Publications by authors named "Eissa Faqeih"

107 Publications

Succinyl-CoA:3-oxoacid coenzyme A transferase (SCOT) deficiency: A rare and potentially fatal metabolic disease.

Biochimie 2021 Feb 14. Epub 2021 Feb 14.

Research Group Inborn Errors of Metabolism, Department of Natural Sciences & Institute for Functional Gene Analytics (IFGA), Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany. Electronic address:

Succinyl-CoA:3-oxoacid coenzyme A transferase deficiency (SCOTD) is a rare autosomal recessive disorder of ketone body utilization caused by mutations in OXCT1. We performed a systematic literature search and evaluated clinical, biochemical and genetic data on 34 previously published and 10 novel patients with SCOTD. Structural mapping and in silico analysis of protein variants is also presented. All patients presented with severe ketoacidotic episodes. Age at first symptoms ranged from 36 h to 3 years (median 7 months). About 70% of patients manifested in the first year of life, approximately one quarter already within the neonatal period. Two patients died, while the remainder (95%) were alive at the time of the report. Almost all the surviving patients (92%) showed normal psychomotor development and no neurologic abnormalities. A total of 29 missense mutations are reported. Analysis of the published crystal structure of the human SCOT enzyme, paired with both sequence-based and structure-based methods to predict variant pathogenicity, provides insight into the biochemical consequences of the reported variants. Pathogenic variants cluster in SCOT protein regions that affect certain structures of the protein. The described pathogenic variants can be viewed in an interactive map of the SCOT protein at https://michelanglo.sgc.ox.ac.uk/r/oxct. This comprehensive data analysis provides a systematic overview of all cases of SCOTD published to date. Although SCOTD is a rather benign disorder with often favourable outcome, metabolic crises can be life-threatening or even fatal. As the diagnosis can only be made by enzyme studies or mutation analyses, SCOTD may be underdiagnosed.
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http://dx.doi.org/10.1016/j.biochi.2021.02.003DOI Listing
February 2021

Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG.

J Inherit Metab Dis 2021 Feb 13. Epub 2021 Feb 13.

Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.

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 GlcNAc 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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http://dx.doi.org/10.1002/jimd.12367DOI Listing
February 2021

Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease.

J Hum Genet 2021 Jan 27. Epub 2021 Jan 27.

Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.

Heterozygous pathogenic variants in SLC12A2 are reported in patients with nonsyndromic hearing loss. Recently, homozygous loss-of-function variants have been reported in two patients with syndromic intellectual disability, with or without hearing loss. However, the clinical and molecular spectrum of SLC12A2 disease has yet to be characterized and confirmed. Using whole-exome sequencing, we detected a homozygous splicing variant in four patients from two independent families with severe developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with or without congenital hearing loss. We also reviewed the reported cases with pathogenic variants associated with autosomal dominant and recessive forms of the SLC12A2 disease. About 50% of the cases have syndromic and nonsyndromic congenital hearing loss. All patients harboring the recessive forms of the disease presented with severe global developmental delay. Interestingly, all reported variants are located in the c-terminal domain, suggesting a critical role of this domain for the proper function of the encoded co-transporter protein. In conclusion, our study provides an additional confirmation of the autosomal recessive SLC12A2 disease.
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http://dx.doi.org/10.1038/s10038-021-00904-2DOI Listing
January 2021

Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update.

Front Genet 2020 31;11:580484. Epub 2020 Dec 31.

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

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 (, and ) 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 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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http://dx.doi.org/10.3389/fgene.2020.580484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806527PMC
December 2020

NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease.

Nat Commun 2020 09 15;11(1):4625. Epub 2020 Sep 15.

The Jackson Laboratory, Bar Harbor, ME, USA.

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway-Ribosome-associated Quality Control (RQC)-by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF's role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.
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http://dx.doi.org/10.1038/s41467-020-18327-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494853PMC
September 2020

Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.

