106 results on '"Amal Alhashem"'
Search Results
2. Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases
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Lama AlAbdi, Hanan E. Shamseldin, Ebtissal Khouj, Rana Helaby, Bayan Aljamal, Mashael Alqahtani, Aisha Almulhim, Halima Hamid, Mais O. Hashem, Firdous Abdulwahab, Omar Abouyousef, Amal Jaafar, Tarfa Alshidi, Mohammed Al-Owain, Amal Alhashem, Saeed Al Tala, Arif O. Khan, Elham Mardawi, Hisham Alkuraya, Eissa Faqeih, Manal Afqi, Salwa Alkhalifi, Zuhair Rahbeeni, Samya T. Hagos, Wijdan Al-Ahmadi, Seba Nadeef, Sateesh Maddirevula, Khalid S. A. Khabar, Alexander Putra, Angel Angelov, Changsook Park, Ana M. Reyes-Ramos, Husen Umer, Ikram Ullah, Patrick Driguez, Yoshinori Fukasawa, Ming Sin Cheung, Imed Eddine Gallouzi, and Fowzan S. Alkuraya
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Long-read sequencing ,Autozygome ,STX3 ,ABHD12 ,C1orf109 ,FLVCR1 ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Long-read whole genome sequencing (lrWGS) has the potential to address the technical limitations of exome sequencing in ways not possible by short-read WGS. However, its utility in autosomal recessive Mendelian diseases is largely unknown. Methods In a cohort of 34 families in which the suspected autosomal recessive diseases remained undiagnosed by exome sequencing, lrWGS was performed on the Pacific Bioscience Sequel IIe platform. Results Likely causal variants were identified in 13 (38%) of the cohort. These include (1) a homozygous splicing SV in TYMS as a novel candidate gene for lethal neonatal lactic acidosis, (2) a homozygous non-coding SV that we propose impacts STK25 expression and causes a novel neurodevelopmental disorder, (3) a compound heterozygous SV in RP1L1 with complex inheritance pattern in a family with inherited retinal disease, (4) homozygous deep intronic variants in LEMD2 and SNAP91 as novel candidate genes for neurodevelopmental disorders in two families, and (5) a promoter SNV in SLC4A4 causing non-syndromic band keratopathy. Surprisingly, we also encountered causal variants that could have been identified by short-read exome sequencing in 7 families. The latter highlight scenarios that are especially challenging at the interpretation level. Conclusions Our data highlight the continued need to address the interpretation challenges in parallel with efforts to improve the sequencing technology itself. We propose a path forward for the implementation of lrWGS sequencing in the setting of autosomal recessive diseases in a way that maximizes its utility.
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- 2023
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3. Novel TLR7 hemizygous variant in post-COVID-19 neurological deterioration: a case report with literature review
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Ahmed Noor Eddin, Mohammed Al-Rimawi, Feham Peer-Zada, Khalid Hundallah, and Amal Alhashem
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COVID-19 ,SARS-CoV-2 ,TLR7 ,hemizygous ,neurological deterioration ,immunodeficiency ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The neurological complications of coronavirus disease 2019 (COVID-19) can range from simple tremors and dystonia to features of encephalopathy. Toll-like receptor 7 (TLR7) belongs to a family of innate immune receptors responsible for viral RNA detection (such as SARS-CoV-2) and immune response initiation. TLR7 loss of function variants have been previously reported as genetic risk factors for severe COVID-19 infection in young patients with no comorbidities. In this case, we report a pediatric patient who developed severe long-term neurological deterioration following his COVID-19 infection. Presenting first to the clinic with episodic dystonia and finger spasticity, the patient’s condition rapidly deteriorated with a significant drop in the Glasgow Coma Scale (GCS). Despite improvement following initial treatment with rituximab and intravenous immunoglobulin, the patient’s symptoms relapsed, and GCS further dropped to 3/15. Serial brain magnetic resonance imaging scans revealed diffuse parenchymal atrophy, ventricular enlargement, and spinal cord thickening. Autoimmune investigations were negative but clinical whole genome sequencing prioritized four gene variants, the most significant of which was a novel frameshift null variant of the X chromosomal TLR7 gene (c.1386_1389dup, p.[His464Ilefs*7]). This case illustrates a role for TLR7 in long-term COVID-19 complications and highlights that TLR7 deficiency in the future may be addressed as a therapeutic measure.
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- 2023
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4. Progressive symmetrical erythrokeratoderma manifesting as harlequin-like ichthyosis with severe thrombocytopenia secondary to a homozygous 3-ketodihydrosphingosine reductase mutation
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Lama Altawil, MD, Hind Alshihry, MD, Huda Alfaraidi, MD, Amal Alhashem, MD, Ahmed Alhumidi, MD, and Fowzan S. Alkuraya, MD
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EKVP4 ,genodermatosis ,harlequin ,ichthyoses ,3-ketodihydrosphingosine reductase ,KDSR ,Dermatology ,RL1-803 - Published
- 2021
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5. Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics
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Sateesh Maddirevula, Hiroyuki Kuwahara, Nour Ewida, Hanan E. Shamseldin, Nisha Patel, Fatema Alzahrani, Tarfa AlSheddi, Eman AlObeid, Mona Alenazi, Hessa S. Alsaif, Maha Alqahtani, Maha AlAli, Hatoon Al Ali, Rana Helaby, Niema Ibrahim, Firdous Abdulwahab, Mais Hashem, Nadine Hanna, Dorota Monies, Nada Derar, Afaf Alsagheir, Amal Alhashem, Badr Alsaleem, Hamoud Alhebbi, Sami Wali, Ramzan Umarov, Xin Gao, and Fowzan S. Alkuraya
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Negative WES ,RNA-based diagnostics ,Mapping ,Mendelian ,Transcriptomics ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Background At least 50% of patients with suspected Mendelian disorders remain undiagnosed after whole-exome sequencing (WES), and the extent to which non-coding variants that are not captured by WES contribute to this fraction is unclear. Whole transcriptome sequencing is a promising supplement to WES, although empirical data on the contribution of RNA analysis to the diagnosis of Mendelian diseases on a large scale are scarce. Results Here, we describe our experience with transcript-deleterious variants (TDVs) based on a cohort of 5647 families with suspected Mendelian diseases. We first interrogate all families for which the respective Mendelian phenotype could be mapped to a single locus to obtain an unbiased estimate of the contribution of TDVs at 18.9%. We examine the entire cohort and find that TDVs account for 15% of all “solved” cases. We compare the results of RT-PCR to in silico prediction. Definitive results from RT-PCR are obtained from blood-derived RNA for the overwhelming majority of variants (84.1%), and only a small minority (2.6%) fail analysis on all available RNA sources (blood-, skin fibroblast-, and urine renal epithelial cells-derived), which has important implications for the clinical application of RNA-seq. We also show that RNA analysis can establish the diagnosis in 13.5% of 155 patients who had received “negative” clinical WES reports. Finally, our data suggest a role for TDVs in modulating penetrance even in otherwise highly penetrant Mendelian disorders. Conclusions Our results provide much needed empirical data for the impending implementation of diagnostic RNA-seq in conjunction with genome sequencing.
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- 2020
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6. The phenotypic spectrum of dihydrolipoamide dehydrogenase deficiency in Saudi Arabia
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Anar Alfarsi, Majid Alfadhel, Seham Alameer, Amal Alhashem, Brahim Tabarki, Faroug Ababneh, Ahmed Al Fares, and Fuad Al Mutairi
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Dihydrolipoamide dehydrogenase deficiency ,Lactic acidosis ,Hypoglycemia ,Pyruvate dehydrogenase complex ,Flavoprotein and E3 ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Background: Dihydrolipoamide dehydrogenase deficiency (DLDD) is a rare metabolic disorder inherited in an autosomal recessive manner. This heterogeneous disease has a variable clinical presentation, onset, and biochemical markers. Materials and methods: We retrospectively reviewed the clinical and molecular diagnosis of eight cases with DLDD from four referral centers in Saudi Arabia. Results: Remarkably, we found hepatic involvement ranging from acute hepatic failure to chronic hepatitis in five patients. In addition, neurological disorders in the form of seizures, developmental delay, ataxia, hypotonia and psychomotor symptoms were found in five patients, two of them with a combination of hepatic and neurological symptoms. In addition, only one patient had recurrent episodes of hypoglycemia. While most patients had the hepatic form of homozygous variant c.685G > T in the DLD gene, one patient was found to have a novel variant c.623C > T that had neurological and hepatic symptoms. Conclusions: We describe the largest reported DLDD cohort in the Saudi population. Clinical, biochemical, radiological, and molecular characterization was reviewed and no clear genotype-phenotype correlation was found in this cohort.
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- 2021
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7. The Leukodystrophy Spectrum in Saudi Arabia: Epidemiological, Clinical, Radiological, and Genetic Data
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Majid Alfadhel, Mohammed Almuqbil, Fuad Al Mutairi, Muhammad Umair, Mohammed Almannai, Malak Alghamdi, Hamad Althiyab, Rayyan Albarakati, Fahad A. Bashiri, Walaa Alshuaibi, Duaa Ba-Armah, Mohammed A. Saleh, Ali Al-Asmari, Eissa Faqeih, Waleed Altuwaijri, Ahmed Al-Rumayyan, Mohammed Ali Balwi, Faroug Ababneh, Abdulrahman Faiz Alswaid, Wafaa M. Eyaid, Naif A. M. Almontashiri, Amal Alhashem, Khalid Hundallah, Aida Bertoli-Avella, Peter Bauer, Christian Beetz, Muhammad Talal Alrifai, Ahmed Alfares, and Brahim Tabarki
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leukodystrophy ,Saudi Arabia ,neurometabolic ,metachromatic leukodystrophy ,novel mutations ,Pediatrics ,RJ1-570 - Abstract
Background: Leukodystrophies (LDs) are inherited heterogeneous conditions that affect the central nervous system with or without peripheral nerve involvement. They are individually rare, but collectively, they are common. Thirty disorders were included by the Global Leukodystrophy Initiative Consortium (GLIA) as LDs.Methods: We conducted a retrospective chart review of a consecutive series of patients diagnosed with different types of LD from four large tertiary referral centers in Riyadh, Saudi Arabia. Only those 30 disorders defined by GLIA as LDs were included.Results: In total, 83 children from 61 families were identified and recruited for this study. The male-to-female ratio was 1.5:1, and a consanguinity rate of 58.5% was observed. An estimated prevalence of 1:48,780 or 2.05/100,000 was observed based on the clinical cohort, whereas a minimum of 1:32,857 or 3.04/100,000 was observed based on the local genetic database. The central region of the country exhibited the highest prevalence of LDs (48.5%). The most common LD was metachromatic leukodystrophy (MLD), and it accounted for 25.3%. The most common disorder based on carrier frequency was AGS. Novel variants were discovered in 51% of the cases, but 49% possessed previously reported variants. Missense variants were high in number and accounted for 73% of all cases. Compared with other disorders, MLD due to saposin b deficiency was more common than expected, Pelizaeus-Merzbacher-like disease was more prevalent than Pelizaeus-Merzbacher disease, and X-linked adrenoleukodystrophy was less common than expected. The mortality rate among our patients with LD was 24%.Conclusion: To the best of our knowledge, this is the largest cohort of patients with LD from Saudi Arabia. We present epidemiological, clinical, radiological, and genetic data. Furthermore, we report 18 variants that have not been reported previously. These findings are of great clinical and molecular utility for diagnosing and managing patients with LD.
