Research Title: Genetic study in a family with dopa-responsive dystonia revealed a novel mutation in sepiapterin reductase gene

Author: Tawfiq Froukh, Published Year: 2019

Pak J Med Sci, 35

Faculty: Science

Abstract: Dopa-responsive dystonia due to sepiapterin reductase deficiency (OMIM#612716) is caused by recessive mutations in the gene encoding sepiapterin reductase (SPR), which plays an important role in the biosynthesis of tetrahydrobiopterin (BH4). One Jordanian patient to first cousin parents is reported in this study. The parents of the proband have recognized the symptoms of their daughter at six months old with motor developmental delay. The symptoms were progressed after-then to include speech delay, seizure, ataxia, oculomotor apraxia, dysarthia and choreoathetosis. Despite of these symptoms, the clinicians in Jordan were unable to diagnose the case. In August 2018, the proband (8 years old) was presented to the department of biotechnology and genetic engineering at Philadelphia University in Jordan for the purposes of performing whole exome sequencing (WES). Analysis of WES data has revealed novel homozygous frameshift variant in the gene SPR (NM_003124.4:c.40delG,p.Ala15Profs*100). The variant is heterozygous in the parents and in the healthy male siblings. Therefore, the studied case was diagnosed with sepiapterin reductase deficiency. Because this disease is likely to be treated recommendations were given to the family immediately to start treatments trials. The case in this study illustrates the difficulties of diagnosing sepiapterin reductase deficiency based on clinical symptoms only and thus renders the possibilities of early management. Also, this study reinforces the importance of running WES to undiagnosed neurodevelopmental cases.

Keywords: Intellectual disability, Serotonin, Dopamine, Autosomal recessive, Genome.

Research Title: First Record Mutations in the Genes ASPA and ARSA Causing Leukodystrophy in Jordan

Author: Tawfiq Froukh, Published Year: 2019

BioMed Research International, 2019

Faculty: Science

Abstract: Leukodystrophies (LDs) are heterogeneous genetic disorders characterized by abnormalwhite matter in the central nervous system. Some of the LDs are progressive and often fatal. In general, LD is primarily diagnosed based on the neuroimaging; however, definitive diagnosis of the LD type is done using genetic testing such as next-generation sequencing. The aim of this study is to identify the genetic causes of LD in two independent Jordanian cases that exhibit MRI findings confirming LD with no definitive diagnosis using whole exome sequencing (WES). The most likely causative variants were identified. In one case, the homozygous pathogenic variant NM 000049.2:c.914C>A;p.Ala305Glu, which is previously reported in ClinVar, in the gene ASPA was identified causing Canavan disease. In the second case, the homozygous novel variant NM 000487.5:c.256C>G;p.Arg86Gly in the gene ARSA was identified causing metachromatic leukodystrophy. The two variants segregate in their families. The phenotypes of the two studied cases overlap with assigned diseases. The present study raises the importance of using WES to identify the precise neurodevelopmental diseases in Jordan.

Keywords: epilepsy; heterozygous; IQ; mental retardation; next generation sequencing

Research Title: Two cases of variant late infantile ceroid lipofuscinosis in Jordan

Author: Tawfiq Froukh, Published Year: 2019

World Journal of Clinical Cases, 7

Faculty: Science

Abstract: Abstract BACKGROUND Late infantile ceroid lipofuscinosis is a rare neurodegenerative disorder that appears between the ages of 2 and 4 years and is difficult to diagnose. In this report we present two sisters with this condition, and the clinical course consisted of delayed developmental skills initially and later regression of previously acquired skills. The cases were initially considered as childhood disintegrative disorder (CDD); however, when whole exome sequencing (WES) genetic testing was done, they proved to be variant late infantile ceroid lipofuscinosis. This is the first report from Jordan. CASE SUMMARY Clinical presentation included developmental delay and initially speech delay, followed by lose of sphincter control. Motor development was normal until 4 years of age, then they developed ataxia (fear of going downstairs) and weakness while walking. Atonic and myoclonic seizures become intractable, and this was followed by inability to stand or sit and loss of expressive language. In addition to complete blood count test, liver function test, kidney function test, serum electrolyte test, and blood sugar test, serum amino acid profile, B12 level test, thyroid function test, and a brain computed tomography scan were also normal. An electroencephalogram showed a generalized spike and wave pattern, and magnetic resonance imaging showed little to no abnormalities. After dealing with the cases as CDD, WES testing proved a final diagnosis of variant late infantile ceroid lipofuscinosis. Current treatment is anti-epileptic drugs and supportive care at home, and they are now in vegetative state. CONCLUSION This report highlights the importance of WES for the identification of genetic diseases, especially neurodegenerative disorders.