Circ Genom Precis Med 2020 Oct 1;13(5):504-514. Epub 2020 Sep 1.

Heart Failure & Transplant Program, Prince Sultan Cardiac Center (A. Alwadai).

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 ().

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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http://dx.doi.org/10.1161/CIRCGEN.120.002969DOI Listing
October 2020

Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort.

Genet Med 2020 Dec 3;22(12):2071-2080. Epub 2020 Aug 3.

Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.

Purpose: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD.

Methods: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia.

Results: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively.

Conclusion: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.
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http://dx.doi.org/10.1038/s41436-020-0919-xDOI Listing
December 2020

DALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine tRNAs for 3-methylcytosine modification.

Nat Commun 2020 05 19;11(1):2510. Epub 2020 May 19.

Department of Biology, Center for RNA Biology, University of Rochester, Rochester, NY, USA.

In mammals, a subset of arginine tRNA isoacceptors are methylated in the anticodon loop by the METTL2 methyltransferase to form the 3-methylcytosine (m3C) modification. However, the mechanism by which METTL2 identifies specific tRNA arginine species for m3C formation as well as the biological role of m3C in mammals is unknown. Here, we show that human METTL2 forms a complex with DALR anticodon binding domain containing 3 (DALRD3) protein to recognize particular arginine tRNAs destined for m3C modification. DALRD3-deficient human cells exhibit nearly complete loss of the m3C modification in tRNA-Arg species. Notably, we identify a homozygous nonsense mutation in the DALRD3 gene that impairs m3C formation in human patients exhibiting developmental delay and early-onset epileptic encephalopathy. These findings uncover an unexpected function for the DALRD3 protein in the targeting of distinct arginine tRNAs for m3C modification and suggest a crucial biological role for DALRD3-dependent tRNA modification in proper neurological development.
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http://dx.doi.org/10.1038/s41467-020-16321-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237682PMC
May 2020

Metabolic Acidosis and Hypoglycemia in a Child with Leigh-Like Phenotype.

Clin Chem 2020 05;66(5):739-741

Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.

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http://dx.doi.org/10.1093/clinchem/hvaa079DOI Listing
May 2020

Further delineation of METTL23-associated intellectual disability.

Am J Med Genet A 2020 04 18;182(4):785-791. Epub 2020 Feb 18.

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

METTL23 belongs to a family of methyltransferase like proteins (METTL) that transfer methyl group to various substrates. Recently, pathogenic homozygous variants in METTL23 were identified in patients from three families who presented with intellectual disability (ID) and variable dysmorphic features. In this report, we present unpublished phenotypic data from the original family as well as six new subjects from four families who also presented with mild to moderate ID and dysmorphic features, and were found to harbor four previously unpublished homozygous or compound heterozygous variants in METTL23. Our report further supports the role of this gene in autosomal recessive ID and emphasizes the mild but consistent facial features.
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http://dx.doi.org/10.1002/ajmg.a.61503DOI Listing
April 2020

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.

Nat Commun 2020 01 30;11(1):595. Epub 2020 Jan 30.

Institute of Medical Biology, A*STAR, Biopolis, Singapore, 138648, Singapore.

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.
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http://dx.doi.org/10.1038/s41467-020-14360-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992768PMC
January 2020

Streamlining and cycle time reduction of the startup phase of clinical trials.

Trials 2020 Jan 29;21(1):115. Epub 2020 Jan 29.

Research Center, King Fahad Medical City, P.O Box 59046, Riyadh, 11525, Saudi Arabia.

Objective: The startup phase of a clinical trial (CT) plays a vital role in the execution of new drug development. Hence, the aim of this study is to identify the factors responsible for delaying the CT startup phase. Further, it focuses on streamlining and reducing the cycle time of the startup phase of newly sponsored CTs.

