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1. A CYP11A1 homozygous exonic variant inducing an alternative splicing, frameshift and truncation in a family with congenital adrenal hyperplasia

Author

Kheloud M. Alhamoudi, Meshael Alswailem, Balgees Alghamdi, Abdullah Alashwal, and Ali S. Alzahrani

Subjects
Congenital adrenal hyperplasia, CYP11A1, Missense variant, Whole exome sequencing, Disorders of sex development, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

Background: Congenital adrenal hyperplasia (CAH) is a heterogeneous group of adrenal steroidogenesis disorders with variable degrees of glucocorticoid, mineralocorticoid and sex steroid deficiencies. CYP11A1 gene encodes the mitochondrial cholesterol side-chain cleavage enzyme (P450scc), which initiates the first reaction in steroidogenesis by converting cholesterol to pregnenolone. Variants in this gene are extremely rare but associated with severe forms of CAH due to its early and critical function in various steroid biosynthesis pathways. Here, we report a CYP11A1 exonic homozygous variant that, although exonic in location, affects splicing by creating an additional aberrant splicing site with frameshift and truncation of the gene. Patients and methods: The proband is a 23-year old 46,XY patient raised as a girl. She was a product of normal pregnancy for first-degree relative parents. Soon after birth, she had vomiting, dehydration, hypotension, hyponatremia and hyperkalemia. She was started on glucocorticoids and mineralocorticoids with prompt recovery. Apart from a chronic need for these medications, her neonatal and childhood history was unremarkable. She sought medical advice at age 19 years for delayed puberty with primary amenorrhea and lack of breast development. On evaluation, she had normal external female genitalia, no breast development, undescended testes and absent uterus and ovaries. Her hormonal evaluation revealed very low estrogen, testosterone, cortisol, aldosterone, 17-hydroxyprogesterone, and androstenedione levels. ACTH, LH, FSH and renin were very high consistent with primary gonadal and adrenal failure. Her parents are healthy first-degree cousins. She has three sisters, all with 46,XX karyotype. One of them is clinically and biochemically normal while the other two sisters have normal female phenotype, normal uterus and ovaries, similar hormonal profile to the proband but different karyotype (46,XX) and absence of undescended testes. gDNA was used for whole exome sequencing (WES). Sanger sequencing was performed to confirm the detected variant and its segregation with the disease. Results: WES identified a homozygous missense variant in CYP11A1 changing the second nucleotide (GCG > GTG) at position 189 in exon 3 and resulting in a change of Alanine to Valine (p.Ala189Val). This variant was confirmed by PCR and Sanger sequencing. It was found in a homozygous form in the proband and her two affected sisters and in a heterozygous form in the unaffected sister. In-silico analysis predicted this variant to create a new splicing site with frameshift and truncation of the gene transcript. This was confirmed by isolation of RNA, cDNA synthesis, gel electrophoresis and sequencing. Conclusion: We describe a family with a very rare form of CAH due to a CYP11A1 variant leading to creation of a new splice site, frameshift and premature truncation of the protein.

Published
2024
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2. 25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations

Author

Sarah Bakhamis, Faiqa Imtiaz, Khushnooda Ramzan, Edward De Vol, Osamah Al-Sagheir, Abdulrahman Al-Rajhi, Abdullah Alashwal, Bassam Bin Abbas, Nadia Sakati, and Afaf Al-Sagheir

Subjects
vitamin d, cyp2r1 mutation, 25-hydroxylase deficiency, rickets, saudi arabia, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Vitamin D deficiency remains a major cause of rickets worldwide. Nutritional factors are the major cause and less commonly, inheritance causes. Rece ntly, CYP2R1 has been reported as a major factor for 25-hydroxylation contributing to the inherited forms of vitamin D deficiency. We conducted a prospective cohort study at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, to review cas es with 25-hydroxylase deficiency and describe their clinical, biochemical, and molecul ar genetic features. We analyzed 27 patients from nine different families who presented with low 25-OH vitamin D and not responding to usual treatment. Genetic testing identi fied two mutations: c.367+1G>A (12/27 patients) and c.768dupT (15/27 patients), whe re 18 patients were homozygous for their identified mutation and 9 patients were het erozygous. Both groups had similar clinical manifestations ranging in severity, but no ne of the patients with the heterozygous mutation had hypocalcemic manifestations. Thirteen out of 18 homozygous patients and all the heterozygous patients responded to high doses of vitamin D treatment, but they regressed after decreasing the dose, requiring lifelon g therapy. Five out of 18 homozygous patients required calcitriol to improve their bioche mical data, whereas none of the heterozygous patients and patients who carried the c.367 +1G>A mutation required calcitriol treatment. To date, this is the largest cohort serie s analyzing CYP2R1-related 25-hydroxylase deficiency worldwide, supporting its major role i n 25-hydroxylation of vitamin D. It is suggested that a higher percentage of CYP2R1 mutations might be found in the Saudi population. We believe that our study will help in th e diagnosis, treatment, and prevention of similar cases in the future.

