Publications by authors named "Mohamed H Al-Hamed"

14 Publications

  • Page 1 of 1

Novel pathogenic variant in a family with nephronophthisis.

Clin Kidney J 2021 Feb 24;14(2):728-730. Epub 2020 Jun 24.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1093/ckj/sfaa090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886576PMC
February 2021

Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans.

Am J Hum Genet 2020 12 25;107(6):1178-1185. Epub 2020 Nov 25.

Deparment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Deparment of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address:

We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820624PMC
December 2020

Fetal Anomalies Associated with Novel Pathogenic Variants in TMEM94.

Genes (Basel) 2020 08 20;11(9). Epub 2020 Aug 20.

Genetics Department, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.

Background: Intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF, MIM 618316) is a newly described disorder. It is characterized by global developmental delay, intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Biallelic pathogenic variants of are associated with IDDCDF.

Methods And Results: In a prenatal setting, where fetal abnormalities were detected using antenatal sonography, we used trio-exome sequencing (trio-ES) in conjunction with chromosomal microarray analysis (CMA) to identify two novel homozygous loss of function variants in the gene (c.606dupG and c.2729-2A>G) in two unrelated Saudi Arabian families.

Conclusions: This study provides confirmation that variants may cause IDDCDF. For the first time we describe the pathogenicity of defects detected during the prenatal period.
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http://dx.doi.org/10.3390/genes11090967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565137PMC
August 2020

Novel loss of function variants in FRAS1 AND FREM2 underlie renal agenesis in consanguineous families.

J Nephrol 2020 Jul 8. Epub 2020 Jul 8.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh, Saudi Arabia.

Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) are a group of abnormalities that affect structure of the kidneys or other structures of the urinary tract. The majority of CAKUT are asymptomatic and are diagnosed prenatally by ultrasound scanning or found incidentally in postnatal life. CAKUT varies in severity and may lead to life-threatening kidney failure and end-stage kidney disease. Renal agenesis, a severe form of CAKUT, is a congenital absence of one or both kidneys. Bilateral renal agenesis belongs to a group of prenatally lethal renal diseases and is often detected on fetal ultrasound scanning during the investigation of oligohydramnios. Approximately 40% of fetuses with bilateral renal agenesis are stillborn or die a few hours postnatally. Mutations in many renal development genes have been shown to be associated with renal agenesis.

Methods: Six consanguineous Saudi Arabian families were recruited to study the molecular genetic causes of recurrent miscarriages and lost fetuses due to oligohydramnios, renal agenesis and other congenital anomalies. Whole exome sequencing was employed to underlying detect genetic defects.

Results: Novel loss of function variants were detected in FRAS1 and FREM2. In FRAS1, a homozygous splice site variant c.9780+2T>C was found in an affected fetus, segregating form each parent. In addition, in three other families both parents were heterozygous for a frameshift variant (c.8981dupT; p.His2995Profs*3) and splice site variants (c.5217+1G>C and c.8098+2T>A), respectively. In FREM2, a homozygous nonsense variant (c.2303C>G; p.Ser768*) was found in an affected fetus, segregating from both parents. In another family, both parents carried a FREM2 heterozygous frameshift variant (c.3969delC; p.Asn1323Lysfs*5).

Conclusion: We describe consanguineous families with clinical features of antenatal oligohydramnios and bilateral renal agenesis, in whom we have identified novel pathogenic variants in FRAS1 and FREM2. These finding highlights the association between mutations in FRAS1 and FREM2 and antenatal/perinatal death.
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http://dx.doi.org/10.1007/s40620-020-00795-0DOI Listing
July 2020

Bialleleic PKD1 mutations underlie early-onset autosomal dominant polycystic kidney disease in Saudi Arabian families.

Pediatr Nephrol 2019 09 11;34(9):1615-1623. Epub 2019 May 11.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh, 11211, Saudi Arabia.

Background: Polycystic kidney disease (PKD) is one of the most common genetic renal diseases and may be inherited in an autosomal dominant or autosomal recessive pattern. Pathogenic variants in two major genes, PKD1 and PKD2, and two rarer genes, GANAB and DNAJB11, cause autosomal dominant PKD (ADPKD). Early onset and severe PKD can occur with PKD1 and PKD2 pathogenic variants and such phenotypes may be modified by second alleles inherited in trans. Homozygous or compound heterozygous hypomorphic PKD1 variants may also cause a moderate to severe disease PKD phenotype.