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- 2021
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8. Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update
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Sateesh Maddirevula, Hanan E. Shamseldin, Amy Sirr, Lama AlAbdi, Russell S. Lo, Nour Ewida, Mashael Al-Qahtani, Mais Hashem, Firdous Abdulwahab, Omar Aboyousef, Namik Kaya, Dorota Monies, May H. Salem, Naffaa Al Harbi, Hesham M. Aldhalaan, Hamad Alzaidan, Hadeel M. Almanea, Abrar K. Alsalamah, Fuad Al Mutairi, Samira Ismail, Ghada M. H. Abdel-Salam, Amal Alhashem, Ali Asery, Eissa Faqeih, Amal AlQassmi, Waleed Al-Hamoudi, Talal Algoufi, Mohammad Shagrani, Aimée M. Dudley, and Fowzan S. Alkuraya
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autozygosity ,diabetes ,yeast ,founder mutation ,disease-gene associations ,Genetics ,QH426-470 - Abstract
There is a growing interest in standardizing gene-disease associations for the purpose of facilitating the proper classification of variants in the context of Mendelian diseases. One key line of evidence is the independent observation of pathogenic variants in unrelated individuals with similar phenotypes. Here, we expand on our previous effort to exploit the power of autozygosity to produce homozygous pathogenic variants that are otherwise very difficult to encounter in the homozygous state due to their rarity. The identification of such variants in genes with only tentative associations to Mendelian diseases can add to the existing evidence when observed in the context of compatible phenotypes. In this study, we report 20 homozygous variants in 18 genes (ADAMTS18, ARNT2, ASTN1, C3, DMBX1, DUT, GABRB3, GM2A, KIF12, LOXL3, NUP160, PTRHD1, RAP1GDS1, RHOBTB2, SIGMAR1, SPAST, TENM3, and WASHC5) that satisfy the ACMG classification for pathogenic/likely pathogenic if the involved genes had confirmed rather than tentative links to diseases. These variants were selected because they were truncating, founder with compelling segregation or supported by robust functional assays as with the DUT variant that we present its validation using yeast model. Our findings support the previously reported disease associations for these genes and represent a step toward their confirmation.
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- 2020
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9. An atypical presentation of severe congenital contractures and lack of cerebellar involvement in a patient with a novel LAMA1 mutation
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Ameur Ammari, Amal Alhashem, Hanen Abdelraouf, Fatma Alzahrani, Fowzan Sami Alkuraya, and Brahim Tabarki
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case report ,lama1 gene ,arthrogryposis ,cerebellum ,Genetics ,QH426-470 - Abstract
Background: LAMA1 gene is mutated in patients with Poretti-Boltshauser syndrome, which include mainly the characteristic neuroimaging findings of cerebellar dysplasia and cysts. Case Presentation: We present a novel homozygous LAMA1 variant that is predicted to cause atypical phenotype of severe arthrogryposis, feeding difficulties, developmental delay, retinopathy, and no cerebellar involvement. Conclusion: Our findings are suggestive of absence of cerebellar involvement in LAMA1 mutations in some cases and phenotype may include severe arthrogryposis. [JBCGenetics 2018; 1(1.000): 43-46]
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- 2018
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10. Accelerating Novel Candidate Gene Discovery in Neurogenetic Disorders via Whole-Exome Sequencing of Prescreened Multiplex Consanguineous Families
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Anas M. Alazami, Nisha Patel, Hanan E. Shamseldin, Shamsa Anazi, Mohammed S. Al-Dosari, Fatema Alzahrani, Hadia Hijazi, Muneera Alshammari, Mohammed A. Aldahmesh, Mustafa A. Salih, Eissa Faqeih, Amal Alhashem, Fahad A. Bashiri, Mohammed Al-Owain, Amal Y. Kentab, Sameera Sogaty, Saeed Al Tala, Mohamad-Hani Temsah, Maha Tulbah, Rasha F. Aljelaify, Saad A. Alshahwan, Mohammed Zain Seidahmed, Adnan A. Alhadid, Hesham Aldhalaan, Fatema AlQallaf, Wesam Kurdi, Majid Alfadhel, Zainab Babay, Mohammad Alsogheer, Namik Kaya, Zuhair N. Al-Hassnan, Ghada M.H. Abdel-Salam, Nouriya Al-Sannaa, Fuad Al Mutairi, Heba Y. El Khashab, Saeed Bohlega, Xiaofei Jia, Henry C. Nguyen, Rakad Hammami, Nouran Adly, Jawahir Y. Mohamed, Firdous Abdulwahab, Niema Ibrahim, Ewa A. Naim, Banan Al-Younes, Brian F. Meyer, Mais Hashem, Ranad Shaheen, Yong Xiong, Mohamed Abouelhoda, Abdulrahman A. Aldeeri, Dorota M. Monies, and Fowzan S. Alkuraya
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Biology (General) ,QH301-705.5 - Abstract
Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.
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- 2015
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11. Spectrum of FAR1 (Fatty <scp>Acyl‐CoA</scp> Reductase 1) Variants and Related Neurological Conditions
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Ana Westenberger, Adriana Ruiz‐Herrera, Sevcan Bozdoğan, Atil Bisgin, Mohammed Almuqbil, Amal Alhashem, Talal Alanzi, Antonio Romito, Arndt Rolfs, Patricia Dias, Raquel Gouveia Silva, Aida M. Bertoli‐Avella, Peter Bauer, and Christian Beetz
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Neurology ,Neurology (clinical) - Published
- 2023
12. NTRK2-Related Obesity, Hyperphagia, and Developmental Delay: Case Report
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Anwar Alhamas, Amal Alhashem, Ali Alasmari, and Eissa Faqeih
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General Medicine - Abstract
Background: NTRK2 is a group of neurological disorders characterized by epilepsy and developmental delay. Neurodevelopmental disorders and obesity are linked to various inherited disorders and are often missed or diagnosed late. Our aim was to review Obesity,hyperphagia,and developmental delay (OBHD) which it overlaps with a wide range of neurodevelopmental disorders with obesity. Also, variable expressivity can mislead the diagnosis, especially if there is a parent with a similar phenotype but a milder presentation. Case presentation: A 8 -year-old girl presented with 6-year history of increase wight. On Neurodevelopmental examination, she found to have a speech delay and autistic features. Parents deny sphincter dysfunction and cognitive delay. Family history was negative for members with a similar presentation. Genetic testing identified a novel mutation in NTKR2 gene. Parents were examined and underwent segregation analysis which came back negative, so it is de novo. Conclusion: Obesity and neurodevelopmental delay are features that are seen in a wide range of inherited disorders, either chromosomal or single-gene disorders. Here we highlight the importance of thorough history, examination, and the application of genetic testing sooner than later to avoid delaying the diagnosis and report a possible novel variant in the NTRK2 gene. Functional studies would be our next step.
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- 2022
13. Mitochondrial 'dysmorphology' in variant classification
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Fowzan S. Alkuraya, Firdous Abdulwahab, Mais Hashem, Brahim Tabarki, Amal Alhashem, Hanan E. Shamseldin, and Rachid Sougrat
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Male ,Mitochondrial Diseases ,Mitochondrial disease ,Mutation, Missense ,Mitochondrion ,Biology ,Mitochondrial Dynamics ,Cell Line ,Mitochondrial Proteins ,Microscopy, Electron, Transmission ,Exome Sequencing ,Genetics ,medicine ,Humans ,Missense mutation ,Child ,Gene ,Genetics (clinical) ,Exome sequencing ,Genetic Variation ,Membrane Proteins ,HSP40 Heat-Shock Proteins ,medicine.disease ,Phenotype ,Human genetics ,Mitochondria ,Molecular Diagnostic Techniques ,Child, Preschool ,DNAJA3 ,Female - Abstract
Mitochondrial disorders are challenging to diagnose. Exome sequencing has greatly enhanced the diagnostic precision of these disorders although interpreting variants of uncertain significance (VUS) remains a formidable obstacle. Whether specific mitochondrial morphological changes can aid in the classification of these variants is unknown. Here, we describe two families (four patients), each with a VUS in a gene known to affect the morphology of mitochondria through a specific role in the fission-fusion balance. In the first, the missense variant in MFF, encoding a fission factor, was associated with impaired fission giving rise to a characteristically over-tubular appearance of mitochondria. In the second, the missense variant in DNAJA3, which has no listed OMIM phenotype, was associated with fragmented appearance of mitochondria consistent with its published deficiency states. In both instances, the highly specific phenotypes allowed us to upgrade the classification of the variants. Our results suggest that, in select cases, mitochondrial "dysmorphology" can be helpful in interpreting variants to reach a molecular diagnosis.
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- 2021
14. Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy
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E El-Anany, Jennifer E. Posey, Shalini N. Jhangiani, S Guliyeva, Jill A. Rosenfeld, Khalid A. Fakhro, Vasiliki Karageorgou, A A Subhi, R. A. Gibbs, A Al-Maraghi, Sarah H. Elsea, Amal Alhashem, Henry Houlden, Charul Gijavanekar, M S Breilyn, Dana Marafi, Joseph G. Gleeson, Christian Beetz, E Sites, Hessa S. Alsaif, Vernon R. Sutton, Jill V. Hunter, Fowzan S. Alkuraya, M Zakkariah, C Gaba, James R. Lupski, Erin Torti, Davut Pehlivan, Z. Coban Akdemir, Matteo P. Ferla, S Duberstein, Haowei Du, Mohamed S. Abdel-Hamid, Ulviyya Guliyeva, M Sebastin, Jenny C. Taylor, E Danish, Reza Maroofian, A Haseeb, Rauan Kaiyrzhanov, Maha S. Zaki, Mohammed Al-Owain, S V Mullegama, Ning Liu, Jawid M Fatih, and Tadahiro Mitani
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Genetics ,Microcephaly ,Nitrogen ,Glutamine ,Biology ,medicine.disease ,Sodium-Calcium Exchanger ,Hypotonia ,Solute carrier family ,Epilepsy ,Metabolome ,medicine ,Humans ,Original Article ,Epilepsy, Generalized ,Histidine ,Neurology (clinical) ,Global developmental delay ,medicine.symptom ,Gene ,Exome sequencing - Abstract
The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.
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- 2021
15. Combining exome/genome sequencing with data repository analysis reveals novel gene–disease associations for a wide range of genetic disorders
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Brahim Tabarki, Malak Alghamdi, Fuad Al Mutairi, Arndt Rolfs, Zuhair N. Al-Hassnan, Najim Ameziane, Aida M. Bertoli-Avella, Abdulrahman Alswaid, Anika Leubauer, Huma Arshad Cheema, Fowzan S. Alkuraya, Suliman Khan, Mohammed AlBalwi, Lihadh Al-Gazali, Oana Moldovan, Wafaa Eyaid, Ahmed Alfares, Vasiliki Karageorgou, Nouriya Al-Sannaa, Alize Urzi, Patrícia Dias, Majid Alfadhel, Amal Alhashem, Nadia Al Hashmi, Krishna Kumar Kandaswamy, Kornelia Tripolszki, Peter Bauer, Fatemeh Hadipour, Irina Hüning, Ruslan Al-Ali, Maha S. Zaki, Maria Eugenia Rocha, Natalia Ordonez-Herrera, Zahra Hadipour, Aisha M. Al-Shamsi, Christian Beetz, and Ronja Hotakainen
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Candidate gene ,Base Sequence ,medicine.diagnostic_test ,Nerve Tissue Proteins ,Disease ,Computational biology ,Biology ,medicine.disease ,Article ,DNA sequencing ,Phenotype ,Intellectual Disability ,Exome Sequencing ,Intellectual disability ,Human Phenotype Ontology ,medicine ,Humans ,Exome ,Gene ,Genetics (clinical) ,Genetic testing - Abstract
Purpose Within this study, we aimed to discover novel gene–disease associations in patients with no genetic diagnosis after exome/genome sequencing (ES/GS). Methods We followed two approaches: (1) a patient-centered approach, which after routine diagnostic analysis systematically interrogates variants in genes not yet associated to human diseases; and (2) a gene variant centered approach. For the latter, we focused on de novo variants in patients that presented with neurodevelopmental delay (NDD) and/or intellectual disability (ID), which are the most common reasons for genetic testing referrals. Gene–disease association was assessed using our data repository that combines ES/GS data and Human Phenotype Ontology terms from over 33,000 patients. Results We propose six novel gene–disease associations based on 38 patients with variants in the BLOC1S1, IPO8, MMP15, PLK1, RAP1GDS1, and ZNF699 genes. Furthermore, our results support causality of 31 additional candidate genes that had little published evidence and no registered OMIM phenotype (56 patients). The phenotypes included syndromic/nonsyndromic NDD/ID, oral–facial–digital syndrome, cardiomyopathies, malformation syndrome, short stature, skeletal dysplasia, and ciliary dyskinesia. Conclusion Our results demonstrate the value of data repositories which combine clinical and genetic data for discovering and confirming gene–disease associations. Genetic laboratories should be encouraged to pursue such analyses for the benefit of undiagnosed patients and their families.