Published
2021
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3. 1. Founder mutation identified in the LDLR gene causing familial hypercholesterolemia associated with increased risk of coronary heart disease

Author

Faisal Al-Allaf, Mohammad Athar, Abdullah Alashwal, Zainularifeen Abduljaleel, Taher Mohiuddin, Abdellatif Bouazzaoui, Halah Abalkhail, Rakan Own, Ahmad Al-Allaf, Iman Abumansour, Zohor Azhar, Fahad Alnouri, and Mawaddah Toonsi

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Basic science research. Presentation Type: Oral presentation. Introduction: Coronary artery diseases (CAD) inflict heavy economical and social cost on most populations including Saudi’s and contribute significantly to their morbidity and mortality rates. Familial hypercholesterolemia (FH) is hereditary in an autosomal dominant disease and is a major risk factor for the development of CAD. FH is predominantly caused by variants in the low-density lipoprotein (LDL) receptor gene (LDLR). Methodology: More than 140 FH samples including 44 probands were collected from 17 unrelated Saudi families who live in the central, northern, western and eastern regions of Saudi Arabia. Patient samples were screened using Next-generation sequencing (NGS) and Capillary sequencing. We described the genetic analysis of severely affected homozygous FH patients who were mostly resistant to statin therapy and were managed on an apheresis program. Results: We identified a common frameshift mutation p. (G676Afs*33) in exon 14 of the LDLR gene in 17 probands and their first-degree blood relatives in apparently unrelated Saudi families. This founder mutation was found in about 40% Saudi FH population. We also describe a three dimensional homology model of the LDL receptor protein (LDLR) structure and examine the consequence of the frameshift mutation p. (G676Afs*33), as this could affect the LDLR structure in a region involved in dimer formation, and protein stability. Conclusion: This finding of a recurrent mutation causing FH in the Saudi population could serve to develop a rapid genetic screening procedure for FH, and the 3D-structure analysis of the mutant LDLR, may provide tools to develop a mechanistic model of the LDLR function.

Published
2017
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4. 4. Identification of a novel nonsense variant C.1332DUP, P. (D445*) in the LDLR gene that causes familial hypercholesterolemia

Author

Faisal Al-Allaf, Mohammad Athar, Zainularifeen Abduljaleel, Abdellatif Bouazzaoui, Taher Mohiuddin, Rakan Own, Ahmad Al-Allaf, Iman Abumansour, Zohor Azhar, Faisal Ba-Hammam, Halah Abalkhail, and Abdullah Alashwal

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Basic Science Research. Presentation type: Digital Poster. Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant disease predominantly caused by a mutation in the low-density lipoprotein receptor (LDLR) gene. Here, we describe two severely affected FH patients from the same Saudi family, who were resistant to statin therapy and were managed on an apheresis program. Methodology: Two proband samples were collected from the patients. Direct sequencing of the LDLR gene was performed by using the Sanger sequencing method. Results: We identified a novel duplication variant c.1332dup, p. (D445*) at exon 9 and a known silent variant c.1413A>G, p. (=), rs5930, NM_001195798.1 at exon 10 of the LDLR gene in both patients. Both probands were homozygous for the mutation, which is located in the EGF-precursor homology domain of the LDLR protein, and show severe FH phenotype. Conclusion: The duplication variant results in the production of a defective LDL receptor containing the p. (D445*) variant. This variant results in a premature stop codon at position 445 in exon 9 of the LDLR gene, which results in truncation of the protein. The segregation pattern of the variant is consistent with the lipid profile, suggesting a more severe FH phenotype when the variant is in the homozygous state. Finding of this study could be very useful in developing critical genetic screen for potential FH patients. In addition, these data contribute to the understanding of the molecular basis of FH in Saudis.

Published
2017
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5. Identification and Treatment of Patients with Homozygous Familial Hypercholesterolaemia: Information and Recommendations from a Middle East Advisory Panel

Author

Nasreen Al-Sayed, Khalid Al-Waili, Maryam Razzaghy-Azar, Jacques Genest, Fahad Alnouri, Hani Sabbour, Abdulraof Al-Mahfouz, Abdullah Alashwal, Raul D. Santos, Yajnavalka Banerjee, Khalid Al-Rasadi, and Faisal A. Al-Allaf

Subjects
medicine.medical_specialty, diagnosis, prevalence, Population, Prevalence, Disease, Article, Hyperlipoproteinemia Type II, Middle East, Ezetimibe, Homozygous familial hypercholesterolaemia, Risk Factors, medicine, Humans, genetics, Disease management (health), education, Pharmacology, education.field_of_study, treatment, Plasma Exchange, business.industry, Anticholesteremic Agents, Incidence (epidemiology), Confounding, medicine.disease, Family medicine, Practice Guidelines as Topic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Metabolic syndrome, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

We present clinical practice guidelines for the diagnosis and treatment of homozygous familial hypercholesterolaemia (HoFH) in the Middle East region. While guidelines are broadly applicable in Europe, in the Middle East we experience a range of confounding factors that complicate disease management to a point whereby the European guidance cannot be applied without significant modification. Specifically, for disease prevalence, the Middle East region has an established epidemic of diabetes and metabolic syndrome that can complicate treatment and mask a clinical diagnosis of HoFH. We have also a high incidence of consanguineous marriages, which increase the risk of transmission of recessive and homozygous genetic disorders. This risk is further augmented in autosomal dominant disorders such as familial hypercholesterolaemia (FH), in which a range of defective genes can be transmitted, all of which contribute to the phenotypic expression of the disease. In terms of treatment, we do not have access to lipoprotein apheresis on the same scale as in Europe, and there remains a significant reliance on statins, ezetimibe and the older plasma exchange methods. Additionally, we do not have widespread access to anti-apolipoprotein B therapies and microsomal transfer protein inhibitors. In order to adapt existing global guidance documents on HoFH to the Middle East region, we convened a panel of experts from Oman, Saudi Arabia, UAE, Iran and Bahrain to draft a regional guidance document for HoFH. We also included selected experts from outside the region. This panel statement will form the foundation of a detailed appraisal of the current FH management in the Middle Eastern population and thereby provide a suitable set of guidelines tailored for the region.