Methods: Targeted renal gene panel followed by Sanger sequencing of PKD1 gene were employed to investigate molecular causes in early onset PKD patients.

Results: In this study, we report four consanguineous Saudi Arabian families with early onset PKD which were associated with biallelic variants in PKD1 gene.

Conclusions: Our findings confirm that PKD1 alleles may combine to produce severe paediatric onset PKD mimicking the more severe autosomal recessive ciliopathy syndromes associated with PKD. Screening of parents of such children may also reveal subclinical PKD phenotypes.
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http://dx.doi.org/10.1007/s00467-019-04267-xDOI Listing
September 2019

Spectrum of mutations underlying Propionic acidemia and further insight into a genotype-phenotype correlation for the common mutation in Saudi Arabia.

Mol Genet Metab Rep 2019 Mar 9;18:22-29. Epub 2019 Jan 9.

Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh 11211, Saudi Arabia.

Propionic acidemia (PA) is an autosomal recessive metabolic disorder. PA is characterized by deficiency of the mitochondrial enzyme propionyl CoA carboxylase (PCC) that results in the accumulation of propionic acid. Alpha and beta subunits of the PCC enzyme are encoded by the and genes, respectively. Pathogenic variants in or disrupt the function of the PCC enzyme preventing the proper breakdown of certain amino acids and metabolites. To determine the frequency of pathogenic variants in PA in our population, 84 Saudi Arabian patients affected with PA were sequenced for both the and genes. We found that variants in accounted for 81% of our cohort (68 patients), while variants in only accounted for 19% (16 patients). In total, sixteen different sequence variants were detected in the study, where 7 were found in and 9 in . The pathogenic variant (c.425G > A; p.Gly142Asp) in is the most common cause of PA in our cohort and was found in 59 families (70.2%), followed by the frameshift variant (c.990dupT; p.E331Xfs*1) in that was found in 7 families (8.3%). The p.Gly142Asp missense variant is likely to be a founder pathogenic variant in patients of Saudi Arabian tribal origin and is associated with a severe phenotype. All variants were inherited in a homozygous state except for one family who was compound heterozygous. A total of 11 novel pathogenic variants were detected in this study thereby increasing the known spectrum of pathogenic variants in the and genes.
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http://dx.doi.org/10.1016/j.ymgmr.2018.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349011PMC
March 2019

Twenty novel mutations in , and genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease.

Mol Genet Metab Rep 2017 Jun 7;11:17-23. Epub 2017 Apr 7.

Department of Medical Genetics, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia.

Maple syrup urine disease (MSUD), an autosomal recessive inborn error of metabolism due to defects in the branched-chain α-ketoacid dehydrogenase (BCKD) complex, is commonly observed among other inherited metabolic disorders in the kingdom of Saudi Arabia. This report presents the results of mutation analysis of three of the four genes encoding the BCKD complex in 52 biochemically diagnosed MSUD patients originating from Saudi Arabia. The 25 mutations (20 novel) detected spanned across the entire coding regions of the , and genes. There were no mutations found in the gene in this cohort of patients. Prediction effects, conservation and modelling of novel mutations demonstrated that all were predicted to be disease-causing. All mutations presented in a homozygous form and we did not detect the presence of a "founder" mutation in any of three genes. In addition, prenatal molecular genetic testing was successfully carried out on chorionic villus samples or amniocenteses in 10 expectant mothers with affected children with MSUD, molecularly characterized by this study.
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http://dx.doi.org/10.1016/j.ymgmr.2017.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388912PMC
June 2017

Renal tubular dysgenesis: antenatal ultrasound scanning and molecular investigations in a Saudi Arabian family.

Clin Kidney J 2016 Dec 1;9(6):807-810. Epub 2016 Jul 1.

Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle, UK.