- Published
- 2021
16. CLEC16A interacts with retromer and TRIM27, and its loss impairs endosomal trafficking and neurodevelopment
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Daphne J, Smits, Jordy, Dekker, Rachel, Schot, Brahim, Tabarki, Amal, Alhashem, Jeroen A A, Demmers, Dick H W, Dekkers, Antonio, Romito, Peter J, van der Spek, Tjakko J, van Ham, Aida M, Bertoli-Avella, and Grazia M S, Mancini
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CLEC16A is a membrane-associated C-type lectin protein that functions as a E3-ubiquitin ligase. CLEC16A regulates autophagy and mitophagy, and reportedly localizes to late endosomes. GWAS studies have associated CLEC16A SNPs to various auto-immune and neurological disorders, including multiple sclerosis and Parkinson disease. Studies in mouse models imply a role for CLEC16A in neurodegeneration. We identified bi-allelic CLEC16A truncating variants in siblings from unrelated families presenting with a severe neurodevelopmental disorder including microcephaly, brain atrophy, corpus callosum dysgenesis, and growth retardation. To understand the function of CLEC16A in neurodevelopment we used in vitro models and zebrafish embryos. We observed CLEC16A localization to early endosomes in HEK293T cells. Mass spectrometry of human CLEC16A showed interaction with endosomal retromer complex subunits and the endosomal ubiquitin ligase TRIM27. Expression of the human variant leading to C-terminal truncated CLEC16A, abolishes both its endosomal localization and interaction with TRIM27, suggesting a loss-of-function effect. CLEC16A knockdown increased TRIM27 adhesion to early endosomes and abnormal accumulation of endosomal F-actin, a sign of disrupted vesicle sorting. Mutagenesis of clec16a by CRISPR-Cas9 in zebrafish embryos resulted in accumulated acidic/phagolysosome compartments, in neurons and microglia, and dysregulated mitophagy. The autophagocytic phenotype was rescued by wild-type human CLEC16A but not the C-terminal truncated CLEC16A. Our results demonstrate that CLEC16A closely interacts with retromer components and regulates endosomal fate by fine-tuning levels of TRIM27 and polymerized F-actin on the endosome surface. Dysregulation of CLEC16A-mediated endosomal sorting is associated with neurodegeneration, but it also causes accumulation of autophagosomes and unhealthy mitochondria during brain development.
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- 2022
17. The genotypic and phenotypic spectrum of pycnodysostosis in Saudi Arabia: Novel variants and clinical findings
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Abdulrahman Alswaid, Khushnooda Ramzan, Amal Alhashem, Mohammed A. Saleh, Faiqa Imtiaz, Eissa Faqeih, Aziza M. Mushiba, and Mohammed Al-Owain
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Pediatrics ,medicine.medical_specialty ,business.industry ,Osteopetrosis ,Bone fracture ,medicine.disease ,Short stature ,Anterior fontanelle ,Acro-Osteolysis ,Craniosynostosis ,Osteosclerosis ,medicine.anatomical_structure ,Pycnodysostosis ,Genetics ,medicine ,medicine.symptom ,business ,Genetics (clinical) - Abstract
Pycnodysostosis is characterized by short stature, osteosclerosis, acro-osteolysis, increased tendency of fractures, and distinctive dysmorphic features. It is a rare autosomal recessive disease caused by biallelic CTSK mutations. The clinical details of 18 patients from Saudi Arabia were reviewed. Short stature, osteopetrosis, acro-osteolysis, and distinctive facial dysmorphism were documented in all cases. Our results highlight the significant complications associated with this disease. The large anterior fontanelle is one of the cardinal signs of this disease; however, half of our patients had small fontanelles and a quarter had craniosynostosis, which caused optic nerve compression. Sleep apnea was of the major complications in three patients. Bone fracture can be a presenting symptom, and in our patients it mainly occurred after the age of 3 years. Bone marrow suppression was seen in a single patient of our cohort who was misdiagnosed initially with malignant osteopetrosis. In this study, we also describe two novel (c.5G > A [p.Trp2Ter], c.538G > A [p.Gly180Ser]) and two reported (c.244-29 A > G, c.830C > T [p.Ala277Val]) CTSK mutations. Our results indicate that the recurrent intronic variant, c.244-29 A > G is likely to be a founder mutation, as it was found in 78% (14/18 patients) of our cohort belonging to the same tribe.
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- 2021
18. Further delineation of GEMIN4 related neurodevelopmental disorder with microcephaly, cataract, and renal abnormalities syndrome
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Ruqaiah Altassan, Ahmad Qudair, Riyadh Alokaili, Khalid Alhasan, Eissa A. Faqeih, Amal Alhashem, Muhammed Alowain, Moeanaldeen Alsayed, Zuhair Rahbeeni, Lama Albadi, Fowzan S. Alkuraya, Eric N. Anderson, Deepa Rajan, and Udai Bhan Pandey
- Subjects
Homozygote ,Syndrome ,Kidney ,Ribonucleoproteins, Small Nuclear ,Cataract ,Pedigree ,Minor Histocompatibility Antigens ,Neurodevelopmental Disorders ,Urogenital Abnormalities ,Genetics ,Microcephaly ,Humans ,Abnormalities, Multiple ,Genetics (clinical) - Abstract
Pathogenic variants in GEMIN4 have recently been linked to an inherited autosomal recessive neurodevelopmental disorder characterized with microcephaly, cataracts, and renal abnormalities (NEDMCR syndrome). This report provides a retrospective review of 16 patients from 11 unrelated Saudi consanguineous families with GEMIN4 mutations. The cohort comprises 11 new and unpublished clinical details from five previously described patients. Only two missense, homozygous, pathogenic variants were found in all affected patients, suggesting a founder effect. All patients shared global developmental delay with variable ophthalmological, renal, and skeletal manifestations. In addition, we knocked down endogenous Drosophila GEMIN4 in neurons to further investigate the mechanism of the functional defects in affected patients. Our fly model findings demonstrated developmental defects and motor dysfunction suggesting that loss of GEMIN4 function is detrimental in vivo; likely similar to human patients. To date, this study presents the largest cohort of patients affected with GEMIN4 mutations. Considering that identifying GEMIN4 defects in patients presenting with neurodevelopmental delay and congenital cataract will help in early diagnosis, appropriate management and prevention plans that can be made for affected families.
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- 2022
19. Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy and periventricular calcifications
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Erik Rosenhahn, Thomas J. O’Brien, Maha S. Zaki, Ina Sorge, Dagmar Wieczorek, Kevin Rostasy, Antonio Vitobello, Sophie Nambot, Fowzan S. Alkuraya, Mais O. Hashem, Amal Alhashem, Brahim Tabarki, Abdullah S. Alamri, Ayat H. Al Safar, Dalal K. Bubshait, Nada F. Alahmady, Joseph G. Gleeson, Mohamed S. Abdel-Hamid, Nicole Lesko, Sofia Ygberg, Sandrina P. Correia, Anna Wredenberg, Shahryar Alavi, Seyed M. Seyedhassani, Mahya Ebrahimi Nasab, Haytham Hussien, Tarek Omar, Ines Harzallah, Renaud Touraine, Homa Tajsharghi, Heba Morsy, Henry Houlden, Mohammad Shahrooei, Maryam Ghavideldarestani, Johannes R. Lemke, Heinrich Sticht, Rami Abou Jamra, Andre E. X. Brown, Reza Maroofian, and Konrad Platzer
- Abstract
PPFIBP1 encodes for the liprin-β1 protein which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 14 individuals from 10 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy and progressive microcephaly. Further common clinical findings included muscular hypertonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired hearing and vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM-domain region that is essential for protein-protein interaction. For further insight in the effects of PPFIBP1 loss-of-function, we performed automated behavioural phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model which revealed defects in spontaneous and light-induced behaviour and confirmed resistance to the acetylcholinesterase inhibitor aldicarb suggesting a defect in the neuronal presynaptic zone. In conclusion, we present bi-allelic loss-of-function variants in PPFIBP1 as a novel cause of an autosomal recessive neurodevelopmental disorder.
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- 2022
20. Expanding the phenotype, genotype and biochemical knowledge of <scp>ALG3‐CDG</scp>
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Eissa Faqeih, Jennifer Friedman, Hudson H. Freeze, Kierstin N Keller, Miao He, Earnest James Paul Daniel, Jie Chen, Hind Alsharhan, Eniko K. Pivnick, Christina Lam, Nicole Engelhardt, Amal Alhashem, Michael J. Bamshad, Deborah A. Nickerson, Pengfei Liu, Kimiyo Raymond, Pamela A Mazzeo, Jill A. Rosenfeld, Bobby G. Ng, and Andrew C. Edmondson
- Subjects
Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Glycan ,Microcephaly ,Adolescent ,Genotype ,Bioinformatics ,Mannosyltransferases ,Article ,Young Adult ,Epilepsy ,Congenital Disorders of Glycosylation ,Genetics ,medicine ,Humans ,Endocrine system ,Genetics (clinical) ,Immunodeficiency ,biology ,Neural tube defect ,business.industry ,Infant, Newborn ,Neural tube ,Infant ,medicine.disease ,Hypotonia ,carbohydrates (lipids) ,Phenotype ,medicine.anatomical_structure ,Child, Preschool ,biology.protein ,Female ,medicine.symptom ,business - Abstract
Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multisystem diseases. Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties. We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3-CDG, we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man(5)GlcNAc(2) consistent with their truncated lipid-linked precursor oligosaccharides. This spectrum of N-glycan changes is unique to ALG3-CDG. These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring.
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- 2021
21. Neuroimaging manifestations and genetic heterogeneity of Walker-Warburg syndrome in Saudi patients
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Kalthoum Tlili-Graiess, Sara Alharbi, Fowzan S. Alkuraya, Amal Alhashem, and Fawaz Kashlan
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Male ,Pediatrics ,medicine.medical_specialty ,Genetic counseling ,Saudi Arabia ,Neuroimaging ,Mannosyltransferases ,Microphthalmia ,Genetic Heterogeneity ,03 medical and health sciences ,0302 clinical medicine ,Developmental Neuroscience ,medicine ,Polymicrogyria ,Humans ,Pentosyltransferases ,Walker–Warburg syndrome ,Retrospective Studies ,business.industry ,Genetic heterogeneity ,Infant, Newborn ,Macrocephaly ,Brain ,Membrane Proteins ,Walker-Warburg Syndrome ,General Medicine ,medicine.disease ,Nucleotidyltransferases ,Buphthalmos ,Schizencephaly ,Mutation ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Background Walker-Warburg syndrome (WWS), an autosomal recessive disease, is the most severe phenotype of congenital muscular dystrophies. Its diagnosis remains primarily clinical and radiological. Identification of its causative variants will assist genetic counseling. We aim to describe genetic and neuroimaging findings of WWS and investigate the correlation between them. Methods We retrospectively reviewed the clinical, genetic and neuroimaging findings of eleven Saudi neonates diagnosed with WWS between April 2012 and December 2018 in a single tertiary care center. Correlation between neuroimaging and genetic findings was investigated. Results All patients had macrocephaly except one who had intrauterine growth restriction. Dysmorphic features were identified in nearly half of the patients. Creatine kinase levels were available in nine patients and were always elevated. Homozygous pathogenic variants were identified in all patients spanning POMT1 (n = 5), TMEM5 (n = 3), ISPD (n = 2) and POMT2 (n = 1) including one patient who had a dual molecular diagnosis of ISPD and PGAP2. On neuroimaging, all patients showed cobblestone cortex, classical infratentorial findings, and hydrocephalus. Other cerebral cortical malformations included subependymal heterotopia, polymicrogyria and open-lip schizencephaly in four, two and one patients, respectively. Buphthalmos and microphthalmia were the most prevalent orbital findings and found in all patients either unilaterally or bilaterally. Conclusion WWS is a genetically heterogeneous disorder among Saudis. The case with an additional PGAP2-related phenotype exemplifies the increased risk of dual autosomal recessive disorders in consanguineous populations. MRI is excellent in demonstrating spectrum of WWS brain and orbital malformations; however, no definite correlation could be found between the MRI findings and the genetic variant.