Published
2015
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6. 1. Founder mutation identified in the LDLR gene causing familial hypercholesterolemia associated with increased risk of coronary heart disease

Author

Mawaddah Toonsi, Fahad Alnouri, Abdullah Alashwal, Halah Abalkhail, Rakan Own, Zainularifeen Abduljaleel, Ahmad F Al-Allaf, Faisal A. Al-Allaf, Mohammad Athar, Zohor Azhar, Abdellatif Bouazzaoui, Iman Abumansour, and Taher Mohiuddin

Subjects
0301 basic medicine, Proband, Genetics, education.field_of_study, lcsh:Diseases of the circulatory (Cardiovascular) system, business.industry, Population, Autosomal dominant trait, Familial hypercholesterolemia, medicine.disease, Frameshift mutation, 03 medical and health sciences, Exon, 030104 developmental biology, lcsh:RC666-701, LDL receptor, medicine, Risk factor, education, business
Abstract

Type Basic science research. Presentation Type Oral presentation. Introduction Coronary artery diseases (CAD) inflict heavy economical and social cost on most populations including Saudi’s and contribute significantly to their morbidity and mortality rates. Familial hypercholesterolemia (FH) is hereditary in an autosomal dominant disease and is a major risk factor for the development of CAD. FH is predominantly caused by variants in the low-density lipoprotein (LDL) receptor gene (LDLR). Methodology More than 140 FH samples including 44 probands were collected from 17 unrelated Saudi families who live in the central, northern, western and eastern regions of Saudi Arabia. Patient samples were screened using Next-generation sequencing (NGS) and Capillary sequencing. We described the genetic analysis of severely affected homozygous FH patients who were mostly resistant to statin therapy and were managed on an apheresis program. Results We identified a common frameshift mutation p. (G676Afs*33) in exon 14 of the LDLR gene in 17 probands and their first-degree blood relatives in apparently unrelated Saudi families. This founder mutation was found in about 40% Saudi FH population. We also describe a three dimensional homology model of the LDL receptor protein (LDLR) structure and examine the consequence of the frameshift mutation p. (G676Afs*33), as this could affect the LDLR structure in a region involved in dimer formation, and protein stability. Conclusion This finding of a recurrent mutation causing FH in the Saudi population could serve to develop a rapid genetic screening procedure for FH, and the 3D-structure analysis of the mutant LDLR, may provide tools to develop a mechanistic model of the LDLR function.

Published
2017

7. Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR): clinical heterogeneity and long-term efficacious management of eight patients from four unrelated Arab families with a loss of function VDR mutation

Author

Muhammad, Faiyaz-Ul-Haque, Waheeb, AlDhalaan, Abdullah, AlAshwal, Bassam S, Bin-Abbas, Afaf, AlSagheir, Maram, Alotaiby, Zulqurnain, Rafiq, and Syed H E, Zaidi

Subjects
Male, Bone Density Conservation Agents, Drug Resistance, Disease Management, Infant, Prognosis, Arabs, Pedigree, Calcitriol, Child, Preschool, Mutation, Humans, Receptors, Calcitriol, Female, Familial Hypophosphatemic Rickets, Child, Follow-Up Studies
Abstract

Vitamin D regulates the concentrations of calcium and phosphate in blood and promotes the growth and remodeling of bones. The circulating active form of vitamin D, 1,25-dihydroxyvitamin D, binds to the vitamin D receptor (VDR), which heterodimerizes with the retinoid X receptor to regulate the expression of target genes. Inactivating mutations in the VDR gene cause hereditary vitamin D-resistant rickets (HVDRR), a rare disorder characterized by an early onset of rickets, growth retardation, skeletal deformities, hypocalcemia, hypophosphatemia and secondary hyperparathyroidism, and in some cases alopecia.We describe eight new HVDRR patients from four unrelated consanguineous families. The VDR gene was sequenced to identify mutations. The management of patients over a period of up to 11 years following the initial diagnosis is assessed.Although all patients exhibit main features of HVDRR and carry the same c.885CA (p.Y295*) loss of function mutation in the VDR gene, there was heterogeneity of the manifestations of HVDRR-associated phenotypes and developmental milestones. These eight patients were successfully treated over a period of 11 years. All clinical symptoms were improved except alopecia.The study concludes that VDR sequencing and laboratory tests are essential to confirm HVDRR and to assess the effectiveness of the treatment.