Autosomal recessive renal tubular dysgenesis (RTD) is a rare lethal disease affecting renal development before birth. RTD is manifested by anuria and severe hypotension resulting in oligohydramnios and birth defects known as Potter's syndrome. Homozygous or compound heterozygous mutations in genes encoding components of the renin-angiotensin system (, , and ) have been reported to cause RTD. A consanguineous family with a history of multiple stillbirths was investigated using prenatal ultrasound and molecular genetic analysis of an affected foetus. Prenatal ultrasound scan suggested RTD, and a novel homozygous frameshift mutation c.299_300delAA (p.Lys100Serfs*4) in the gene was identified by whole-exome sequencing, which segregated with parental DNA samples. RTD remains a rare but important cause of prenatal and perinatal death and may present with antenatally hyperechogenic kidneys.
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http://dx.doi.org/10.1093/ckj/sfw057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162405PMC
December 2016

Phenotypic comparison of individuals with homozygous or heterozygous mutation of NOTCH3 in a large CADASIL family.

J Neurol Sci 2016 Aug 1;367:239-43. Epub 2016 Jun 1.

Division of Neurology, Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. Electronic address:

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy caused by mutations in NOTCH3, very rarely homoallelic.

Objective: To describe the clinical, radiological, and neuropsychological features in an extended CADASIL family including members with either a homozygous or heterozygous NOTCH3 R1231C mutation.

Methods: The pedigree included 3 generations of a family with 13 affected individuals. The patients were examined clinically and radiologically. Neuropsychological testing was performed on the proband. Sequencing of the entire coding DNA sequence (CDS) and flanking regions of NOTCH3 was undertaken using PCR amplification and direct Sanger sequencing.

Results: Homozygous C3769T mutation, predicting R1231C in exon 22 of NOTCH3 was found in 7 family members. Six other family members harbored the same in the heterozygous state. Homozygous individuals showed a slightly more severe clinical and radiological phenotype of earlier onset compared to their heterozygous counterparts.

Conclusion: This study reports the largest number of patients with homozygous NOTCH3 mutation. The phenotype and imaging features of homozygous individuals is within the spectrum of CADASIL, although slightly at the severe end when compared to heterozygotes carrying the same mutation. Both genetic modifiers and environmental factors may play an essential role in modification and alteration of the clinical phenotype and white matter changes among CADASIL patients.
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http://dx.doi.org/10.1016/j.jns.2016.05.061DOI Listing
August 2016

Genetic spectrum of Saudi Arabian patients with antenatal cystic kidney disease and ciliopathy phenotypes using a targeted renal gene panel.

J Med Genet 2016 05 9;53(5):338-47. Epub 2016 Feb 9.

Genetics Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Background: Inherited cystic kidney disorders are a common cause of end-stage renal disease. Over 50 ciliopathy genes, which encode proteins that influence the structure and function of the primary cilia, are implicated in cystic kidney disease.

Methods: To define the phenotype and genotype of cystic kidney disease in fetuses and neonates, we correlated antenatal ultrasound examination and postnatal renal ultrasound examination with targeted exon sequencing, using a renal gene panel. A cohort of 44 families in whom antenatal renal ultrasound scanning findings in affected cases included bilateral cystic kidney disease, echogenic kidneys or enlarged kidneys was investigated.

Results: In this cohort, disease phenotypes were severe with 36 cases of stillbirth or perinatal death. Extra renal malformations, including encephalocele, polydactyly and heart malformations, consistent with ciliopathy phenotypes, were frequently detected. Renal gene panel testing identified causative mutations in 21 out of 34 families (62%), where patient and parental DNA was available. In the remaining 10 families, where only parental DNA was available, 7 inferred causative mutations were found. Together, mutations were found in 12 different genes with a total of 13 novel pathogenic variants, including an inferred novel variant in NEK8. Mutations in CC2D2A were the most common cause of an antenatal cystic kidney disease and a suspected ciliopathy in our cohort.

Conclusions: In families with ciliopathy phenotypes, mutational analysis using a targeted renal gene panel allows a rapid molecular diagnosis and provides important information for patients, parents and their physicians.
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http://dx.doi.org/10.1136/jmedgenet-2015-103469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853542PMC
May 2016

Molecular characterization of novel splice site mutation causing protein C deficiency.

Blood Coagul Fibrinolysis 2016 Jul;27(5):585-8

aSaudi Diagnostics Laboratory (SDL), Genetics Department, King Faisal Specialist Hospital and Research Centre bPediatric Hematology Division, Pediatrics Department, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.