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- 2021
22. Further delineation of <scp> SMG9 </scp> ‐related heart and brain malformation syndrome
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Fowzan S. Alkuraya, Mona Abdelbaky, Fatema Alzahrani, Maha S Alrakaf, Norah K. Altuwaijri, Amal Alhashem, and Mais Hashem
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Genotype ,business.industry ,Developmental Disabilities ,Homozygote ,Brain ,Biology ,Bioinformatics ,Text mining ,Genetics ,Humans ,Abnormalities, Multiple ,Child ,business ,Genetics (clinical) - Published
- 2021
23. De Novo Ring Chromosome 15: Molecular Cytogenetic and Clinical Characterization of First Case from Saudi Arabia
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Amal Alhashem, Saria Alazmeh, Ayla Barakat, Ahmed Alfares, and Hatem Elghezal
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Pathology ,medicine.medical_specialty ,Renal ectopia ,business.industry ,Ring chromosome ,Chromosomal disorder ,Variable presentation ,medicine.disease ,Short stature ,Café au lait spot ,Pediatrics, Perinatology and Child Health ,Speech delay ,medicine ,medicine.symptom ,Presentation (obstetrics) ,business ,Genetics (clinical) - Abstract
Ring chromosome 15 is a rare chromosomal disorder, which usually occurs during early embryonic development via spontaneous errors and has variable presentation. To date, 89 cases of this condition have been reported. This case report describes a 5-year-old Saudi boy who was diagnosed as having de novo 46,XY,r(15). The patient presented with short stature, speech delay, café au lait spots, and facial dysmorphic features, together with new findings of left crossed fused renal ectopia and 11 ribs. This presentation was compared with the findings of cases reported previously.
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- 2020
24. Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy
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Ali Al Asmari, Maarab Alkorashy, Nawal Azhari, Zarghuna M.A. Shinwari, Mohammed Alhabdan, Saud Takroni, Walaa Alshuaibi, Sameera Sogaty, Ali Awaji, Faten Alhadeq, Aisha Alqahtani, Abdullah Alqwaee, Abduljabbar Alshenqiti, Ahmed Alomrani, Raghad Z. Al-Hassnan, Nadiah Alruwaili, Zuhair N. Al-Hassnan, Amal Alhashem, Fadel Al-Fadley, Waleed Al-Manea, Sahar Tulbah, Abdullah Alwadai, Abdulrahman Almesned, Malak Alghamdi, Majid Al-Fayyadh, Abdulrahman M. Bakhaider, Buthaina Albash, Dimpna C. Albert Brotons, Eissa Faqeih, Ahmad M. Al-Rashdan, Ali A. Al-Akhfash, Monther Rbabeh, Zainab Al humaidi, and Salwa M. Alkhalifi
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Male ,0301 basic medicine ,Adolescent ,Cardiomyopathy ,Consanguinity ,030204 cardiovascular system & hematology ,Biology ,Genome ,Genetic analysis ,L-Aminoadipate-Semialdehyde Dehydrogenase ,03 medical and health sciences ,0302 clinical medicine ,Exome Sequencing ,medicine ,Humans ,Genetic Testing ,Child ,Founder mutation ,Exome ,Genetics ,Heterogeneous group ,Homozygote ,Infant, Newborn ,Infant ,General Medicine ,medicine.disease ,Pedigree ,DNA-Binding Proteins ,030104 developmental biology ,Child, Preschool ,Female ,Cardiomyopathies ,Acetyl-CoA Carboxylase ,Transcription Factors - Abstract
Background: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. Methods: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. Results: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates ( ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1 ). Conclusions: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.
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- 2020
25. A Biallelic Variant in
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Norah, Alsaleh, Amal, Alhashem, Brahim, Tabarki, Sarar, Mohamed, Essa, Alharby, Fowzan S, Alkuraya, and Naif A M, Almontashiri
- Abstract
Our objective was to identify the genetic cause in a family with a remarkable history of neurodevelopmental disease and growth retardation.A neurologic evaluation was performed, and DNA samples were obtained from the affected siblings and parents to perform whole-exome sequencing (WES).Both siblings presented with dysmorphic features, failure to thrive, global developmental delay, generalized hypotonia, feeding problems, and congenital heart disease. WES revealed a homozygous nonsense variant in theA recent study has reported the first association of biallelic variants in the spliceosomal C complex gene
- Published
- 2022
26. Biallelic ZNFX1 variants are associated with a spectrum of immuno-hematological abnormalities
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Aida M. Bertoli-Avella, Samah Al-Tawalbeh, Nadia Al-Hashmi, Melis Köse, Roberta Trunzo, Fahad Al Abbas, Hasan Tawamie, Vasiliki Karageorgou, Peter Bauer, Ana Westenberger, Ghaleb Elyamany, Omar Abu Adas Blanco, Fuad Al Mutairi, Bruno Reversade, Kornelia Tripolszki, Salem Alawbathani, Mariam Al-Hilali, Fadiah Al-Khattabi, Suliman Khan, André Mégarbané, Natalia Ordonez-Herrera, Mohammed Al-raqad, Danielle Sng, Amal Alhashem, Ruslan Al-Ali, Nashat Al Sukaiti, Homoud Al Hebby, ACS - Heart failure & arrhythmias, and ARD - Amsterdam Reproduction and Development
- Subjects
Proband ,ZNFX1 ,Primary Immunodeficiency Diseases ,DNA Mutational Analysis ,Hepatosplenomegaly ,Frameshift mutation ,Monocytosis ,Antigens, Neoplasm ,Databases, Genetic ,Genetics ,medicine ,Humans ,Missense mutation ,Genetic Predisposition to Disease ,Alleles ,Genetic Association Studies ,Genetics (clinical) ,Immunodeficiency ,Genetic testing ,Hemophagocytic lymphohistiocytosis ,medicine.diagnostic_test ,business.industry ,Homozygote ,Chromosome Mapping ,Computational Biology ,Facies ,medicine.disease ,Hematologic Diseases ,Pedigree ,Phenotype ,monocytosis ,hemophagocytic lymphohistiocytosis ,Mutation ,Immunology ,hepatosplenomegaly ,medicine.symptom ,business ,immunodeficiency - Abstract
Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense-mediated decay, and two frameshift changes that likely introduce a truncation. Our findings (i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, (ii) expand the genetic and clinical spectrum of ZNFX1-related disease, and (iii) illustrate the utility of large, well-curated, and continually updated genotype-phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings.
- Published
- 2022
27. Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort
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Najim Ameziane, Dan Diego-Alvarez, Wafaa Eyaid, Nouriya Al-Sannaa, Catarina Pereira, Ahmed Alfares, Aida M. Bertoli-Avella, Jozef Hertecant, Pilar Guatibonza, Abdulrahman Alswaid, Susan Zielske, Arndt Rolfs, María Calvo, Marius-Ionuț Iurașcu, Aisha M. Al-Shamsi, Yasemin Alanay, Florian Vogel, Christian Beetz, Peter Bauer, Krishna Kumar Kandaswamy, Monica Segura-Castel, Amal Alhashem, Kapil Kampe, Maria Eugenia Rocha, Willie Reardon, Majid Alfadhel, Dimitar Ugrinovski, Michal Zawada, Gitte Warnack, Mohammed AlBalwi, Martin Werber, Claudia Cozma, Omid Paknia, Fuad Al Mutairi, Natalia Herrera-Ordonez, and Acibadem University Dspace
- Subjects
Oncology ,0303 health sciences ,medicine.medical_specialty ,Diagnostic methods ,business.industry ,030305 genetics & heredity ,Genomics ,Article ,DNA sequencing ,03 medical and health sciences ,Unknown Significance ,RNA analysis ,Internal medicine ,Genetics research ,Cohort ,Genetics ,medicine ,Biomarker (medicine) ,Medical diagnosis ,business ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology - Abstract
Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients’ phenotype in 212 of the 1007 cases (21.1%). In 245 additional cases (24.3%), a variant of unknown significance (VUS) related to the phenotype was reported. We especially investigated patients which had had ES with no genetic diagnosis (n = 358). For this group, GS diagnostic yield was 14.5% (52 patients with P/LP out of 358). GS should be especially indicated for ES-negative cases since up to 29.6% of them could benefit from GS testing (14.5% with P/LP, n = 52 and 15.1% with VUS, n = 54). Genetic diagnoses in most of the ES-negative/GS-positive cases were determined by technical superiority of GS, i.e., access to noncoding regions and more uniform coverage. Importantly, we reported 79 noncoding variants, of which, 41 variants were classified as P/LP. Interpretation of noncoding variants remains challenging, and in many cases, complementary methods based on direct enzyme assessment, biomarker testing and RNA analysis are needed for variant classification and diagnosis. We present the largest cohort of patients with GS performed in a clinical setting to date. The results of this study should direct the decision for GS as standard second-line, or even first-line stand-alone test.
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- 2020
28. Epilepsy, neuropsychiatric phenotypes, neuroimaging findings, and genotype-neurophenotype correlation in 22q11.2 deletion syndrome
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Norah M. AlJohar, Hatem M. ElGhezal, Aliyah M. Abo Thneen, Heeba Y. AlKalaf, Atif H. Sahari, Kalthoum Tlili-Graiess, Norah S. AlSaleh, Brahim M. Tabarki, Inesse B. Bouhjar, and Amal Alhashem
- Subjects
Male ,Psychosis ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Developmental Disabilities ,Neuroimaging ,Young Adult ,Epilepsy ,Intellectual Disability ,Intellectual disability ,DiGeorge Syndrome ,medicine ,Genetic predisposition ,Humans ,Attention deficit hyperactivity disorder ,Genetic Association Studies ,Retrospective Studies ,business.industry ,Mental Disorders ,Neuropsychology ,medicine.disease ,Psychiatry and Mental health ,Autism spectrum disorder ,Child, Preschool ,Original Article ,Neurology (clinical) ,business - Abstract
Objectives: To describe the epilepsy, neuropsychiatric manifestations, and neuroimaging findings in a group of patients with 22q11.2 DS, and to correlate the size of the deleted genetic material with the severity of the phenotype. Methods: We retrospectively analyzed the medical records of 28 patients (21 pediatric patients and 7 adults) with a genetically confirmed diagnosis of 22q11.2 DS. Clinical data (epilepsy, neurological exam, neuropsychological and developmental assessment, and psychiatric disorders), neuroimaging, and cytogenetic tests were analyzed. Results: Of the 28 patients with 22q11.2 DS, 6 (21.4%) had epileptic seizures, 2 had symptomatic hypocalcemic seizures, 4 (14.2%) had a psychiatric disorder, which comprised of attention deficit hyperactivity disorder, autism spectrum disorder, psychosis, and mood disorder, and 17 (60.7%) had developmental delay. All patients with epilepsy had a developmental delay. Twelve patients underwent a neuropsychology assessment. Intellectual levels ranged from moderate intellectual disability (7/12, 58%) to average (5/12, 41.6%). Of the 16 patients, 6 (37.5%) had a normal brain, while 10 (62.5%) had abnormal neuroimaging findings. No significant correlation was found between the size of the deleted genetic material and the severity of the phenotype. Conclusion: 22q11.2DS patients are at high risk to develop epilepsy, neuropsychiatric manifestations, and structural brain abnormalities. This indicates that this defined genetic locus is crucial for the development of the nervous system, and patients with 22q11.2 DS have genetic susceptibility to develop epilepsy.
