Publications by authors named "Mais O Hashem"

7 Publications

  • Page 1 of 1

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

An intellectual disability-associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity.

Hum Mutat 2020 03 16;41(3):600-607. Epub 2020 Jan 16.

Department of Biology, Center for RNA Biology, University of Rochester, Rochester, New York.

The human TRMT1 gene encodes an RNA methyltransferase enzyme responsible for catalyzing dimethylguanosine (m2,2G) formation in transfer RNAs (tRNAs). Frameshift mutations in TRMT1 have been shown to cause autosomal-recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Here, we describe a homozygous TRMT1 missense variant in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes an arginine residue to a cysteine (R323C) within the methyltransferase domain and is expected to perturb protein folding. Patient cells expressing TRMT1-R323C exhibit a deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss of function. Notably, the TRMT1 R323C mutant retains tRNA binding but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that perturbs tRNA modification activity and demonstrate that m2,2G modifications are disrupted in the cells of patients with TRMT1-associated ID disorders.
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http://dx.doi.org/10.1002/humu.23976DOI Listing
March 2020

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Am J Hum Genet 2019 08 27;105(2):384-394. Epub 2019 Jun 27.

Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698938PMC
August 2019

De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome.

Am J Hum Genet 2019 03 28;104(3):542-552. Epub 2019 Feb 28.

King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia. Electronic address:

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.
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http://dx.doi.org/10.1016/j.ajhg.2019.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407605PMC
March 2019

Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities.

Am J Med Genet A 2018 03 31;176(3):715-721. Epub 2018 Jan 31.

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

Temtamy syndrome is a syndromic form of intellectual disability characterized by ocular involvement, epilepsy and dysgenesis of the corpus callosum. After we initially mapped the disease to C12orf57, we noted a high carrier frequency of an ancient startloss founder mutation [c.1A>G; p.M1?] in our population, and variable phenotypic expressivity in newly identified cases. This study aims to combine 33 previously published patients with 23 who are described here for the first time to further delineate the phenotype of this syndrome. In addition to the known p.M1? founder, we describe four novel homozygous variants, thus increasing the number of Temtamy syndrome-related C12orf57 variants to seven, all but one predicted to be loss of function. While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable: 73.2% (41/56) had epilepsy, 63% (34/54) had corpus callosal abnormalities, 14.5% (8/55) had coloboma, and 16.4% (9/55) had microphthalmia. Our analysis also revealed a high frequency of less recognized features such as congenital heart disease (51.4%), and brain white matter abnormalities (38%, 19/50). We conclude that C12orf57 variants should be considered in the etiology of developmental delay/intellectual disability, even when typical syndromic features are lacking, especially in those who trace their ancestry to Saudi Arabia where a founder C12orf57 mutation is among the most common recessive causes of intellectual disability.
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http://dx.doi.org/10.1002/ajmg.a.38615DOI Listing
March 2018

The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population.

Genet Med 2015 Sep 11;17(9):719-25. Epub 2014 Dec 11.

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

Purpose: Molecular karyotyping has rapidly become the test of choice in patients with neurocognitive phenotypes, but studies of its clinical utility have largely been limited to outbred populations. In consanguineous populations, single-gene recessive causes of neurocognitive phenotypes are expected to account for a relatively high percentage of cases, thus diminishing the yield of molecular karyotyping. The aim of this study was to test the clinical yield of molecular karyotyping in the highly consanguineous population of Saudi Arabia.

Methods: We have reviewed the data of 584 patients with neurocognitive phenotypes (mainly referred from pediatric neurology clinics), all evaluated by a single clinical geneticist.

Results: At least 21% of tested cases had chromosomal aberrations that are likely disease-causing. These changes include both known and novel deletion syndromes. The higher yield of molecular karyotyping in this study as compared with the commonly cited 11% can be explained by our ability to efficiently identify single-gene disorders, thus enriching the samples that underwent molecular karyotyping for de novo chromosomal aberrations. We show that we were able to identify a causal mutation in 37% of cases on a clinical basis with the help of autozygome analysis, thus bypassing the need for molecular karyotyping.

Conclusion: Our study confirms the clinical utility of molecular karyotyping even in highly consanguineous populations.
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http://dx.doi.org/10.1038/gim.2014.184DOI Listing
September 2015