Keywords: Ceroid lipofuscinosis; Childhood disintegrative disorder; Lysosomal storage disorders; Neurodegenerative disorders; Variant late infantile; Case report

Research Title: Next Generation Sequencing and Genome-Wide Genotyping Identify the Genetic Causes of Intellectual Disability in Ten Consanguineous Families from Jordan

Author: Tawfiq Froukh, Published Year: 2017

Tohoku J. Exp. Med., 243

Faculty: Science

Abstract: Intellectual disability (ID), occurs in approximately 1 to 3% of the population and tends to be higher in low-income countries and in inbred communities. Despite the high rates of consanguineous marriages and the likely enrichment for recessive forms of ID, the genetic bases of ID in Jordan are largely unstudied. In this study, whole exome sequencing (WES) and homozygosity mapping were used to identify the genetic causes of ID in ten families from Jordan. The studied families are characterized by consanguineous marriage and having one or more progeny with ID. Likely disease-causing missense mutations were identified in eight families; four families are due to mutations in genes previously implicated with ID and the other four families are due to mutations in genes that are not previously implicated with ID. The novel genes include: BSN (Protein Basson), PTCHD2 (Protein dispatched homolog 3), DHRS3 (Short-chain dehydrogenase/reductase 3), and LGI3 (Leucine-rich repeat LGI family member 3). In addition, copy number variant (CNV) deletion and/or duplication were identified in 2 families; one family with 3.5 mega base (Mb) deletion on chromosome17 previously implicated with Smith Magenis Syndrome, and the other family with a novel combination of deletion and duplication in chromosomes 5 and 11. In this pilot study, four genes and one CNV deletion/duplication are identified for the first time in association with ID. The finding of this study further demonstrates the power of WES and homozygosity mapping for clinical diagnostics of ID in consanguineous families in small populations.

Keywords: epilepsy; heterozygous; IQ; mental retardation; next generation sequencing

Research Title: Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders

Author: Tawfiq Froukh, Published Year: 2017

JAMAPsychiatry, 74

Faculty: Science

Abstract: IMPORTANCE Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. OBJECTIVES To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families. DESIGN, SETTING, AND PARTICIPANTS Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016. RESULTS Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH, CBS, MTHFR, CYP27A1, and HIBCH), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7, STX1A, CCAR2, EEF1D, GALNT2, SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, NARG2, FAM234B, and TRAP1. The diagnostic yield was higher in individuals with severe ID (35 of 77 [45.5%]), in multiplex families (42 of 107 [39.3%]), in patients with additional features (30 of 70 [42.9%]), and in those with remotely related parents (15 of 34 [44.1%]). CONCLUSIONS AND RELEVANCE Because of the high diagnostic yield of 36.8%and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.

Keywords: ID, NGS, WES

Research Title: Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features

Author: Tawfiq Froukh, Published Year: 2016

The American Journal of Human Genetics, 99

Faculty: Science

Abstract: The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features.

Keywords: ID, NGS, WES

Research Title: Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A

Author: Tawfiq Froukh, Published Year: 2016

The American Journal of Human Genetics, 99

Faculty: Science

Abstract: Epileptic encephalopathies are a catastrophic group of epilepsies characterized by refractory seizures and cognitive arrest, often resulting from abnormal brain development. Here, we have identified an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features caused by recessive loss-of-function mutations in DENND5A. DENND5A contains a DENN domain, an evolutionarily ancient enzymatic module conferring guanine nucleotide exchange factor (GEF) activity to multiple proteins serving as GEFs for Rabs, which are key regulators of membrane trafficking.DENND5A is detected predominantly in neuronal tissues, and its highest levels occur during development.KnockdownofDENND5Aleads to striking alterations in neuronal development. Mechanistically, these changes appear to result from upregulation of neurotrophin receptors, leading to enhanced down stream signaling. Thus, we have identified a link between a DENN domain protein and neuronal development, dysfunction of which is responsible for a form of epileptic encephalopathy.