Methods: Thirteen sponsored CTs conducted between 2016 and 2017 at the Clinical Research Department of King Fahad Medical City, Riyadh, Saudi Arabia, were considered for this study. Eight trials were analyzed to identify the data specific to startup metrics using the FOCUS-PDCA cycle (Find an improvement area-Organize a team-Clarify current practices-Understand the source of variation/problem-Select a Strategy-Plan-Do-Check-Act). Six measures incorporated in the metrics were (1) date of initial contact with site to the signing of confidentiality agreement, (2) date of receiving questionnaire from sponsor to date of its completion, (4) time taken to review protocol and approve investigational drug service form, and (5) time taken to study protocol and approve pharmacy and pathology and clinical laboratory medicine form and date of receipt of institutional review board (IRB) submission package to final IRB approval. Fishbone analysis was used to understand the potential causes of process variation. Mean (SD) time was calculated for each metric before and after implementation of the intervention protocol to analyze and compare percentage reduction in the mean cycle time of CTs. Data were represented as mean (SD), and the P value was calculated for each metric. The significance level was set at P < 0.05.

Results: Of the various potential factors of delay identified through fishbone analysis, the two major ones were lack of a well-defined timeline for approval and review of the study protocol and inconsistent IRB meetings. After introduction of the new intervention protocol, the entire CT life cycle was reduced by 45.6% (mean [SD], 24.8 [8.2] weeks vs. 13.5 [11.6] weeks before and after the intervention, respectively).

Conclusion: Various factors are responsible for the delay of the startup phase of CTs, and understanding the impact of each element allows for optimization and faster execution of the startup phase of CTs.
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http://dx.doi.org/10.1186/s13063-020-4079-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988200PMC
January 2020

Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction.

Am J Hum Genet 2019 12 27;105(6):1237-1253. Epub 2019 Nov 27.

Centre Hospitalier Universitaire Saint-Justine Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada. Electronic address:

We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.
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http://dx.doi.org/10.1016/j.ajhg.2019.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904826PMC
December 2019

Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature.

Am J Hum Genet 2019 11 10;105(5):907-920. Epub 2019 Oct 10.

Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland. Electronic address:

We report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotonia in which homozygous non-synonymous variants were identified in IQSEC1 (GenBank: NM_001134382.3). In a Pakistani family, the IQSEC1 segregating variant is c.1028C>T (p.Thr343Met), while in a Saudi Arabian family the variant is c.962G>A (p.Arg321Gln). IQSEC1-3 encode guanine nucleotide exchange factors for the small GTPase ARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptor trafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth cone guidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1 cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1 cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2 instar larvae by moderate expression of the human reference cDNA. However, the p.Arg321Gln and p.Thr343Met variants failed to rescue embryonic lethality. These data indicate that the variants behave as loss-of-function mutations. We also show that schizo in photoreceptors is required for phototransduction. Finally, mice with a conditional Iqsec1 deletion in cortical neurons exhibited an increased density of dendritic spines with an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1 variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidance and dendritic projection defects as well as dendritic spine dysgenesis may underlie disease pathogenesis.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848997PMC
November 2019

Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.

Hepatology 2020 Jun 20;71(6):2067-2079. Epub 2020 Feb 20.

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

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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http://dx.doi.org/10.1002/hep.30982DOI Listing
June 2020

Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies.

Genome Med 2019 06 17;11(1):38. Epub 2019 Jun 17.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test.

Methods: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors.

Results: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%).

Conclusion: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.
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http://dx.doi.org/10.1186/s13073-019-0649-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572765PMC
June 2019

Evaluation of long-term effectiveness of the use of carglumic acid in patients with propionic acidemia (PA) or methylmalonic acidemia (MMA): study protocol for a randomized controlled trial.

BMC Pediatr 2019 06 13;19(1):195. Epub 2019 Jun 13.

Genetics Division, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), PO Box 22490 11426, Riyadh, Saudi Arabia.