Published
2017

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

Author

Malak Alghamdi, Susan Alhumaidi, Saeed Altala, Mirna Assoum, Aziza Chedrawi, Moeen Al-Sayed, Hisham Aldhalaan, Suzan A AlKhater, M. Abouelhoda, Turki Alshareef, Maha Alotaibi, Khalid S. Alqadi, Alya Alkaff, Syed Ahmed, Musad Abu Khaled, Suad Al Yamani, Bassem Albeirouti, Ali Al-Mehaidib, Walaa Alshuaibi, Nawal Makhseed, Ghada M H Abdel-Salam, Ewa Goljan, Zuhair Rahbeeni, Maisoon Almugbel, Shaza Makki, Ranad Albar, Fuad Al Mutairi, Khalid Alsaleem, Hanaa Banjar, Fahad A. Bashiri, Abdulaziz Bin Manee, Mona Alsaleh, Marwan Shaheen, Mohammed Fawzy, Sami Wali, Fahad Almohareb, Hisham Alkuraya, Shakir Bahzad, Ayman Shawli, Wesam Kurdi, Wajeeh Aldekhail, Somaya Alzelaye, Rand Arnaout, Abdullah Alsonbul, Sami Al-Hajjar, Saeed Hassan, Sameena Khan, Mohammed AlBalwi, Khalid Awartani, Sulaiman M. Al-Mayouf, Amal Alhashem, Hamoud Al-Mousa, Abdulaziz Alsemari, Hadeel Elbardisy, Mohamed El-Kalioby, Edward Cupler, Bandar Al-Saud, Hadeel Alghamdi, Isam Salih, Saadeh Sermin, Fahad Alsohaibaini, Shapar Nahrir, Hibah Alruwaili, Hamad Al-Zaidan, Nada Alsahan, Abdullah Alfaifi, Dalal K. Bubshait, Mohammed Nasr, Ahmed Alnahari, Ameen Tajuddin, Maged H. Hussein, Muddathir H Hamad, Asma Akilan, Afaf Alsagheir, Dorota Monies, Shamsad Shahrukh, Emadia Alaki, Tariq Abalkhail, Ahmed Sahly, Hamsa T. Tayeb, Badi Alenazi, Fowzan S. Alkuraya, Mohammed Al-Owain, Mohammed Abanemai, Ali Al-Ahmari, Maha Faden, Neama Meriki, Amal Alqasmi, Talal A. Basha, Hatem Murad, Hanna Akleh, Nabil Moghrabi, Asma I. Tahir, Abdulhadi Altalhi, Amal Jaafar, Ola Jarrad, Salah Baz, Abdullah Tamim, Ibraheem F. Abosoudah, Shazia Subhani, Manal Badawi, Raashida Sulaiman, Essam Al-Sabban, Brian F. Meyer, Talal Algoufi, Alya Qari, Mohammed Mahnashi, Hasan Al-Dhekri, Saeed Bohlega, Rafiullah Rafiullah, Naif A.M. Almontashiri, Mustafa A. Salih, Shahrukh K. Hashmi, Ibrahim Ghemlas, Zeeshan Shah, Abdullah Alashwal, and Ehab Tous

Subjects
0301 basic medicine, Male, Candidate gene, Population, Saudi Arabia, Germline mosaicism, Genes, Recessive, Consanguinity, 030105 genetics & heredity, Biology, Article, Cohort Studies, 03 medical and health sciences, Pregnancy, Genotype, Exome Sequencing, Genetics, Humans, Genetic Predisposition to Disease, Allele, education, Child, Exome, Exome sequencing, Genetics (clinical), education.field_of_study, Homozygote, Correction, Genetic Diseases, X-Linked, 030104 developmental biology, Phenotype, Mutation, Female
Abstract

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.

Published
2019
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9. Abstracts from the 3rd International Genomic Medicine Conference (3rd IGMC 2015)

