These variants included loss of function and missense changes in 18 genes that were never previously linked to PD (NOTCH4, BCOR, ITM2B, HRH4, CELSR1, SNAP91, FAM174A, BSN, SPG7, MAGI2, HEPHL1, EPRS, PUM1, CLSTN1, PLCB3, CLSTN3, DNAJB9 and NEFH) and 2 genes that were previously associated with PD (EIF4G1 and ATP13A2). These genes either play a critical role in neuronal function and/or have mouse models with disease related phenotypes. We highlight NOTCH4 as an interesting candidate in which we identified a deleterious truncating and a splice variant in 2 patients. Our combined molecular approach provides a comprehensive strategy applicable for complex genetic disorders.
MeSH term(s)	DNA Copy Number Variations ; Exons ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Parkinson Disease/genetics ; Sequence Deletion ; Ubiquitin-Protein Ligases/genetics ; Whole Exome Sequencing
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; parkin protein (EC 2.3.2.27)
Language	English
Publishing date	2019-03-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-40102-x
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Article ; Online: Identification of a novel genetic locus underlying tremor and dystonia.

Monies, Dorota / Abou Al-Shaar, Hussam / Goljan, Ewa A / Al-Younes, Banan / Al-Breacan, Muna Monther Abdullah / Al-Saif, Maher Mohammed / Wakil, Salma M / Meyer, Brian F / Khabar, Khalid S A / Bohlega, Saeed

Human genomics

2017 Volume 11, Issue 1, Page(s) 25

Abstract: Background: Five affected individuals with syndromic tremulous dystonia, spasticity, and white matter disease from a consanguineous extended family covering a period of over 24 years are presented. A positional cloning approach utilizing genome-wide ... ...

Abstract	Background: Five affected individuals with syndromic tremulous dystonia, spasticity, and white matter disease from a consanguineous extended family covering a period of over 24 years are presented. A positional cloning approach utilizing genome-wide linkage, homozygozity mapping and whole exome sequencing was used for genetic characterization. The impact of a calmodulin-binding transcription activator 2, (CAMTA2) isoform 2, hypomorphic mutation on mRNA and protein abundance was studied using fluorescent reporter expression cassettes. Human brain sub-region cDNA libraries were used to study the expression pattern of CAMTA2 transcript variants. Results: Linkage analysis and homozygozity mapping localized the disease allele to a 2.1 Mb interval on chromosome 17 with a LOD score of 4.58. Whole exome sequencing identified a G>A change in the transcript variant 2 5'UTR of CAMTA2 that was only 6 bases upstream of the translation start site (c.-6G > A) (NM_001171166.1) and segregated with disease in an autosomal recessive manner. Transfection of wild type and mutant 5'UTR-linked fluorescent reporters showed no impact upon mRNA levels but a significant reduction in the protein fluorescent activity implying translation inhibition. Conclusions: Mutation of CAMTA2 resulting in post-transcriptional inhibition of its own gene activity likely underlies a novel syndromic tremulous dystonia.
MeSH term(s)	5' Untranslated Regions ; Adolescent ; Calcium-Binding Proteins/genetics ; Calcium-Binding Proteins/metabolism ; Child ; Chromosomes, Human, Pair 17 ; Dystonia/etiology ; Dystonia/genetics ; Female ; Humans ; Male ; Mutation ; Pedigree ; Syndrome ; Trans-Activators/genetics ; Trans-Activators/metabolism ; Tremor/etiology ; Tremor/genetics ; Young Adult
Chemical Substances	5' Untranslated Regions ; CAMTA2 protein, human ; Calcium-Binding Proteins ; Trans-Activators
Language	English
Publishing date	2017-11-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1479-7364
ISSN (online)	1479-7364
DOI	10.1186/s40246-017-0123-5
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Article ; Online: Corrigendum: Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation.

Monies, Dorota / Maddirevula, Sateesh / Kurdi, Wesam / Alanazy, Mohammed H / Alkhalidi, Hisham / Al-Owain, Mohammed / Sulaiman, Raashda A / Faqeih, Eissa / Goljan, Ewa / Ibrahim, Niema / Abdulwahab, Firdous / Hashem, Mais / Abouelhoda, Mohamed / Shaheen, Ranad / Arold, Stefan T / Alkuraya, Fowzan S

Genetics in medicine : official journal of the American College of Medical Genetics

2018 Volume 20, Issue 3, Page(s) 380

Abstract: This corrects the article DOI: 10.1038/gim.2017.22. ...

Abstract	This corrects the article DOI: 10.1038/gim.2017.22.
Language	English
Publishing date	2018-01-04
Publishing country	United States
Document type	Journal Article ; Published Erratum
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1038/gim.2017.203
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