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- 2020
29. Incidence of newborn screening disorders among 56632 infants in Central Saudi Arabia. A 6-year study
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Sulaiman A. AlMohaimeed, Amer N. Ammari, Maher Almashary, Lujane Alahaideb, Amal Alhashem, Fahad M. Alharbi, Horia AlMalawi, Aida I. Al-Aqeel, Wafa Elsheikh, Sarar Mohamed, and Ali Al-Odaib
- Subjects
Newborn screening ,Pediatrics ,medicine.medical_specialty ,business.industry ,Citrullinemia ,Maple syrup urine disease ,Biotinidase deficiency ,Incidence (epidemiology) ,screening ,Galactosemia ,lcsh:R ,lcsh:Medicine ,General Medicine ,Glutaric aciduria type 1 ,030204 cardiovascular system & hematology ,medicine.disease ,Congenital hypothyroidism ,03 medical and health sciences ,0302 clinical medicine ,newborn ,medicine ,incidence ,saudi arabia ,030212 general & internal medicine ,business - Abstract
Objectives: To determine the incidence of newborn screening (NBS) disorders and to study the key performance indicators of the program. Methods: This retrospective single-center study enrolled all infants who underwent NBS from January 2012 to December 2017 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. We screened 17 NBS disorders. Blood samples were collected 24 hours after birth. If the initial result was positive, a second sample was collected. True positive cases were immediately referred for medical management. Data were extracted from laboratory computerized and non-computerized records using case report forms. Results: During the study period, 56632 infants underwent NBS with a coverage rate of 100%. Thirty-eight cases were confirmed. The incidence of congenital hypothyroidism was 1:3775. The positive predictive value for the detection of congenital hypothyroidism was 11.8%. Propionic aciduria was the most common metabolic disorder, with an incidence of 1:14158. Very long-chain acyl CoA dehydrogenase deficiency and glutaric aciduria type 1 had an incidence of 1:18877 each. Phenylketonuria, biotinidase deficiency, maple syrup urine disease, and citrullinemia had an incidence of 1:28316 each. However, galactosemia and 3-methyl crotonyl carboxylase deficiency had the lowest incidence of 1:56632. Conclusion: The NBS coverage rate at our facility was 100%. Congenital hypothyroidism was the most frequently detected disorder with an incidence that matches worldwide figures. The incidence of other inherited disorders was consistent with regional figures.
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- 2020
30. Molecular and clinical characteristics of very long-chain acyl-CoA dehydrogenase deficiency . A single-center experience in Saudi Arabia
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Manal Abdelraheem, Sarar Mohamed, Bushra AlGufaydi, Amal Alhashem, and Aida I. Al-Aqeel
- Subjects
Newborn screening ,Pediatrics ,medicine.medical_specialty ,business.industry ,lcsh:R ,Cardiomyopathy ,vlcad deficiency ,lcsh:Medicine ,General Medicine ,Hypoglycemia ,medicine.disease ,clinical ,Very Long-Chain Acyl-CoA Dehydrogenase Deficiency ,Cohort ,saudi arabia ,Medicine ,Carnitine ,molecular ,business ,Case report form ,Rhabdomyolysis ,clinical characteristics ,medicine.drug - Abstract
Objectives: To describe the clinical and molecular characteristics of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Methods: A retrospective observational cross-sectional analysis was conducted on all patients with VLCAD deficiency at (Genetic/Metabolic Section), Prince Sultan Military Medical City (PSMMC), Riyadh, Saudi Arabia from 2000 to 2019. Demographic, clinical, and laboratory data were abstracted from the electronic hospital records using a case report form. Results: A total of 14 children were analyzed. Six presented with hypoglycemia, 4 with cardiomyopathy, and 10 had rhabdomyolysis. Five patients had early onset severe phenotype, while 9 had mild form. The molecular study revealed homozygous mutations in ACADVL in all 14 patients. Three variants were not reported before. All patients were treated with medium-chain triglyceride and carnitine. Ten patients are alive and have normal development, while 4 died. Conclusion: Most of the patients in this cohort presented in the neonatal period either by newborn screening or clinically with hypoglycemia, cardiomyopathy, and rhabdomyolysis. The new molecular variants detected in this study broaden the genetic spectrum of VLCAD deficiency in Saudi Arabia.
- Published
- 2020
31. Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans
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Fowzan S. Alkuraya, Ranad Shaheen, Dorota Monies, Awad Al Qahtani, Mohammad Shagrani, Muneerah A. Alzouman, Nour Ewida, Homoud A. Al-Hebbi, Eman Alobeid, Mohamed Abouelhoda, Tarfa Al-Sheddi, Abdulrahman Al-Hussaini, Amal Alhashem, Fatema Alzahrani, Saud Alsahli, Hanan E. Shamseldin, Nisha Patel, Eissa Faqeih, and Rana Alomar
- Subjects
0301 basic medicine ,Cholestasis, Intrahepatic ,Biology ,Severity of Illness Index ,Ciliopathies ,Infant, Newborn, Diseases ,Diagnosis, Differential ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Intraflagellar transport ,Exome Sequencing ,medicine ,Animals ,Humans ,Tetratricopeptide Repeat ,Hedgehog Proteins ,Neonatal cholestasis ,Chromosome 7 (human) ,Genetics ,Hepatology ,Genetic heterogeneity ,Cilium ,Infant, Newborn ,Intracellular Signaling Peptides and Proteins ,medicine.disease ,Phenotype ,Protein Transport ,Ciliopathy ,030104 developmental biology ,Mutation ,030211 gastroenterology & hepatology ,Microtubule-Associated Proteins - Abstract
Background and aims The clinical consequences of defective primary cilium (ciliopathies) are characterized by marked phenotypic and genetic heterogeneity. Although fibrocystic liver disease is an established ciliopathy phenotype, severe neonatal cholestasis is rarely recognized as such. Approach and results We describe seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two). Positional mapping revealed a single critical locus on chromosome 7. Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype. TTC26 (intraflagellar transport [IFT] 56/DYF13) is an atypical component of IFT-B complex, and deficiency of its highly conserved orthologs has been consistently shown to cause defective ciliary function in several model organisms. We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic clustering with cells derived from individuals with closely related ciliopathies. We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system. Conclusions In addition to establishing a TTC26-related ciliopathy phenotype in humans, our results highlight the importance of considering ciliopathies in the differential diagnosis of severe neonatal cholestasis even in the absence of more typical features.
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- 2020
32. Fructose-1,6-bisphosphatase deficiency with confirmed molecular diagnosis. An important cause of hypoglycemia in children
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Esraa A. Mohammed, Rihab M. Salih, Amal Alhashem, Aida I. Al-Aqeel, and Sarar Mohamed
- Subjects
Pediatrics ,medicine.medical_specialty ,Cross-sectional study ,Recurrent hypoglycemia ,lcsh:Medicine ,030204 cardiovascular system & hematology ,Hypoglycemia ,fructose ,03 medical and health sciences ,0302 clinical medicine ,6-bisphosphatase ,medicine ,030212 general & internal medicine ,fbp1 gene ,Acidosis ,FBP1 ,business.industry ,lcsh:R ,Metabolic acidosis ,General Medicine ,medicine.disease ,hypoglycemia ,Lactic acidosis ,Speech delay ,fbpase ,fructose-1 ,medicine.symptom ,business - Abstract
Objectives: To draw attention towards fructose-1,6-bisphosphatase (FBPase) deficiency as an important cause of hypoglycemia and lactic acidosis and to implement preventive strategies. Methods: This observational, cross-sectional study was conducted on 7 Saudi patients with genetically confirmed FBPase deficiency from 2008 to 2018 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. Results: Participants ranged in age from 1-10 years, and all presented with recurrent hypoglycemia. All but one had associated severe metabolic acidosis, and 3 patients (42.9%) presented with hypoglycemia and severe acidosis since birth. The mean duration from presentation to diagnosis was 39.4 months, as other diagnoses, like glycogen storage diseases and mitochondrial diseases needed to be ruled out. Development was normal apart from speech delay in one patient with a novel variant of the FBP1 gene. All patients have homozygous variants in the FBP1 gene. Conclusion: Fructose-1,6-bisphosphatase is an important cause of hypoglycemia and acidosis; therefore, it is important to offer early molecular diagnostics in any child presenting with these symptoms. Molecular diagnostics should always be undertaken to confirm the diagnosis and for further preventive strategies. Saudi Med J 2020; Vol. 41 (2): 199-202 doi: 10.15537/smj.2020.2.24885 How to cite this article: Rihab M. Salih, Esraa A. Mohammed, Amal M. Alhashem, Sarar Mohamed, Aida I. Al-Aqeel. Fructose-1,6-bisphosphatase deficiency with confirmed molecular diagnosis. An important cause of hypoglycemia in children. Saudi Med J 2020; 41: 199-202. doi: 10.15537/smj.2020.2.24885
- Published
- 2020
33. ADAMTS19-associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype
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Suliman Khan, Aida M. Bertoli-Avella, Atia Sheereen, Iman Almohammed, Ingrid M.E. Frohn-Mulder, Peter Bauer, Salam Massadeh, Ingrid M.B.H. van de Laar, Farah Chaikhouni, Amal Alhashem, Manal Alaamery, Fahad Alhabshan, Mohamed S. Kabbani, Bader Alghamdi, Natalia Ordonez, Salem Alawbathani, Marja W. Wessels, Christian Beetz, Salim Ahmad, Clinical Genetics, and Pediatrics
- Subjects
Heart Defects, Congenital ,Heart Septal Defects, Ventricular ,Male ,0301 basic medicine ,medicine.medical_specialty ,Heart Ventricles ,Heart Valve Diseases ,030105 genetics & heredity ,Heart Septal Defects, Atrial ,03 medical and health sciences ,ADAMTS Proteins ,Internal medicine ,medicine.artery ,Ascending aorta ,Genetics ,Discrete Subaortic Stenosis ,Humans ,Medicine ,Heart valve ,Child ,Aorta ,Genetics (clinical) ,Exome sequencing ,Atrioventricular valve ,business.industry ,Genetic Variation ,medicine.disease ,Heart Valves ,Stenosis ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Child, Preschool ,Aortic valve stenosis ,Pulmonary valve ,cardiovascular system ,Cardiology ,Female ,business - Abstract
Recently, ADAMTS19 was identified as a novel causative gene for autosomal recessive heart valve disease (HVD), affecting mainly the aortic and pulmonary valves. Exome sequencing and data repository (CentoMD) analyses were performed to identify patients with ADAMTS19 variants (two families). A third family was recognized based on cardiac phenotypic similarities and SNP array homozygosity. Three novel loss of function (LoF) variants were identified in six patients from three families. Clinically, all patients presented anomalies of the aortic/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. Three patients had (recurrent) subaortic membrane, suggesting that ADAMTS19 is the first gene identified related to discrete subaortic stenosis. One case presented a bi-commissural pulmonary valve. All patients displayed some degree of atrioventricular valve insufficiency. Other cardiac anomalies included atrial/ventricular septal defects, persistent ductus arteriosus, and mild dilated ascending aorta. Our findings confirm that biallelic LoF variants in ADAMTS19 are causative of a specific and recognizable cardiac phenotype. We recommend considering ADAMTS19 genetic testing in all patients with multiple semilunar valve abnormalities, particularly in the presence of subaortic membrane. ADAMTS19 screening in patients with semilunar valve abnormalities is needed to estimate the frequency of the HVD related phenotype, which might be not so rare.
- Published
- 2020
34. The phenotypic spectrum of dihydrolipoamide dehydrogenase deficiency in Saudi Arabia
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Majid Alfadhel, Anar Alfarsi, Ahmed Al Fares, Faroug Ababneh, Brahim Tabarki, Fuad Al Mutairi, Seham Alameer, and Amal Alhashem
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KAIMRC, King Abdullah International Medical Research Centre ,IRB, Institutional Review Board ,medicine.medical_specialty ,Medicine (General) ,Ataxia ,MRI, Magnetic resonance imaging ,QH301-705.5 ,Population ,education ,Disease ,Hypoglycemia ,Gastroenterology ,Endocrinology ,R5-920 ,Pyruvate dehydrogenase complex ,Internal medicine ,Genetics ,Medicine ,Dihydrolipoamide dehydrogenase deficiency ,BCKDH, Branched-chain a-keto acid dehydrogenase ,Biology (General) ,BCAAs, Branched Chain Amino Acids ,Molecular Biology ,education.field_of_study ,Dihydrolipoamide dehydrogenase ,Flavoprotein and E3 ,business.industry ,Lactic acidosis ,Metabolic disorder ,DCA, Dichloroacetate ,medicine.disease ,Hypotonia ,Cohort ,PDH, Pyruvate dehydrogenase ,medicine.symptom ,αKGDH, alpha-ketoglutarate dehydrogenase ,business ,DLDD, Dihydrolipoamide Dehydrogenase Deficiency ,WES, Whole Exome Sequencing ,Research Paper - Abstract
Background Dihydrolipoamide dehydrogenase deficiency (DLDD) is a rare metabolic disorder inherited in an autosomal recessive manner. This heterogeneous disease has a variable clinical presentation, onset, and biochemical markers. Materials and methods We retrospectively reviewed the clinical and molecular diagnosis of eight cases with DLDD from four referral centers in Saudi Arabia. Results Remarkably, we found hepatic involvement ranging from acute hepatic failure to chronic hepatitis in five patients. In addition, neurological disorders in the form of seizures, developmental delay, ataxia, hypotonia and psychomotor symptoms were found in five patients, two of them with a combination of hepatic and neurological symptoms. In addition, only one patient had recurrent episodes of hypoglycemia. While most patients had the hepatic form of homozygous variant c.685G > T in the DLD gene, one patient was found to have a novel variant c.623C > T that had neurological and hepatic symptoms. Conclusions We describe the largest reported DLDD cohort in the Saudi population. Clinical, biochemical, radiological, and molecular characterization was reviewed and no clear genotype-phenotype correlation was found in this cohort.