Author

Jerry W. Shay, Noriko Homma, Ruyun Zhou, Muhammad Imran Naseer, Adeel G. Chaudhary, Mohammed Al-Qahtani, Nobutaka Hirokawa, Maryam Goudarzi, Albert J. Fornace, Saleh Baeesa, Deema Hussain, Mohammed Bangash, Fahad Alghamdi, Hans-Juergen Schulten, Angel Carracedo, Ishaq Khan, Hanadi Qashqari, Nawal Madkhali, Mohamad Saka, Kulvinder S. Saini, Awatif Jamal, Jaudah Al-Maghrabi, Adel Abuzenadah, Adeel Chaudhary, Mohammed Al Qahtani, Ghazi Damanhouri, Heba Alkhatabi, Anne Goodeve, Laura Crookes, Nikolas Niksic, Nicholas Beauchamp, Adel M. Abuzenadah, Jim Vaught, Bruce Budowle, Mourad Assidi, Abdelbaset Buhmeida, Leena Merdad, Sudhir Kumar, Sayaka Miura, Karen Gomez, Mahmood Rasool, Ahmed Rebai, Sajjad Karim, Hend F. Nour Eldin, Heba Abusamra, Elham M. Alhathli, Nada Salem, Mohammed H. Al-Qahtani, Hossam Faheem, Ashok Agarwa, Eberhard Nieschlag, Joachim Wistuba, Oliver S. Damm, Mohd A. Beg, Taha A. Abdel-Meguid, Hisham A. Mosli, Osama S. Bajouh, Serdar Coskun, Muhammad Abu-Elmagd, Ashraf Dallol, Sahar Hakamy, Wejdan Al-Qahtani, Asia Al-Harbi, Shireen Hussain, Burak Ozkosem, Rick DuBois, Safia S. Messaoudi, Maryam T. Dandana, Touhami Mahjoub, Wassim Y. Almawi, S. Abdalla, M. Nabil Al-Aama, Asmaa Elzawahry, Tsuyoshi Takahashi, Sachiyo Mimaki, Eisaku Furukawa, Rie Nakatsuka, Isao Kurosaka, Takahiko Nishigaki, Hiromi Nakamura, Satoshi Serada, Tetsuji Naka, Seiichi Hirota, Tatsuhiro Shibata, Katsuya Tsuchihara, Toshirou Nishida, Mamoru Kato, Sajid Mehmood, Naeem Mahmood Ashraf, Awais Asif, Muhammad Bilal, Malik Siddique Mehmood, Aadil Hussain, Qazi Mohammad Sajid Jamal, Mughees Uddin Siddiqui, Mohammad A. Alzohairy, Mohammad A. Al Karaawi, Taoufik Nedjadi, Heba Al-Khattabi, Adel Al-Ammari, Ahmed Al-Sayyad, Hédia Zitouni, Nozha Raguema, Marwa Ben Ali, Wided Malah, Raja Lfalah, Wassim Almawi, Mohammed Elanbari, Andrey Ptitsyn, Sana Mahjoub, Rabeb El Ghali, Bechir Achour, Nidhal Ben Amor, Brahim N’siri, Hamid Morjani, Esam Azhar, Vera Chayeb, Maryam Dendena, Hedia Zitouni, Khedija Zouari-Limayem, Bassem Refaat, Ahmed M. Ashshi, Sarah A. Batwa, Hazem Ramadan, Amal Awad, Ahmed Ateya, Adel Galal Ahmed El-Shemi, Ahmad Ashshi, Mohammed Basalamah, Youjin Na, Chae-Ok Yun, Adel Galal El-Shemi, Osama Kensara, Amr Abdelfattah, Batol Imran Dheeb, Mohammed M. F. Al-Halbosiy, Rghad Kadhim Al lihabi, Basim Mohammed Khashman, Djouhri Laiche, Chaudhary Adeel, Nedjadi Taoufik, Hani Al-Afghani, Maria Łastowska, Haya H. Al-Balool, Harsh Sheth, Emma Mercer, Jonathan M. Coxhead, Chris P. F. Redfern, Heiko Peters, Alastair D. Burt, Mauro Santibanez-Koref, Chris M. Bacon, Louis Chesler, Alistair G. Rust, David J. Adams, Daniel Williamson, Steven C. Clifford, Michael S. Jackson, Mala Singh, Mohmmad Shoab Mansuri, Shahnawaz D. Jadeja, Hima Patel, Yogesh S. Marfatia, Rasheedunnisa Begum, Amal M. Mohamed, Alaa K. Kamel, Nivin A. Helmy, Sayda A. Hammad, Hesham F. Kayed, Marwa I. Shehab, Assad El Gerzawy, Maha M. Ead, Ola M. Ead, Mona Mekkawy, Innas Mazen, Mona El-Ruby, S. M. A. Shahid, J. M. Arif, Mohtashim Lohani, Moumni Imen, Chaouch Leila, Ouragini Houyem, Douzi Kais, Chaouachi Dorra Mellouli Fethi, Bejaoui Mohamed, Abbes Salem, Areeg Faggad, Amanuel T. Gebreslasie, Hani Y. Zaki, Badreldin E. Abdalla, Maha S. AlShammari, Rhaya Al-Ali, Nader Al-Balawi, Mansour Al-Enazi, Ali Al-Muraikhi, Fadi Busaleh, Ali Al-Sahwan, Francis Borgio, Abdulazeez Sayyed, Amein Al-Ali, Sadananda Acharya, Maha S. Zaki, Hala T. El-Bassyouni, Mohammed F. Elshal, Kaleemuddin M., Alia M. Aldahlawi, Omar Saadah, J. Philip McCoy, Adel E. El-Tarras, Nabil S. Awad, Abdulla A. Alharthi, Mohamed M. M. Ibrahim, Haneen S. Alsehli, Abdullah M. Gari, Mohammed M. Abbas, Roaa A. Kadam, Mazen M. Gari, Mohmmed H. Alkaff, Mamdooh A. Gari, Hend F. Nour eldin, Fatima A. Moradi, Omran M. Rashidi, Zuhier A. Awan, Ibrahim Hamza Kaya, Olfat Al-Harazi, Dilek Colak, Nabila A. Alkousi, Takis Athanasopoulos, Afnan O. Bahmaid, Etimad A. Alhwait, Mohammed H. Alkaf, Roaa Kadam, Gauthaman Kalamegam, Elham Alhathli, Salma N. Alsayed, Fawziah H. Aljohani, Samaher M. Habeeb, Rawan A. Almashali, Sulman Basit, Samia M. Ahmed, Rakesh Sharma, Ashok Agarwal, Damayanthi Durairajanayagam, Luna Samanta, Edmund S. Sabanegh, Zhihong Cui, Alaa A. Alboogmi, Nuha A. Alansari, Maha M. Al-Quaiti, Fai T. Ashgan, Afnan Bandah, Hasan S. Jamal, Abdullraheem Rozi, Zeenat Mirza, Ahmad J. Al Sayyad, Hasan M. A. Farsi, Jaudah A. Al-Maghrabi, Reem Alotibi, Alaa Al-Ahmadi, Alaa A. Albogmi, Rasha A. Ebiya, Samia M. Darwish, Metwally M. Montaser, Vladimir B. Bajic, Wafaey Gomaa, Mehenaz Hanbazazh, Mahmoud Al-Ahwal, Saher Hakamy, Ghali Baba, Abdullah Al-Harbi, Ghalia Baba, Hend Nour Eldin, Aisha