Introduction: Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive inborn errors of metabolism characterized by hyperammonemia due to N-acetylglutamate synthase (NAGS) dysfunction. Carglumic acid (Carbaglu®; Orphan Europe Ltd.) is approved by the US Food and Drug Administration (USFDA) for the treatment of hyperammonemia due hepatic NAGS deficiency. Here we report the rationale and design of a phase IIIb trial that is aimed at determining the long-term efficacy and safety of carglumic acid in the management of PA and MMA.

Methods: This prospective, multicenter, open-label, randomized, parallel group phase IIIb study will be conducted in Saudi Arabia. Patients with PA or MMA (≤15 years of age) will be randomized 1:1 to receive twice daily carglumic acid (50 mg/kg/day) plus standard therapy (protein-restricted diet, L-carnitine, and metronidazole) or standard therapy alone for a 2-year treatment period. The primary efficacy outcome is the number of emergency room visits due to hyperammonemia. Safety will be assessed throughout the study and during the 1 month follow-up period after the study.

Discussion: Current guidelines recommend conservative medical treatment as the main strategy for the management of PA and MMA. Although retrospective studies have suggested that long-term carglumic acid may be beneficial in the management of PA and MMA, current literature lacks evidence for this indication. This clinical trial will determine the long-term safety and efficacy of carglumic acid in the management of PA and MMA.

Trial Registration: King Abdullah International Medical Research Center ( KAIMRC ): (RC13/116) 09/1/2014. Saudi Food and Drug Authority (SFDA) (33066) 08/14/2014. ClinicalTrials.gov (identifier: NCT02426775) 04/22/2015.
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http://dx.doi.org/10.1186/s12887-019-1571-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563377PMC
June 2019

6-Pyruvoyltetrahydropterin Synthase Deficiency: Review and Report of 28 Arab Subjects.

Pediatr Neurol 2019 07 18;96:40-47. Epub 2019 Feb 18.

Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. Electronic address:

Background: Tetrahydrobiopterin is an essential cofactor for the hydroxylation of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Therefore, tetrahydrobiopterin deficiency results in hyperphenylalaninemia as well as dopamine and serotonin depletion in the central nervous system. The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the second step of de novo synthesis of tetrahydrobiopterin, and its deficiency is the most frequent cause of tetrahydrobiopterin metabolism disorders.

Method: We conducted a retrospective chart review of 28 subjects from 24 families with molecularly confirmed 6-pyruvoyltetrahydropterin synthase deficiency from six centers in three Arab countries. We reviewed clinical, biochemical, and molecular data. We also reviewed previously published cohorts of subjects with 6-pyruvoyltetrahydropterin synthase deficiency.

Results: Similar to previous observations, we show that early treatment (less than two months) is associated with better outcome. We identify eight PTS variants in 24 independent families. The most common variant is (c.238A>G; p.M80V) with an allele count of 33%. We also identify one novel variant (c.2T>G; p.?).

Conclusion: The deficiency of 6-pyruvoyltetrahydropterin synthase is relatively common in the Arab population and should be considered in individuals with hyperphenylalaninemia. More natural history studies with comprehensive biochemical and molecular genetics data are needed for a robust base for the development of future therapy.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.02.008DOI Listing
July 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

The many faces of peroxisomal disorders: Lessons from a large Arab cohort.

Clin Genet 2019 02 18;95(2):310-319. Epub 2018 Dec 18.

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

Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.
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http://dx.doi.org/10.1111/cge.13481DOI Listing
February 2019

Genomic and phenotypic delineation of congenital microcephaly.

Genet Med 2019 03 14;21(3):545-552. Epub 2018 Sep 14.

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

Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM.

Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis.

Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1.

Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.
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http://dx.doi.org/10.1038/s41436-018-0140-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986385PMC
March 2019

FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance.

Mol Genet Metab 2018 11 29;125(3):281-291. Epub 2018 Jul 29.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ymgme.2018.07.014DOI Listing
November 2018

Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration.

