scholarly journals A missense variant impairing TRMT1 function in tRNA modification is linked to intellectual disability

2019 ◽  
Author(s):  
Kejia Zhang ◽  
Jenna M Lentini ◽  
Christopher T Prevost ◽  
Mais O Hashem ◽  
Fowzan S Alkuraya ◽  
...  
Keyword(s):  
Protein Folding ◽  
Intellectual Disability ◽  
Human Population ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Trna Modification ◽  
Loss Of Function ◽  
Severe Deficiency ◽  
Trna Methyltransferase ◽  
The Impact

AbstractThe human TRMT1 gene encodes a tRNA methyltransferase enzyme responsible for the formation of the dimethylguanosine (m2,2G) modification in cytoplasmic and mitochondrial tRNAs. Frameshift mutations in the TRMT1 gene have been shown to cause autosomal-recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Moreover, the impact of ID-associated TRMT1 mutations on m2,2G levels in ID-affected patients is unknown. Here, we describe a homozygous missense variant in TRMT1 in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes a conserved arginine residue to a cysteine (R323C) within the methyltransferase domain of TRMT1 and is expected to perturb protein folding. Patient cells expressing the TRMT1-R323C variant exhibit a severe deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss-of-function. Notably, the TRMT1 R323C mutant retains the ability to bind tRNA but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that severely perturbs tRNA modification activity, and provide the first demonstration that m2,2G modifications are disrupted in patients with TRMT1-associated ID disorders.

scholarly journals Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

2021 ◽  
pp. mcs.a006130
Author(s):  
Ryan J Patrick ◽  
Jill M Weimer ◽  
Laura Davis-Keppen ◽  
Megan L Landsverk
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Facial Features ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
The Family ◽  
Novel Variants ◽  
In Trans

Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine) and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole exome sequencing of the family identified a missense variant, c.2066G>A (p.Arg689His), in trans with a frameshift variant, c.1169_1173del (p.Ile390LysfsTer4), in CKAP2L. To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.

scholarly journals Loss of function of SVBP leads to autosomal recessive intellectual disability, microcephaly, ataxia, and hypotonia

2019 ◽  
Vol 21 (8) ◽  
pp. 1790-1796 ◽  
Author(s):  
Zafar Iqbal ◽  
Hasan Tawamie ◽  
Wei Ba ◽  
André Reis ◽  
Bassam Al Halak ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Loss Of Function

scholarly journals RSRC1 loss-of-function variants cause mild to moderate autosomal recessive intellectual disability

Brain ◽  
2020 ◽  
Vol 143 (4) ◽  
pp. e31-e31
Author(s):  
Marcello Scala ◽  
Majid Mojarrad ◽  
Saima Riazuddin ◽  
Karlla W Brigatti ◽  
Zineb Ammous ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Loss Of Function

scholarly journals Novel homozygous variant in the TPO gene associated with congenital hypothyroidism and mild-intellectual disability

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Amjad Khan ◽  
Muhammad Umair ◽  
Rania Abdulfattah Sharaf ◽  
Muhammad Ismail Khan ◽  
Amir Ullah ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Congenital Hypothyroidism ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Thyroid Peroxidase ◽  
Mild Intellectual Disability ◽  
Complex Disorder ◽  
Whole Exome ◽  
Hereditary Disorders ◽  
Autosomal Recessive Manner

AbstractCongenital hypothyroidism (CH) is one of the most common hereditary disorders affecting neonates worldwide. CH is a multifactorial complex disorder and can be caused by either environmental factors or genetic factors. We studied one Pakistani family with segregating mutations in CH inherited in an autosomal recessive manner. Using whole-exome sequencing (WES), we found a novel homozygous missense variant (c.2315A>G; p.Tyr772Cys) in the thyroid peroxidase (TPO) gene. Different bioinformatics prediction tools and Sanger sequencing were performed to verify the identified variant. Our findings highlight the importance of this gene in causing CH and mild-intellectual disability (ID) in two affected brothers. WES is a convenient and useful tool for the clinical diagnosis of CH and other associated disorders.

scholarly journals Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

2016 ◽  
Author(s):  
Ricardo Harripaul ◽  
Nasim Vasli ◽  
Anna Mikhailov ◽  
Muhammad Arshad Rafiq ◽  
Kirti Mittal ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Autosomal Recessive ◽  
De Novo ◽  
Clinical Diagnostics ◽  
High Yield ◽  
Disease Genes ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Whole Exome

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations(ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7,andUSP44),and missense mutations include the first reports of variants inBDNForTET1associated with ID. The genes identified also showed overlap withde novogene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

A novel missense variant in GPT2 causes non-syndromic autosomal recessive intellectual disability in a consanguineous Iranian family