A. Alyamani, Rawan Gadi, Saadiah M. Alfakeeh, Rubi Ghazala, Shilu Mathew, M. Haroon Hamed, Ishtiaq Qadri, Lobna Mira, Manal Shaabad, Mikhlid H. Almutairi, Angie Ambers, Jennifer Churchill, Jonathan King, Monika Stoljarova, Harrell Gill-King, Muhammad Al-Qatani, Farid Ahmed, Taha Abo Almagd, Muhammad Al-Qahtani, Abdelbaset Buhmaida, Rukhsana Satar, Waseem Ahmad, Nazia Nazam, Mohamad I. Lone, Muhammad I. Naseer, Mohammad S. Jamal, Syed K. Zaidi, Peter N. Pushparaj, Mohammad A. Jafri, Shakeel A. Ansari, Mohammed H. Alqahtani, Hanan Bashier, Abrar Al Qahtani, Amal M. Nour, Adel M. Abu Zenadah, Muhammed Al Qahtani, Muhammad Faheem, Shiny Mathew, Peter Natesan Pushparaj, Mohammad H. Al-Qahtani, Hani A. Alhadrami, Ibtessam R. Hussein, Rima S. Bader, Randa Bassiouni, Maha Alquaiti, Fai Ashgan, Hans Schulten, Mohamed Nabil Alama, Mohammad H. Al Qahtani, Mohammad I. Lone, Nazia Nizam, Muhammed H. Al-Qahtani, Eradah Alshihri, Lina Alharbi, Peter Pushparaj Natesan, Fazal Khan, Khalid Hussain Wali Sait, Nisreen Anfinan, Lobna S. Mira, Mohammed H. AlQahtani, Sameera Sogaty, Randa I. Bassiouni, Abdulrahman M. S. Sibiani, Mohiuddin K. Warsi, null Rubi, Kundan Kumar, Ahmad A. T. Naqvi, Faizan Ahmad, Md I. Hassan, Ashraf Ali, Jummanah Jarullah, Abdelbasit Buhmeida, Shahida Khan, Ghufrana Abdussami, Maryam Mahfooz, Mohammad A. Kamal, Ghazi A. Damanhouri, Bushra Jarullah, Mohammad S. S. Jarullah, Osama Bajouh, Abdulah E. A. Mathkoor, Hashim M. A. Alsalmi, Anas M. M. Oun, Ghazi A. Damanhauri, Adeel G. Chudhary, Yousif A. Abutalib, Daniele Merico, Susan Walker, Christian R. Marshall, Mehdi Zarrei, Stephen W. Scherer, Fai Talal Ashgan, Syed Kashif Zaidi, Mohammed M. Jan, Maryam Al-Zahrani, Sahira Lary, Emmanuel Dermitzakis, Abeer A. Al-refai, Mona Saleh, Rehab I. Yassien, Mahmmoud Kamel, Rabab M. Habeb, Najlaa Filimban, Nadia Ghannam, Adel Mohammed Abuzenadah, Fehmida Bibi, Sana Akhtar, Esam I. Azhar, Muhammad Yasir, Muhammad I. Nasser, Asif A. Jiman-Fatani, Ali Sawan, Ruaa A. Lahzah, Asho Ali, Syed A. Hassan, Seyed E. Hasnain, Iftikhar A. Tayubi, Hamza A. Abujabal, Alaa O. Magrabi, Adel Abuzenada, Taha Abduallah Kumosani, Elie Barbour, Manal Shabaad, Adnan Merdad, Kalamegam Gauthaman, Mamdooh Gari, Hani M. A. Aljahdali, Reham Al Nono, Haneen Alsehli, Mohammed Abbas, Mohammed Sarwar Jamal, Shakeel Ansari, Mansour A. Alghamdi, Magdy Shamy, Max Costa, Mamdouh I. Khoder, Najla Kharrat, Sabrine Belmabrouk, Rania Abdelhedi, Riadh Benmarzoug, Mohammed H. Al Qahtani, Ghazi Dhamanhouri, Abdelwahab Noorwali, Mohammad Khalid Alwasiyah, Afnan Bahamaid, Saadiah Alfakeeh, Aisha Alyamani, Ali Mobasheri, Mohammad Sarwar Jamal, Raziuddin Khan, Kanchan Bhatia, Saif Ahmad, Iftikhar AslamTayubi, Manish Tripathi, Syed Asif Hassan, Rahul Shrivastava, Syed Hassan, Hamza A. S. Abujabal, Ishani Shah, Ishfaq A. Sheikh, Ejaz Ahmad, Mohd Rehan, Samera F. AlBasri, Rola F. Turki, Sahar A. F. Hammoudah, Khalid M. AlHarbi, Lama M. El-Attar, Ahmed M. Z. Darwish, Sara M. Ibrahim, Hani Choudhry, Jalaludden Awlia, Imran khan, Sameera Al-basri, Taha Kumosani, Heba M. EL Sayed, Eman A. Hafez, Aisha Hassan Elaimi, Randa Ibrahim Bassiouni, Richard F. Wintle, Vikram Gopalakrishna Pillai, Sujata Sharma, Punit Kaur, Alagiri Srinivasan, Tej P. Singh, Fatima Al-Adwani, Deema Hussein, Mona Al-Sharif, Fahad Al-Ghamdi, Saleh S. Baeesa, Taha Abdullah Kumosani, Faisal A. Al-Allaf, Zainularifeen Abduljaleel, Abdullah Alashwal, Mohiuddin M. Taher, Abdellatif Bouazzaoui, Halah Abalkhail, Faisal A. Ba-Hammam, Mohammad Athar, Khalid HussainWali Sait, Naira Ben Mami, Yosr Z. Haffani, Mouna Medhioub, Lamine Hamzaoui, Ameur Cherif, Msadok Azouz, Mohammed Imran Nasser, Shereen A. Turkistany, Lina M. Al-harbi, Jamal Sabir, Basmah Al-Madoudi, Bayan Al-Aslani, Khulud Al-Harbi, Rwan Al-Jahdali, Hanadi Qudaih, Emad Al Hamzy, Asad M. Ilyas, Youssri Ahmed, Mohammed Alqahtani, Alaa Alamandi, Ohoud Subhi, Nadia Bagatian, Adel Al-Johari, Osman Abdel Al-Hamour, Hosam Al-Aradati, Abdulmonem Al-Mutawa, Faisal Al-Mashat, Mohammad Al-Qahtani, Muhammad W. shah, Esam I Azhar, Saad Al-Masoodi, Emna Khamla, Chaima Jlassi, Ahmed S. Masmoudi, Lassaad Belbahri, Shadi Al-Khayyat, Roba Attas, Atlal Abu-Sanad, Mohammed Abuzinadah, Habib Bouazzi, Carlos Trujillo, Maha Alotaibi, Rami Nassir, Essam H. Jiffri, Ghulam M. Ashraf, Mohammad A. Aziz, Rizwan Ali, Nusaibah Samman, Sathish Periyasamy, Mohammed Aldress, Majed Al Otaibi, Zeyad Al Yousef, Mohamed Boudjelal, Ibrahim AlAbdulkarim, Mohd Suhail, Abid Qureshi, Adil Jamal, Mahmoud Z. El-Readi, Safaa Y. Eid, Michael Wink, Ahmed M. Isa, Lulu Alnuaim, Johara Almutawa, Basim Abu-Rafae, Saleh Alasiri, Saleh Binsaleh, and Mohamed H. Alqahtani