Congenital protein C deficiency is an inherited coagulation disorder associated with an elevated risk of venous thromboembolism. A Saudi Arabian male from a consanguineous family was admitted to neonatal intensive care unit in his first days of life because of transient tachypnea and hematuria. Laboratory investigations determined low platelet and protein C deficiency. Direct sequencing of PROC gene and RNA analysis were performed. Analysis of factor V Leiden (G1691A) and factor II (G20210A) mutations was also done. Novel homozygous splice site mutation c.796+3A>T was detected in the index case and segregation was confirmed in the family. RNA analysis revealed the pathogenicity of the mutation by skipping exon 8 of PROC gene and changing the donor splice site of the exon. Detection of the molecular cause of protein C deficiency reduces life threatening and facilitates inductive carrier testing, prenatal and preimplantation genetic diagnosis for families.
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http://dx.doi.org/10.1097/MBC.0000000000000490DOI Listing
July 2016

Functional modelling of a novel mutation in BBS5.

Cilia 2014 Feb 21;3(1). Epub 2014 Feb 21.

International Centre for Life, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle NE1 3BZ, UK.

Background: Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy disorder with 18 known causative genes (BBS1-18). The primary clinical features are renal abnormalities, rod-cone dystrophy, post-axial polydactyly, learning difficulties, obesity and male hypogonadism.

Results: We describe the clinical phenotype in three Saudi siblings in whom we have identified a novel mutation in exon 12 of BBS5 (c.966dupT; p.Ala323CysfsX57). This single nucleotide duplication creates a frame shift results in a predicted elongated peptide. Translation blocking Morpholino oligonucleotides were used to create zebrafish bbs5 morphants. Morphants displayed retinal layering defects, abnormal cardiac looping and dilated, cystic pronephric ducts with reduced cilia expression. Morphants also displayed significantly reduced dextran clearance via the pronephros compared to wildtype embryos, suggesting reduced renal function in morphants. The eye, kidney and heart defects reported in morphant zebrafish resemble the human phenotype of BBS5 mutations. The pathogenicity of the novel BBS5 mutation was determined. Mutant mRNA was unable to rescue pleiotropic phenotypes of bbs5 morphant zebrafish and in cell culture we demonstrate a mislocalisation of mutant BBS5 protein which fails to localise discretely with the basal body.

Conclusions: We conclude that this novel BBS5 mutation has a deleterious function that accounts for the multisystem ciliopathy phenotype seen in affected human patients.
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http://dx.doi.org/10.1186/2046-2530-3-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931281PMC
February 2014

ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption.

J Clin Invest 2013 Dec 25;123(12):5179-89. Epub 2013 Nov 25.

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.
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http://dx.doi.org/10.1172/JCI69000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859425PMC
December 2013

A molecular genetic analysis of childhood nephrotic syndrome in a cohort of Saudi Arabian families.

J Hum Genet 2013 Jul 18;58(7):480-9. Epub 2013 Apr 18.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Nephrotic syndrome (NS) is a renal disease characterized by heavy proteinuria, hypoalbuminemia, edema and hyperlipidemia. Its presentation within the first 3 months of life or in multiple family members suggests an underlying inherited cause. To determine the frequency of inherited NS, 62 cases (representing 49 families with NS) from Saudi Arabia were screened for mutations in NPHS1, NPHS2, LAMB2, PLCE1, CD2AP, MYO1E, WT1, PTPRO and Nei endonuclease VIII-like 1 (NEIL1). We detected likely causative mutations in 25 out of 49 families studied (51%). We found that the most common genetic cause of NS in our cohort was a homozygous mutation in the NPHS2 gene, found in 11 of the 49 families (22%). Mutations in the NPHS1 and PLCE1 genes allowed a molecular genetic diagnosis in 12% and 8% of families, respectively. We detected novel MYO1E mutations in three families (6%). No mutations were found in WT1, PTPRO or NEIL1. The pathogenicity of novel variants was analyzed by in silico tests and by genetic screening of ethnically matched control populations. This is the first report describing the molecular genetics of NS in the Arabian Peninsula.
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http://dx.doi.org/10.1038/jhg.2013.27DOI Listing
July 2013