Nat Genet 2018 08 16;50(8):1093-1101. Epub 2018 Jul 16.

Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.

Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between β-catenin and Arp2/3 actin filament activities. Loss of αN-catenin did not affect β-catenin signaling, but recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.
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http://dx.doi.org/10.1038/s41588-018-0166-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072555PMC
August 2018

Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.

Am J Hum Genet 2018 05;102(5):858-873

Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in vitro in affected individuals' fibroblasts and skeletal muscle and in vivo in zebrafish. The clinical presentation was severe, early-onset, progressive SMA-like motor neuronopathy, cerebellar atrophy, and in one affected individual, congenital fractures of the long bones. Three affected individuals of different ethnicity carried the homozygous c.41T>C (p.Leu14Pro) variant, whereas one affected individual was compound heterozygous for c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161). We detected reduced EXOSC9 in fibroblasts and skeletal muscle and observed a reduction of the whole multi-subunit exosome complex on blue-native polyacrylamide gel electrophoresis. RNA sequencing of fibroblasts and skeletal muscle detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration, demonstrating the widespread effect of the variants. Morpholino oligonucleotide knockdown and CRISPR/Cas9-mediated mutagenesis of exosc9 in zebrafish recapitulated aspects of the human phenotype, as they have in other zebrafish models of exosomal disease. Specifically, portions of the cerebellum and hindbrain were absent, and motor neurons failed to develop and migrate properly. In summary, we show that variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies.
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http://dx.doi.org/10.1016/j.ajhg.2018.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986733PMC
May 2018

Expanding the phenome and variome of skeletal dysplasia.

Genet Med 2018 12 5;20(12):1609-1616. Epub 2018 Apr 5.

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

Purpose: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized.

Methods: Detailed phenotyping and next-generation sequencing (panel and exome).

Results: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average.

Conclusion: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.
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http://dx.doi.org/10.1038/gim.2018.50DOI Listing
December 2018

Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome.

Am J Hum Genet 2018 04 29;102(4):696-705. Epub 2018 Mar 29.

Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA; Center for Individualized Medicine, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address:

AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1 mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers-Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.
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http://dx.doi.org/10.1016/j.ajhg.2018.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985336PMC
April 2018

Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation.

Am J Hum Genet 2018 01;102(1):188-195

Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address:

Fucosyltransferase 8 (FUT8) encodes a Golgi-localized α1,6 fucosyltransferase that is essential for transferring the monosaccharide fucose into N-linked glycoproteins, a process known as "core fucosylation." Here we describe three unrelated individuals, who presented with intrauterine growth retardation, severe developmental and growth delays with shortened limbs, neurological impairments, and respiratory complications. Each underwent whole-exome sequencing and was found to carry pathogenic variants in FUT8. The first individual (consanguineous family) was homozygous for c.715C>T (p.Arg239), while the second (non-consanguineous family) was compound heterozygous for c.1009C>G (p.Arg337Gly) and a splice site variant c.1259+5G>T. The third individual (consanguineous family) was homozygous for a c.943C>T (p.Arg315). Splicing analysis confirmed the c.1259+5G>T resulted in expression of an abnormal FUT8 transcript lacking exon 9. Functional studies using primary fibroblasts from two affected individuals revealed a complete lack of FUT8 protein expression that ultimately resulted in substantial deficiencies in total core fucosylated N-glycans. Furthermore, serum samples from all three individuals showed a complete loss of core fucosylation. Here, we show that loss of function mutations in FUT8 cause a congenital disorder of glycosylation (FUT8-CDG) characterized by defective core fucosylation that phenotypically parallels some aspects of the Fut8 knockout mouse. Importantly, identification of additional affected individuals can be easily achieved through analysis of core fucosylation of N-glycans.
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http://dx.doi.org/10.1016/j.ajhg.2017.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777984PMC
January 2018