Keywords: ID, NGS, WES

Research Title: The Political Status of Jordanian Women: Constants and Variables

Author: Muwafaq Abu Hammoud, Published Year: 2019

مجلة دراسات - العلوم الانسانية والاجتماعية في الجامعة الاردنية,

Faculty: Arts

Abstract: This study highlights the political status of Jordanian women in the past two decades through analyzing certain indicators that reflect women’s presence and representation in political life in order to identify the level of the participation of Jordanian women in public life, reveal the most important obstacles facing this participation, and reach a number of recommendations that would improve the political status of Jordanian women. The importance of the study stems from emphasizing the participation of women in political activity as a national necessity taking into consideration the fact that women comprise half of the society and support men in shouldering life’s responsibilities. What makes the issue more urgent is the fact that the political status of Jordanian women is still weak and disproportionate to their abilities, potential and energies. It is also important to emphasize that the mobilization of women's forces and their active participation in various aspects of development will help boost the social and political progress in Jordan, which faces many challenges and problems. It would also enhance women's status in society and develop their capacity to educate future generations. The questions that this study purports to answer are the following: Are Jordanian women still suffering from the legacy of backward social and cultural heritage that prevents their active political participation? Has the constitutional, legal, administrative and political reform over the past two decades contributed to activating the role of Jordanian women in the political process?

Keywords: Political participation, Women's Empowerment, Institutions of civil society, Women's Quota

Research Title: دولة القانون والتنمية الإنسانية: مدخل نظري

Author: Muwafaq Abu Hammoud, Published Year: 2019

مجلة العلوم الانسانية لجامعة ام البواقي في الجزائر, المجلد 6، العدد 16

Faculty: Arts

Abstract: جاءت د ا رستنا هذه لتأكد على أهمية دولة القانون وحيويتها وضرورتها في وقتنا الحالي لتحقيق التنمية الإنسانية، وللخروج من الأزمات والمشكلات والتحديات التي تواجه أغلب الدول العربية، ولعل أبرزها: ت ا رجع الحريات وغياب المساءلة والمحاسبة والم ا رقبة، وانتشار الفساد، وغياب الديمق ا رطية، وغياب العدالة والمساواة، وضعف المشاركة الفاعلة، وافتقار القطاع العام إلى الفعالية والكفاءة، وعدم الاستجابة لاحتياجات الناس ومتطلبات التنمية الإنسانية. ففي ظل استفحال الأزمات الاجتماعية والسياسية والاقتصادية، وتفاقم الاحتياجات والمظاه ا رت والح ا ركات الشعبية الواسعة. ودولة القانون ضرورة ملحّة في الوقت الحالي لحفظ التوازن بين الدولة والمجتمع ولتحقيق الأمن والاستق ا رر للإنسان، وتحريره من الخوف والقلق اليومي الذي يهدّد حياته. ولذلك لا بد من الاتجاه نحو تدعيم وعي المواطن العربي بدولة القان ون ودورها في تحقيق عملية التنمية الإنسانية، وإيجاد دولة قوية قادرة على تحقيق التنمية الشاملة

Keywords: دولة القانون،التنمية الإنسانية

Research Title: Fighting Illiteracy in the Arab World

Author: Muwafaq Abu Hammoud, Published Year: 2017

International Education Studies, Vol. 10, No. 11

Faculty: Arts

Abstract: Illiteracy in the Arab world is becoming an urgent necessity particularly facing problems of poverty, ignorance, extremism, which impede the required economic, social, political and cultural development processes. Extremism, violence and terrorism, in the Arab world, can only be eliminated by spreading of knowledge, fighting illiteracy. The study shows that illiteracy rate among males in the Arab world is 25% for males, (46%) for Females. Results of the study show that if the educational situation in all Arab countries does not change, illiteracy rates will increase in the Arab world, and the number of illiterates in the Arab world will reach 49 million in the category of age of 15 years, and by 2024,it may reach 5.5 million of youth (15 - 24 years). The study identifies factors affecting the rise of illiteracy in the Arab world, particularly: Low economic level of many Arab countries, the growing security, political turmoil and internal problems experienced by most Arab countries, Social reasons, and random policies and contradiction in the trends and areas of combating illiteracy. The study concluded that illiteracy has a significant impact on social behavior, and that democracy, political participation, violence, cultural development, respect, pluralism, and accepting diversity, are all affected by illiteracy. The study recommends that Arab governments must formulate clear strategies linked to development plans to save 100 million Arab citizens who suffer from illiteracy, and ignorance. Illiteracy is to be taken seriously because it entails misunderstanding democracy, lack of youth interest in political affairs, corruption, and therefore the absence of comprehensive reform programs.

Keywords: illiteracy, Arab world, extremism, violence, terrorism, political participation, political development