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, Differentially expressed genes, Gene expression, Genetics, Feature selection, Computational biology, Biology, Cluster analysis, Classifier (UML), Biotechnology
Published
2016
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10. Compound heterozygous LDLR variant in severely affected familial hypercholesterolemia patient

Author

Hala Abalkhail, Zainularifeen Abduljaleel, Abdellatif Bouazzaoui, Ahmad F Al-Allaf, Mohammad Athar, Faisal A. Al-Allaf, Abdullah Alashwal, and Mohiuddin M. Taher

Subjects
Proband, Adult, Male, Heterozygote, Adolescent, Population, Mutation, Missense, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Biology, Compound heterozygosity, General Biochemistry, Genetics and Molecular Biology, Frameshift mutation, Hyperlipoproteinemia Type II, 03 medical and health sciences, 0302 clinical medicine, medicine, Missense mutation, Humans, 030212 general & internal medicine, education, Child, Frameshift Mutation, Exome sequencing, Genetics, education.field_of_study, Genetic Variation, Sequence Analysis, DNA, medicine.disease, Pedigree, Phenotype, Receptors, LDL, LDL receptor, Codon, Terminator, lipids (amino acids, peptides, and proteins), Female
Abstract

Familial hypercholesterolemia (FH) is most commonly caused by mutations in the LDL receptor (LDLR), which is responsible for hepatic clearance of LDL from the blood circulation. We described a severely affected FH proband and their first-degree blood relatives; the proband was resistant to statin therapy and was managed on an LDL apheresis program. In order to find the causative genetic variant in this family, direct exon sequencing of the LDLR, APOB and PCSK9 genes was performed. We identified a compound heterozygous mutation in the proband with missense p.(W577C) and frameshift p.(G676Afs33) variants at exons 12 and 14 of the LDLR gene respectively. DNA sequencing of LDLR gene from the parents demonstrated that the missense variant was inherited from the mother and frameshift variant was inherited from the father. The frameshift variant resulted in a stop signal 33 codons downstream of the deletion, which most likely led to a truncated protein that lacks important functional domains, including the trans-membrane domain and the cytoplasmic tail domain. The missense variant is also predicted to be likely pathogenic and affect EGF-precursor homology domain of the LDLR protein. The segregation pattern of the variants was consistent with the lipid profile, suggesting a more severe FH phenotype when the variants are in the compound heterozygous state. The finding of a compound heterozygous mutation causing severe FH phenotype is important for the genotype-phenotype correlation and also enlarges the spectrum of FH-causative LDLR variants in the Arab population, including the Saudi population.