2020 ◽  
Vol 63 (5) ◽  
pp. 103853 ◽  
Author(s):  
Sima Binaafar ◽  
Ehsan Razmara ◽  
Nejat Mahdieh ◽  
Hamidreza Sahebjame ◽  
Ali Reza Tavasoli ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Iranian Family

scholarly journals tRNA methyltransferase 10 homologue A (TRMT10A) mutation in a Chinese patient with diabetes, insulin resistance, intellectual deficiency and microcephaly

2020 ◽  
Vol 8 (1) ◽  
pp. e001601 ◽  
Author(s):  
Hu Lin ◽  
Xuelian Zhou ◽  
Xuefeng Chen ◽  
Ke Huang ◽  
Wei Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Intellectual Disability ◽  
Current Knowledge ◽  
Genetic Diagnosis ◽  
Insulin Dependent Diabetes ◽  
Homozygous Mutation ◽  
Intellectual Deficiency ◽  
Loss Of Function ◽  
Trna Methyltransferase ◽  
Insulin Dependent

IntroductionLoss-of-function mutations in tRNA methyltransferase 10 homologue A (TRMT10A), a tRNA methyltransferase, have recently been described as a monogenic cause of early-onset diabetes with microcephaly, epilepsy and intellectual disability.Research design and methodsWe report a Chinese young patient who was diagnosed with diabetes mellitus as a result of a TRMT10A mutation.ResultsA homozygous mutation c.496–1G>A in TRMT10A was identified using targeted next-generation sequencing and confirmed by PCR/Sanger sequencing. In addition to being diagnosed with diabetes, the patient also has microcephaly and intellectual deficiency. The diabetes was due to marked insulin resistance and responded very well to metformin treatment.ConclusionOur case is the first report in the Asian population. It adds to current knowledge of TRMT10A related with young-onset non-insulin-dependent diabetes and confirms the a single previous report of insulin resistance in this syndrome. Genomic testing should be considered in children with non-insulin-dependent diabetes with intellectual disability and microcephaly. A clear genetic diagnosis is helpful for early detection and treatment addressing insulin resistance.

scholarly journals Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Neil V Morgan ◽  
Bryndis Yngvadottir ◽  
Mary O’Driscoll ◽  
Graeme R Clark ◽  
Diana Walsh ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Neurological Disease ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Disease Status ◽  
Missense Variant ◽  
Spastic Cerebral Palsy ◽  
Single Family ◽  
Loss Of Function ◽  
Candidate Mutation

Abstract A subset of individuals diagnosed with cerebral palsy will have an underlying genetic diagnosis. Previously, a missense variant in GAD1 was described as a candidate mutation in a single family diagnosed with autosomal recessive spastic cerebral palsy-1 (CPSQ1; OMIM 603513). Following the ascertainment of a further branch of the CPSQ1 kindred, we found that the previously reported GAD1 variant did not segregate with the neurological disease phenotype in the recently ascertained branch of the kindred. Following genetic linkage studies to map autozygous regions and whole-exome sequencing, a missense variant (c.527 T > C; p. Leu176Pro, rs773333490) in the HPDL gene was detected and found to segregate with disease status in both branches of the kindred. HPDL encodes a 371-amino acid protein (4-Hydroxyphenylpyruvate Dioxygenase Like) that localizes to mitochondria but whose function is uncertain. Recently, biallelic loss of function variants and missense substitution-causing variants in HPDL were reported to cause a childhood onset progressive spastic movement disorder with a variable presentation. These findings suggest that HPDL-related neurological disease may mimic spastic cerebral palsy and that GAD1 should not be included in diagnostic gene panels for inherited cerebral palsy.

scholarly journals Bi-allelic variants in TSPOAP1, encoding the active zone protein RIMBP1, cause autosomal recessive dystonia

2020 ◽  
Author(s):  
Niccolò E. Mencacci ◽  
Marisa M. Brockmann ◽  
Jinye Dai ◽  
Sander Pajusalu ◽  
Burcu Atasu ◽  
...  
Keyword(s):  
Active Zone ◽  
Autosomal Recessive ◽  
Critical Role ◽  
Cerebellar Atrophy ◽  
Missense Variant ◽  
Loss Of Function ◽  
Generalized Dystonia ◽  
Motor Abnormalities ◽  
Vitro Analysis

ABSTRACTDystonia is a debilitating hyperkinetic movement disorder, frequently transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense and missense variants in TSPOAP1, encoding the active zone RIM-binding protein 1 (RIMBP1), as a novel genetic cause of autosomal recessive dystonia in seven subjects from three unrelated families. Subjects carrying loss-of-function variants presented with juvenile- onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between presynaptic RIMBP1 dysfunction and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

scholarly journals An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

2020 ◽  
Vol 41 (3) ◽  
pp. 600-607 ◽  
Author(s):  
Kejia Zhang ◽  
Jenna M. Lentini ◽  
Christopher T. Prevost ◽  
Mais O. Hashem ◽  
Fowzan S. Alkuraya ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Enzymatic Activity ◽  
Missense Variant ◽  
Trna Modification
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