- Published
- 2021
35. Author response for 'Molecular autopsy by proxy in preconception counseling'
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Esra Alghamdi, Fowzan S. Alkuraya, Malak Ali Alghamdi, Hanan E. Shamseldin, Nouran Adly, Majid Alfadhel, Ameinah Alrasheedi, Amal Alhashem, Wajeih Y. AlAali, and Abdulaziz Alshahrani
- Subjects
medicine.medical_specialty ,business.industry ,Family medicine ,Molecular autopsy ,Medicine ,business ,Proxy (statistics) - Published
- 2021
36. Molecular autopsy by proxy in preconception counseling
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Nouran Adly, Ameinah Alrasheedi, Fowzan S. Alkuraya, Malak Alghamdi, Abdulaziz Alshahrani, Wajeih Y. AlAali, Amal Alhashem, Hanan E. Shamseldin, Esra Alghamdi, and Majid Alfadhel
- Subjects
Genetic Markers ,Male ,Pediatrics ,medicine.medical_specialty ,Offspring ,Genetic counseling ,Saudi Arabia ,Genetic Counseling ,Disease ,Consanguinity ,Polymerase Chain Reaction ,Pregnancy ,Exome Sequencing ,Genetics ,Medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Genetics (clinical) ,Exome sequencing ,Genetic Association Studies ,Genetic testing ,Cause of death ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Phenotype ,Molecular Diagnostic Techniques ,Female ,Autopsy ,Preconception Care ,business ,Nucleic Acid Amplification Techniques - Abstract
Monogenic diseases that result in early pregnancy loss or neonatal death are genetically and phenotypically highly variable. This often poses significant challenges in arriving at a molecular diagnosis for reproductive planning. Molecular autopsy by proxy (MABP) refers to the genetic testing of relatives of deceased individuals to deduce the cause of death. Here, we specifically tested couples who lost one or more children/pregnancies with no available DNA. We developed our testing strategy using whole exome sequencing data from 83 consanguineous Saudi couples. We detected the shared carrier state of 50 pathogenic variants/likely pathogenic variants in 43 families and of 28 variants of uncertain significance in 24 families. Negative results were seen in 16 couples after variant reclassification. In 10 families, the risk of more than one genetic disease was documented. Secondary findings were seen in 10 families: either genetic variants with potential clinical consequences for the tested individual or a female carrier for X-linked conditions. This couple-based approach has enabled molecularly informed genetic counseling for 52% (43/83 families). Given the predominance of autosomal recessive causes of pregnancy and child death in consanguineous populations, MABP can be a helpful approach to consanguineous couples who seek counseling but lack molecular data on their deceased offspring.
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- 2021
37. Further clinical and genetic evidence of ASC-1 complex dysfunction in congenital neuromuscular disease
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Anett Marais, Aida M. Bertoli-Avella, Christian Beetz, Umut Altunoglu, Amal Alhashem, Sarar Mohamed, Abdulaziz Alghamdi, Patrick Willems, Eirini Tsoutsou, Helena Fryssira, Roser Pons, Reem Almarzooq, Elif Yüksel Karatoprak, Akif Ayaz, Gökçen Ünverengil, Maria Calvo, Zafer Yüksel, and Peter Bauer
- Subjects
ASC-1 ,Myopathy ,Homozygote ,General Medicine ,Nervous System Malformations ,Fractures, Bone ,TRIP4 ,Phenotype ,Muscular Diseases ,Spinal Muscular Atrophy ,Transcriptional Coregulator ,Mutation ,Exome Sequencing ,Genetics ,Humans ,Carrier Proteins ,Genetics (clinical) ,ASCC1 ,Transcription Factors - Abstract
Transcriptional coregulators modulate the efficiency of transcription factors. Bi-allelic variants in TRIP4 and ASCC1, two genes that encode members of the tetrameric coregulator ASC-1, have recently been associated with congenital bone fractures, hypotonia, and muscular dystrophy in a total of 22 unrelated families. Upon exome sequencing and data repository mining, we identified six new patients with pathogenic homozygous variants in either TRIP4 (n = 4, two novel variants) or ASCC1 (n = 2, one novel variant). The associated clinical findings confirm and extend previous descriptions. Considering all patients reported to date, we provide supporting evidence suggesting that ASCC1-related disease has a more severe phenotype compared to TRIP4-related disorder regarding higher incidence of perinatal bone fractures and shorter survival. Prince Abdullah Ben Khalid Celiac Disease Research Chair King Saud University
- Published
- 2021
38. Mutations in phospholipase C eta-1 ( PLCH1 ) are associated with holoprosencephaly
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Kalthoum Tlili-Graiess, Hayley J. Sharpe, Susan Lindsay, Emily V. Fletcher, Geoff Woods, Amal Alhashem, Katherine Schon, Ranad Shaheen, Michael S. Nahorski, Ichrak Drissi, Sarah F. Smithson, Fowzan S. Alkuraya, Steve Lisgo, Alberto Fernández-Jaén, Drissi, Ichrak [0000-0002-8077-2101], Lisgo, Steve [0000-0001-5186-3971], Fernández-Jaén, Alberto [0000-0003-3306-9832], Alkuraya, Fowzan S [0000-0003-4158-341X], Woods, Geoff [0000-0002-8077-2101], and Apollo - University of Cambridge Repository
- Subjects
Cerebellum ,Immunocytochemistry ,cerebellar diseases ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Holoprosencephaly ,medicine ,Animals ,Humans ,Hedgehog Proteins ,genetics ,Sonic hedgehog ,Neurogenetics ,Genetics (clinical) ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Mammals ,Genetics ,0303 health sciences ,Mutation ,biology ,congenital ,Embryo ,Cyclopia ,medicine.disease ,Phenotype ,medicine.anatomical_structure ,Type C Phospholipases ,biology.protein ,and neonatal diseases and abnormalities ,mutation ,hereditary ,030217 neurology & neurosurgery - Abstract
Funder: NIHR Cambridge Biomedical Research centre, Background: Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities. Methods: We describe two families in which offspring had holoprosencephaly spectrum and homozygous predicted-deleterious variants in phospholipase C eta-1 (PLCH1). Immunocytochemistry was used to examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of developmental stage and of early embryonic anatomy. Results: In the first family, two siblings had congenital hydrocephalus, significant developmental delay and a monoventricle or fused thalami with a homozygous PLCH1 c.2065C>T, p.(Arg689*) variant. In the second family, two siblings had alobar holoprosencephaly and cyclopia with a homozygous PLCH1 c.4235delA, p.(Cys1079ValfsTer16) variant. All parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the subcellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome, all tissues producing or responding to SHH. Furthermore, the embryonic subcellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mislocalisation contributing to the pathogenicity of the p.(Cys1079ValfsTer16) variant. Conclusion: Our data support the contention that PLCH1 has a role in prenatal mammalian neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly spectrum phenotype.
- Published
- 2021
39. A de novo splicing variant supports the candidacy of TLL1 in ASD pathogenesis
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Fatema Alzahrani, Talal AlAnzi, Khalid Dagriri, Amal Alhashem, and Fowzan S. Alkuraya
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Nodal Protein ,Tolloid-Like Metalloproteinases ,RNA Splicing ,Population ,Septum secundum ,Brief Communication ,Heart Septal Defects, Atrial ,Pathogenesis ,03 medical and health sciences ,symbols.namesake ,Genetics ,Humans ,Medicine ,education ,Genetics (clinical) ,0303 health sciences ,education.field_of_study ,business.industry ,030305 genetics & heredity ,Infant ,Phenotype ,Great arteries ,Mutation ,RNA splicing ,Mendelian inheritance ,symbols ,Multifactorial Inheritance ,Female ,business ,Gene Deletion - Abstract
Congenital heart disease (CHD) is the most common type of birth defects with family- and population-based studies supporting a strong hereditary component. Multifactorial inheritance is the rule although a growing number of Mendelian forms have been described including candidates that have yet to be confirmed independently. TLL1 is one such candidate that was proposed in the etiology of atrial septal defect (ASD). We describe a girl with congenitally corrected transposition of the great arteries (ccTGA) and ASD secundum whose whole-exome sequencing (WES) revealed a de novo splicing (c.1379-2A>G) variant in TLL1 as well as an inherited truncating variant in NODAL. The identification of this dual molecular diagnosis both supports the candidacy of TLL1 in ASD pathogenesis and highlights the power of WES in revealing multilocus cardiac phenotypes.
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- 2019
40. Patterns, prevalence, risk factors, and survival of newborns with congenital heart defects in a Saudi population: a three-year, cohort case-control study
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Merna Atiyah, Ester Garne, Ahmed M. Kurdi, Maha S. Rakaf, Amal Alhashem, Muhammad A. Majeed-Saidan, Mohamed Shoukri, and Amer N. Ammari
- Subjects
Pediatrics ,medicine.medical_specialty ,education.field_of_study ,lcsh:Diseases of the circulatory (Cardiovascular) system ,medicine.diagnostic_test ,Survival ,business.industry ,Population ,Case-control study ,Prenatal diagnosis ,Retrospective cohort study ,Physical examination ,Birth defects ,Congenital heart defects ,Risk factors ,lcsh:RC666-701 ,Cohort ,medicine ,Prevalence ,education ,business ,Prospective cohort study ,Body mass index - Abstract
Background Congenital heart defects (CHD) are the most common types of birth defects. The prevalence of CHD, mostly from retrospective studies, ranges between 2.1 and 10.7/1000 live births. For physicians to provide appropriate health care, it is important to know the prevalence of CHD within their patient populations. In this prospective study, we assessed the prevalence, risk factors, types, and survival of CHD among babies born to Saudi mothers over a three-year period. Methods In this prospective cohort study, all women delivered at Prince Sultan Military Medical City, Saudi Arabia over a three-year period and were recruited during their antenatal care visits or at delivery. Antenatal foetal anomaly scan, postnatal clinical examination, echocardiography, cardiac catheterization, and follow-up to 2 years of age were used to assess the patterns, prevalence, and survival of babies with CHD. A case-control study was nested within the original cohort to assess risk factors for CHD. Results Of 28,646 eligible births, 424 babies were diagnosed with CHD (14.8/1000 births), and 91 of these babies had severe CHD (3.2/1000 births). Associated non-cardiac anomalies were found in 40.1% (170 of 424) of these babies. Trisomy 21 was the most frequent chromosomal anomaly. Within the first 2 years of life, 74 of 424 babies died (17.4%). Among mothers with infants who had CHD without associated non-cardiac anomalies, risk factors for CHD included maternal age ≥ 31 years, body mass index ≥30, insulin-dependent diabetes, and an occupation of an unemployed housewife. Conclusion In the Saudi population we studied, the prevalence of CHD was higher than reported in other populations in the Middle East and in Europe. Plans to ameliorate modifiable risk factors and improve prenatal diagnosis of CHD are needed.