Published
2016

11. Identification of a recurrent frameshift mutation at the LDLR exon 14 (c.2027delG, p.(G676Afs*33)) causing familial hypercholesterolemia in Saudi Arab homozygous children

Author

Faisal A. Ba-Hammam, Rakan Aun, Zainularifeen Abduljaleel, Mohiuddin M. Taher, Faisal A. Al-Allaf, Ahmad F Al-Allaf, Abdellatif Bouazzaoui, Iman Abumansour, Shahid S. Siddiqui, Wajahatullah Khan, Hala Abalkhail, Abdullah Alashwal, Mohammad Athar, and Zohor Azhar

Subjects
0301 basic medicine, Proband, Adult, Male, Adolescent, Population, Mutant, Molecular Sequence Data, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Biology, Frameshift mutation, Hyperlipoproteinemia Type II, 03 medical and health sciences, Exon, 0302 clinical medicine, Genetics, medicine, Humans, Amino Acid Sequence, education, Child, Frameshift Mutation, education.field_of_study, nutritional and metabolic diseases, Autosomal dominant trait, Exons, medicine.disease, Pedigree, 030104 developmental biology, Receptors, LDL, Child, Preschool, LDL receptor, lipids (amino acids, peptides, and proteins), Female
Abstract

Familial hypercholesterolemia (FH) is an autosomal dominant disease, predominantly caused by variants in the low-density lipoprotein (LDL) receptor gene (LDLR). Herein, we describe genetic analysis of severely affected homozygous FH patients who were mostly resistant to statin therapy and were managed on an apheresis program. We identified a recurrent frameshift mutation p.(G676Afs*33) in exon 14 of the LDLR gene in 9 probands and their relatives in an apparently unrelated Saudi families. We also describe a three dimensional homology model of the LDL receptor protein (LDLR) structure and examine the consequence of the frameshift mutation p.(G676Afs*33), as this could affect the LDLR structure in a region involved in dimer formation, and protein stability. This finding of a recurrent mutation causing FH in the Saudi population could serve to develop a rapid genetic screening procedure for FH, and the 3D-structure analysis of the mutant LDLR, may provide tools to develop a mechanistic model of the LDLR function.

Published
2015

12. Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease

Author

Wajahatullah Khan, Faisal A. Al-Allaf, Abdullah Alashwal, Mohammad Athar, Zainularifeen Abduljaleel, Hala Abalkhail, Faisal A. Ba-Hammam, and Mohiuddin M. Taher

Subjects
Apolipoprotein E, Proband, Male, Apolipoprotein B, Coronary Disease, Familial hypercholesterolemia, Hyperlipoproteinemia Type II, Exon, Genetics, medicine, Humans, biology, PCSK9, Serine Endopeptidases, nutritional and metabolic diseases, Autosomal dominant trait, Genetic Variation, High-Throughput Nucleotide Sequencing, General Medicine, Sequence Analysis, DNA, medicine.disease, Pedigree, Receptors, LDL, LDL receptor, Apolipoprotein B-100, biology.protein, lipids (amino acids, peptides, and proteins), Female, Proprotein Convertases, Proprotein Convertase 9
Abstract

Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). It is an autosomal dominant disease, caused by variants in Ldlr, ApoB or Pcsk9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease. Sequencing whole genome for screening variants for FH are not suitable due to high cost. Hence, in this study we performed targeted customized sequencing of FH 12 genes (Ldlr, ApoB, Pcsk9, Abca1, Apoa2, Apoc3, Apon2, Arh, Ldlrap1, Apoc2, ApoE, and Lpl) that have been implicated in the homozygous phenotype of a proband pedigree to identify candidate variants by NGS Ion torrent PGM. Only three genes (Ldlr, ApoB, and Pcsk9) were found to be highly associated with FH based on the variant rate. The results showed that seven deleterious variants in Ldlr, ApoB, and Pcsk9 genes were pathological and were clinically significant based on predictions identified by SIFT and PolyPhen. Targeted customized sequencing is an efficient technique for screening variants among targeted FH genes. Final validation of seven deleterious variants conducted by capillary resulted to only one novel variant in Ldlr gene that was found in exon 14 (c.2026delG, p. Gly676fs). The variant found in Ldlr gene was a novel heterozygous variant derived from a male in the proband.

Published
2014

13. Identification of a novel nonsense variant c.1332dup, p.(D445*) in the LDLR gene that causes familial hypercholesterolemia

Author

Abdellatif Bouazzaoui, Hala Abalkhail, Zainularifeen Abduljaleel, Rakan Own, Faisal A. Ba-Hammam, Ahmad F Al-Allaf, Abdullah Alashwal, Iman Abumansour, Mohiuddin M. Taher, Mohammad Athar, Zohor Azhar, and Faisal A. Al-Allaf

Subjects
Genetics, Mutation, business.industry, media_common.quotation_subject, Nonsense, Autosomal dominant trait, nutritional and metabolic diseases, Familial hypercholesterolemia, medicine.disease_cause, medicine.disease, Biochemistry, Article, Exon, Gene duplication, LDL receptor, medicine, lipids (amino acids, peptides, and proteins), business, Molecular Biology, Gene, media_common
Abstract

Familial hypercholesterolemia (FH) is an autosomal dominant disease predominantly caused by a mutation in the low-density lipoprotein receptor (LDLR) gene. Here, we describe two severely affected FH patients who were resistant to statin therapy and were managed on an apheresis program. We identified a novel duplication variant c.1332dup, p.(D445*) at exon 9 and a known silent variant c.1413A>G, p.(=), rs5930, NM_001195798.1 at exon 10 of the LDLR gene in both patients.

Published
2014

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