- Published
- 2019
41. Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis
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Flavia Palombo, Maarten Fornerod, Grazia M.S. Mancini, Joseph G. Gleeson, Lily Bazak, Esmee Kasteleijn, Natalia Ordonez-Herrera, Milena Laure-Kamionowska, Fowzan S. Alkuraya, Pawel Gawlinski, William B. Dobyns, Mariasavina Severino, Marjolein H G Dremmen, Marco Seri, Marie Claire Y. de Wit, Robert B. Hufnagel, Ghayda Mirzaa, Laura Vandervore, Rachel Schot, Maarten H. Lequin, Lina Basel-Salmon, Arndt Rolfs, Robert J. Hopkin, Ahmed Al Fares, Nicola Brunetti-Pierri, Bella Davidov, Gerarda Cappuccio, Maria Teresa Divizia, Rolf W. Stottmann, Daphne J. Smits, Aida M. Bertoli-Avella, Wojciech Wiszniewski, Damir Musaev, Valentina Stanley, Hanah Akleh, Peter Bauer, Amal Alhashem, Martina Wilke, Jeroen Demmers, Malak Al Ghamdi, Marjon van Slegtenhorst, Pasquale Striano, Mees van der Ent, Pamela Magini, Tommaso Pippucci, Marta Columbaro, Maha S. Zaki, Anna Jansen, Deema Aljeaid, Peter J. van der Spek, Noa Ruhrman Shahar, Frans W. Verheijen, Clinical Biology, Clinical sciences, Faculty of Medicine and Pharmacy, Physiotherapy, Human Physiology and Anatomy, Pediatrics, Public Health Sciences, Mental Health and Wellbeing research group, Neurogenetics, Magini, P., Smits, D. J., Vandervore, L., Schot, R., Columbaro, M., Kasteleijn, E., van der Ent, M., Palombo, Francesco, Lequin, M. H., Dremmen, M., de Wit, M. C. Y., Severino, M., Divizia, M. T., Striano, P., Ordonez-Herrera, N., Alhashem, A., Al Fares, A., Al Ghamdi, M., Rolfs, A., Bauer, P., Demmers, J., Verheijen, F. W., Wilke, M., van Slegtenhorst, M., van der Spek, P. J., Seri, M., Jansen, A. C., Stottmann, R. W., Hufnagel, R. B., Hopkin, R. J., Aljeaid, D., Wiszniewski, W., Gawlinski, P., Laure-Kamionowska, M., Alkuraya, F. S., Akleh, H., Stanley, V., Musaev, D., Gleeson, J. G., Zaki, M. S., Brunetti-Pierri, N., Cappuccio, G., Davidov, B., Basel-Salmon, L., Bazak, L., Shahar, N. R., Bertoli-Avella, A., Mirzaa, G. M., Dobyns, W. B., Pippucci, T., Fornerod, M., Mancini, G. M. S., Clinical Genetics, Clinical Chemistry, Cell biology, Radiology & Nuclear Medicine, Neurology, Biochemistry, Pathology, Magini P., Smits D.J., Vandervore L., Schot R., Columbaro M., Kasteleijn E., van der Ent M., Palombo F., Lequin M.H., Dremmen M., de Wit M.C.Y., Severino M., Divizia M.T., Striano P., Ordonez-Herrera N., Alhashem A., Al Fares A., Al Ghamdi M., Rolfs A., Bauer P., Demmers J., Verheijen F.W., Wilke M., van Slegtenhorst M., van der Spek P.J., Seri M., Jansen A.C., Stottmann R.W., Hufnagel R.B., Hopkin R.J., Aljeaid D., Wiszniewski W., Gawlinski P., Laure-Kamionowska M., Alkuraya F.S., Akleh H., Stanley V., Musaev D., Gleeson J.G., Zaki M.S., Brunetti-Pierri N., Cappuccio G., Davidov B., Basel-Salmon L., Bazak L., Shahar N.R., Bertoli-Avella A., Mirzaa G.M., Dobyns W.B., Pippucci T., Fornerod M., and Mancini G.M.S.
- Subjects
Male ,0301 basic medicine ,Microcephaly ,Ceramide ,RNA Splicing ,Mitosis ,Cell fate determination ,Biology ,Endoplasmic Reticulum ,Article ,arthrogryposis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Cell Lineage ,microcephaly ,Nuclear pore ,Child ,SMPD4 ,Genetics (clinical) ,Arthrogryposis ,arthrogryposi ,neutral-sphingomyelinase ,Gene Expression Profiling ,Autophagy ,medicine.disease ,Sphingolipid ,Pedigree ,NET13 ,Cell biology ,HEK293 Cells ,Sphingomyelin Phosphodiesterase ,030104 developmental biology ,chemistry ,Neurodevelopmental Disorders ,Female ,medicine.symptom ,Sphingomyelin ,030217 neurology & neurosurgery - Abstract
Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.
- Published
- 2019
42. FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance
- Author
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Abdulaziz Al-Saman, Mohammed Almannai, Matthew A. Lines, Amal Alhashem, Panagiotis Katsonis, Yaser I. Aljadhai, Julia Wang, Brahim Tabarki, Ayman W. El-Hattab, Mohammed A. Saleh, Adel A H Mahmoud, Ruba Benini, Dorothy K. Grange, Ali H Alwadei, Eissa Faqeih, Lee-Jun C. Wong, Hongzheng Dai, Ali Al Asmari, and Olivier Lichtarge
- Subjects
Adult ,Male ,0301 basic medicine ,Mitochondrial Diseases ,Adolescent ,Phenylalanine ,Endocrinology, Diabetes and Metabolism ,Mitochondrion ,Biology ,Biochemistry ,Amino Acyl-tRNA Synthetases ,Mitochondrial Proteins ,Structure-Activity Relationship ,Young Adult ,03 medical and health sciences ,Endocrinology ,Genetics ,Humans ,Protein Isoforms ,Missense mutation ,Child ,Molecular Biology ,Loss function ,Paraplegia ,chemistry.chemical_classification ,Evolutionary significance ,Phenotype ,Mitochondria ,Amino acid ,030104 developmental biology ,chemistry ,Child, Preschool ,Mutation ,Transfer RNA ,Female ,Phenylalanine-tRNA Ligase ,Trans-acting ,Gene Deletion - Abstract
An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.
- Published
- 2018
43. Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish
- Author
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Sheng-Jia Lin, Barbara Vona, Patricia G. Barbalho, Rauan Kaiyrzhanov, Reza Maroofian, Cassidy Petree, Mariasavina Severino, Valentina Stanley, Pratishtha Varshney, Paulina Bahena, Fatema Alzahrani, Amal Alhashem, Alistair T. Pagnamenta, Gudrun Aubertin, Juvianee I. Estrada-Veras, Héctor Adrián Díaz Hernández, Neda Mazaheri, Andrea Oza, Jenny Thies, Deborah L. Renaud, Sanmati Dugad, Jennifer McEvoy, Tipu Sultan, Lynn S. Pais, Brahim Tabarki, Daniel Villalobos-Ramirez, Aboulfazl Rad, J.C. Ambrose, P. Arumugam, M. Bleda, F. Boardman-Pretty, C.R. Boustred, H. Brittain, M.J. Caulfield, G.C. Chan, T. Fowler, A. Giess, A. Hamblin, S. Henderson, T.J.P. Hubbard, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, P. O‘Donovan, C.A. Odhams, C. Patch, D. Perez-Gil, M.B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, S.C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, E.R.A. Thomas, S.R. Thompson, A. Tucci, E. Walsh, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, Hamid Galehdari, Farah Ashrafzadeh, Afsaneh Sahebzamani, Kolsoum Saeidi, Erin Torti, Houda Z. Elloumi, Sara Mora, Timothy B. Palculict, Hui Yang, Jonathan D. Wren, null Ben Fowler, Manali Joshi, Martine Behra, Shawn M. Burgess, Swapan K. Nath, Michael G. Hanna, Margaret Kenna, J. Lawrence Merritt, Henry Houlden, Ehsan Ghayoor Karimiani, Maha S. Zaki, Thomas Haaf, Fowzan S. Alkuraya, Joseph G. Gleeson, and Gaurav K. Varshney
- Subjects
Genetics ,Lysine-tRNA Ligase ,biology ,Disease ,biology.organism_classification ,medicine.disease ,Phenotype ,Human genetics ,Disease Models, Animal ,Neurodevelopmental Disorders ,medicine ,Missense mutation ,Autism ,Animals ,Humans ,Allele ,Hearing Loss ,Zebrafish ,Genetics (clinical) ,Gene knockout ,Alleles - Abstract
Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo. Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish. We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1−/− knockouts. Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.
- Published
- 2021
44. Hypospadias in ring X syndrome
- Author
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Ayesh Almazyad, Abdullah Al Jasser, Amal Alhashem, Omar Alsuhaibani, Ahmed Alfares, Khowla Alfayez, Inesse Ben Abdallah, Hatem Elghezal, and Nasser Almobadel
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Male ,Ring chromosome ,Pseudoautosomal region ,Chromosome Disorders ,Biology ,Short stature ,Short Stature Homeobox Protein ,Gene Duplication ,Turner syndrome ,Gene duplication ,Genetics ,medicine ,Humans ,Ring Chromosomes ,Genetics (clinical) ,X chromosome ,Chromosomes, Human, X ,Hypospadias ,Karyotype ,General Medicine ,Syndrome ,medicine.disease ,Child, Preschool ,Microcephaly ,medicine.symptom ,Gene Deletion - Abstract
Ring X is a chromosomal anomaly mainly seen in females with turner syndrome and usually present in mosaic form with 45,X cells (45,X/46,X,r(X)) because of their mitotic instability. In males it is an extremely rare finding because large nullisomy for X chromosome material is likely not compatible with survival. Only two cases of male with ring chromosome X were previously reported. We report here a four-year-old male with ring chromosome X characterized using Karyotype, FISH and array CGH and presenting short stature, microcephaly and hypospadias. Molecular investigations showed 923 Kb terminal deletion on the pseudoautosomal region 1 (PAR1) including SHOX gene followed by a duplication of 2.4 Mb. The absence of functional nullisomy because of a second copy of deleted genes was present in chromosome Y PAR1 region may explain the compatibility with survival in our case of male with ring X. Short stature common with the two previously reported cases is likely related to SHOX gene deletion but also to the effect of “ring syndrome”. However, hypospadias was not reported in the previous cases and can be due to the associated duplication outside PAR1 region including in particular PRKX gene coding for a protein involved in urogenital system morphogenesis.
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- 2020
45. Survey of disorders of sex development in a large cohort of patients with diverse Mendelian phenotypes
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Dalia Abualsaud, Amal Alhashem, Mais Hashem, and Fowzan S. Alkuraya
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Male ,Disorders of Sex Development ,Biology ,Cohort Studies ,Dysgenesis ,symbols.namesake ,Human Phenotype Ontology ,Databases, Genetic ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Disorders of sex development ,Child ,Gene ,Genetics (clinical) ,Sex reversal ,Mendelian Randomization Analysis ,medicine.disease ,Phenotype ,Cohort ,Mendelian inheritance ,symbols ,Female - Abstract
Disorders of sex development (DSD) are congenital conditions with atypical development of chromosomal, gonadal, or anatomical sex. The estimated incidence ranges from 1 in 4,500-5,500 for strictly defined "ambiguous genitalia" to 1 in 300 or higher when a broader definition is implemented. In this study, we aim to define DSD phenotypes encountered in a large heterogeneous cohort of molecularly characterized Mendelian disorders in a single center. Data were retrieved for patients with documented abnormal genitalia based on the 2006 consensus criteria. Out of 149 patients (129 families) with compatible human phenotype ontology, 76 patients (68 families) had an identified genetic cause and were included in our analysis. Potentially causal variants were identified in 42 genes, and two patients had a dual molecular diagnosis. Six genes have no associated phenotype in OMIM (PIANP, CELSR2, USP2, FAM179B, TXNDC15, and CCDC96). Thirteen genes have non-DSD OMIM phenotypes, thus we are expanding their phenotype to include DSD. We also highlight how certain disorders are under-recognized despite their established DSD phenotype in OMIM, especially CTU2-related DREAM-PL syndrome and TSPYL1-related sudden infant death with dysgenesis of the testes syndrome. In conclusion, this study of a large heterogeneous Mendelian cohort expands the list of genes and disorders beyond those classically DSD-linked.
- Published
- 2020
46. Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics
- Author
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Badr Alsaleem, Rana Helaby, Hanan E. Shamseldin, Nisha Patel, Sami Wali, Hamoud Alhebbi, Firdous Abdulwahab, Nour Ewida, Eman Alobeid, Xin Gao, Dorota Monies, Amal Alhashem, Sateesh Maddirevula, Ramzan Umarov, Maha Alqahtani, Afaf Alsagheir, Fowzan S. Alkuraya, Hiroyuki Kuwahara, Nadine Hanna, Maha AlAli, Niema Ibrahim, Fatema Alzahrani, Nada Derar, Hessa S. Alsaif, Mona M. Alenazi, Tarfa Al-Sheddi, Mais Hashem, and Hatoon Al Ali
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lcsh:QH426-470 ,In silico ,Saudi Arabia ,Mendelian ,Biology ,DNA sequencing ,Cohort Studies ,Transcriptome ,03 medical and health sciences ,symbols.namesake ,Exome Sequencing ,Humans ,Computer Simulation ,Genetic Testing ,Negative WES ,Transcriptomics ,lcsh:QH301-705.5 ,030304 developmental biology ,Genetics ,0303 health sciences ,Models, Genetic ,Sequence Analysis, RNA ,Research ,030305 genetics & heredity ,Genetic Diseases, Inborn ,RNA ,Phenotype ,Penetrance ,Human genetics ,lcsh:Genetics ,Mapping ,lcsh:Biology (General) ,RNA-based diagnostics ,Mendelian inheritance ,symbols - Abstract
Background At least 50% of patients with suspected Mendelian disorders remain undiagnosed after whole-exome sequencing (WES), and the extent to which non-coding variants that are not captured by WES contribute to this fraction is unclear. Whole transcriptome sequencing is a promising supplement to WES, although empirical data on the contribution of RNA analysis to the diagnosis of Mendelian diseases on a large scale are scarce. Results Here, we describe our experience with transcript-deleterious variants (TDVs) based on a cohort of 5647 families with suspected Mendelian diseases. We first interrogate all families for which the respective Mendelian phenotype could be mapped to a single locus to obtain an unbiased estimate of the contribution of TDVs at 18.9%. We examine the entire cohort and find that TDVs account for 15% of all “solved” cases. We compare the results of RT-PCR to in silico prediction. Definitive results from RT-PCR are obtained from blood-derived RNA for the overwhelming majority of variants (84.1%), and only a small minority (2.6%) fail analysis on all available RNA sources (blood-, skin fibroblast-, and urine renal epithelial cells-derived), which has important implications for the clinical application of RNA-seq. We also show that RNA analysis can establish the diagnosis in 13.5% of 155 patients who had received “negative” clinical WES reports. Finally, our data suggest a role for TDVs in modulating penetrance even in otherwise highly penetrant Mendelian disorders. Conclusions Our results provide much needed empirical data for the impending implementation of diagnostic RNA-seq in conjunction with genome sequencing.
- Published
- 2020
47. An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia
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Raghu R. Chivukula, Waleed Ameen, Talal AlAnzi, Adel S. Alharbi, Khaled Baqais, Afaf Saghier, Mansour Alqwaiee, Hanan E. Shamseldin, Niema Ibrahim, Mais Hashem, Firdous Abdulwahab, Amal Alhashem, Fowzan S. Alkuraya, Ibrahim Al Mogarri, Muslim M. Alsaadi, and Jason H. Yang
- Subjects
Male ,animal structures ,Ubiquitin-Protein Ligases ,Saudi Arabia ,Gene Expression ,Respiratory Mucosa ,Biology ,Bioinformatics ,Autoantigens ,03 medical and health sciences ,Consanguinity ,Exome Sequencing ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Cilia ,Sinusitis ,Exome ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology ,Primary ciliary dyskinesia ,Phenocopy ,0303 health sciences ,Respiratory Distress Syndrome, Newborn ,Cilium ,030305 genetics & heredity ,Golgi Matrix Proteins ,Nuclear Proteins ,Pneumonia ,medicine.disease ,Phenotype ,Human genetics ,Pedigree ,DNA-Binding Proteins ,Repressor Proteins ,Mutation ,Motile cilium ,Microtubule Proteins ,Female ,Ciliary Motility Disorders ,Transcription Factors - Abstract
Unlike disorders of primary cilium, primary ciliary dyskinesia (PCD) has a much narrower clinical spectrum consistent with the limited tissue distribution of motile cilia. Nonetheless, PCD diagnosis can be challenging due to the overlapping features with other disorders and the requirement for sophisticated tests that are only available in specialized centers. We performed exome sequencing on all patients with a clinical suspicion of PCD but for whom no nasal nitric oxide test or ciliary functional assessment could be ordered. Among 81 patients (56 families), in whom PCD was suspected, 68% had pathogenic or likely pathogenic variants in established PCD-related genes that fully explain the phenotype (20 variants in 11 genes). The major clinical presentations were sinopulmonary infections (SPI) (n = 58), neonatal respiratory distress (NRD) (n = 2), laterality defect (LD) (n = 6), and combined LD/SPI (n = 15). Biallelic likely deleterious variants were also encountered in AKNA and GOLGA3, which we propose as novel candidates in a lung phenotype that overlaps clinically with PCD. We also encountered a PCD phenocopy caused by a pathogenic variant in ITCH, and a pathogenic variant in CEP164 causing Bardet–Biedl syndrome and PCD presentation as a very rare example of the dual presentation of these two disorders of the primary and motile cilia. Exome sequencing is a powerful tool that can help “democratize” the diagnosis of PCD, which is currently limited to highly specialized centers.
- Published
- 2019
48. Genetic variants in components of the NALCN–UNC80–UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies)
- Author
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Peter Bauer, Nuria C. Bramswig, Hartmut Engels, Abdelrahim Abdrabou Sadek, Hasnaa M. Elbendary, Beate Albrecht, Lara Segebrecht, Joseph G. Gleeson, Boris Keren, Diane Doummar, Arndt Rolfs, Jennifer McEvoy-Venneri, Nicole Philip, Christel Depienne, Thomas Wieland, Samira Ismail, Laurent Villard, Tim M. Strom, Michèle Mayer, Aida M. Bertoli-Avella, Maha S. Zaki, Svetlana Gorokhova, Alma Kuechler, Dagmar Wieczorek, Caroline Nava, Nathalie Dorison, André Mégarbané, Amal Alhashem, Stéphanie Valence, Cyril Mignot, Delphine Héron, Valentina Stanley, Isabelle Marey, Nadja Ehmke, Nouriya Al-Sannaa, Hermann-Josef Lüdecke, Sarar Mohamed, Denise Horn, Camille Trautman, Kiely N. James, Katharina Bröhl, Cecile Ravix, Aida I. Al Aqeel, Maissa Bah, Mahmoud Y. Issa, Institut für Humangenetik [Essen], Universitätsklinikum Essen, Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neuropédiatrie [Trousseau], Centre de Génétique Moléculaire et Chromosomique du GH Pitié-Salpêtrière, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Service de génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de biochimie et de génétique moléculaire [CHU Cochin], CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Pitié-Salpêtrière [APHP], Unité Fonctionnelle de Génétique Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Centre de Référence des Déficiences Intellectuelles de Causes Rares, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Albrecht-Kossel-Institut fur Neuroregeneration, Universität Rostock, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Institute of Human Genetics, Helmholtz-Zentrum München (HZM)-Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Rheinische Friedrich-Wilhelms-Universität Bonn, Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Laboratory of Neurogenetics, Howard Hughes Medical Institute, Department of Neurosciences, University of California [San Diego] (UC San Diego), University of California-University of California, Universität Duisburg-Essen [Essen], Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Helmholtz Zentrum München = German Research Center for Environmental Health-Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, University of California (UC)-University of California (UC), and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
- Subjects
Adult ,Genetic Markers ,Male ,0301 basic medicine ,Adolescent ,Developmental Disabilities ,[SDV]Life Sciences [q-bio] ,Medizin ,Disease ,Biology ,Ion Channels ,Sodium Channels ,Article ,Young Adult ,03 medical and health sciences ,Ion channel complex ,Genetic variation ,Genetics ,medicine ,Humans ,Missense mutation ,Child ,ComputingMilieux_MISCELLANEOUS ,Genetics (clinical) ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Psychomotor retardation ,Infant, Newborn ,Genetic Variation ,Infant ,Membrane Proteins ,Phenotype ,Hypotonia ,Human genetics ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Child, Preschool ,Channelopathies ,Female ,medicine.symptom ,Carrier Proteins - Abstract
NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.
- Published
- 2018
49. The morbid genome of ciliopathies: an update
- Author
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Maha Tulba, Amal Alhashem, Ali Howaidi, Tarfa Alshidi, Sawsan R. Nowilaty, Abdullah Alfaifi, Mais Hashem, Mohammad Shagrani, Mustafa A. Salih, Rubina Khan, Dalal K. Bubshait, Maged H. Hussein, Essam Al Sabban, Maisoon Almugbel, Ranad Shaheen, Hisham Alkuraya, Nour Ewida, Mohammad A. Al Muhaizea, Eman Alobeid, Zuhair Rahbeeni, Jameel M. Alghamdi, Niema Ibrahim, Yasser Sabr, Sameera Sogaty, Elham Al-Mardawi, Neama Meriki, Khalid Alhazmi, Mona M. Alenazi, Mohammed Zain Seidahmed, Heba Morsy, Ebtesam M. Abdalla, Mohammed Mahnashi, Abrar K. Alsalamah, Fowzan S. Alkuraya, Ahmed Alfares, Hamad Al-Zaidan, Afaf Alsagheir, Alya Qari, Firdous Abdulwahab, Hanan E. Shamseldin, and Mohammed Al–Owain
- Subjects
Candidate gene ,Cilium ,Computational biology ,Biology ,medicine.disease ,Genome ,Phenotype ,Ciliopathies ,Human genetics ,Sodium Channels ,Stargardt disease ,medicine ,Humans ,Cilia ,Gene ,Bardet-Biedl Syndrome ,Genetics (clinical) ,Alleles - Abstract
Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly. Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes. In this study, we describe 125 families with ciliopathies and show that deleterious variants in previously reported genes, including cryptic splicing variants, account for 87% of cases. Additionally, we further support a number of previously reported candidate genes (BBIP1, MAPKBP1, PDE6D, and WDPCP), and propose nine novel candidate genes (CCDC67, CCDC96, CCDC172, CEP295, FAM166B, LRRC34, TMEM17, TTC6, and TTC23), three of which (LRRC34, TTC6, and TTC23) are supported by functional assays that we performed on available patient-derived fibroblasts. From a phenotypic perspective, we expand the phenomenon of allelism that characterizes ciliopathies by describing novel associations including WDR19-related Stargardt disease and SCLT1- and CEP164-related Bardet–Biedl syndrome. In this cohort of phenotypically and molecularly characterized ciliopathies, we draw important lessons that inform the clinical management and the diagnostics of this class of disorders as well as their basic biology.
- Published
- 2019
50. Recurrent Homozygous Damaging Mutation in TMX2, Encoding a Protein Disulfide Isomerase, in Four Families with Microlissencephaly
- Author
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Xiaoxu Yang, Martin W. Breuss, Samia A. Temtamy, Joshua D. Green, Matloob Azam, Bryan J. Traynor, Laila Bastaki, Danica Ross, Lu Wang, Laila Selim, Hanan I Elbastawisy, Amal Alhashem, Shereen G. Ghosh, Valentina Stanley, Joseph G. Gleeson, and Maha S. Zaki
- Subjects
0301 basic medicine ,Male ,Microcephaly ,Protein Folding ,Endoplasmic Reticulum ,Medical and Health Sciences ,Exon ,Consanguinity ,0302 clinical medicine ,Thioredoxins ,2.1 Biological and endogenous factors ,Aetiology ,Protein disulfide-isomerase ,Child ,Genetics (clinical) ,Exome sequencing ,Pediatric ,Genetics & Heredity ,Genetics ,Homozygote ,Exons ,Biological Sciences ,protein disulfide isomerase ,Child, Preschool ,Neurological ,Female ,ER stress ,Intellectual and Developmental Disabilities (IDD) ,Protein Disulfide-Isomerases ,Biology ,Article ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,Exome Sequencing ,medicine ,Humans ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Allele ,Preschool ,TMX2 ,Human Genome ,Neurosciences ,Membrane Proteins ,thioredoxin ,Protein superfamily ,medicine.disease ,Brain Disorders ,030104 developmental biology ,Mutation ,Unfolded protein response ,Congenital Structural Anomalies ,microlissencephaly ,Trinucleotide repeat expansion ,030217 neurology & neurosurgery - Abstract
BackgroundProtein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways.MethodsEight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis.ResultsAn identical homozygous variant in TMX2 (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While TMX2 is an activator of cellular C9ORF72 repeat expansion toxicity, patients showed no evidence of C9ORF72 repeat expansions.ConclusionThe TMX2 c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of C9ORF72 expansions. TMX2 is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.
- Published
- 2019
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