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

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.

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

10.1101/817247 ◽

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.

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Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

Molecular Case Studies ◽

10.1101/mcs.a006130 ◽

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.

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A novel homozygous missense variant in the NAXE gene in an Iranian family with progressive encephalopathy with brain edema and leukoencephalopathy

Acta Neurologica Belgica ◽

10.1007/s13760-021-01717-y ◽

2021 ◽

Author(s):

Pouria Mohammadi ◽

Morteza Heidari ◽

Mahmoud Reza Ashrafi ◽

Nejat Mahdieh ◽

Masoud Garshasbi

Keyword(s):

Brain Edema ◽

Missense Variant ◽

Progressive Encephalopathy ◽

Iranian Family

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TBL1XR1 associated intellectual disability, a new missense variant with dysmorphic features plus autism: Expanding the phenotypic spectrum

Clinical Genetics ◽

10.1111/cge.13937 ◽

2021 ◽

Author(s):

Ignacio Arroyo Carrera ◽

Miguel Fernández‐Burriel ◽

Pablo Lapunzina ◽

Jair Antonio Tenorio ◽

Verónica Deyanira García Navas ◽

...

Keyword(s):

Intellectual Disability ◽

Missense Variant ◽

Dysmorphic Features ◽

Phenotypic Spectrum

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A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01033-4 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Giada Moresco ◽

Jole Costanza ◽

Carlo Santaniello ◽

Ornella Rondinone ◽

Federico Grilli ◽

...

Keyword(s):

Intellectual Disability ◽

Clinical Presentation ◽

De Novo ◽

Clinical Signs ◽

Missense Variant ◽

Psychomotor Development ◽

Helicase Domain ◽

Protein Activity ◽

Mrna Metabolism ◽

Pathogenic Variants

Abstract Background De novo pathogenic variants in the DDX3X gene are reported to account for 1–3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs. Case presentation We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). We identified a novel de novo missense mutation in the DDX3X gene (c.625C > G) by whole exome sequencing (WES). The DDX3X gene encodes a DEAD-box ATP-dependent RNA-helicase broadly implicated in gene expression through regulation of mRNA metabolism. The identified mutation is located just upstream the helicase domain and is suggested to impair the protein activity, thus resulting in the altered translation of DDX3X-dependent mRNAs. The proband, presenting with the typical PMG phenotype related to the syndrome, does not show other clinical signs frequently reported in presence of missense DDX3X mutations that are associated with a most severe clinical presentation. In addition, she has brachycephaly, never described in female DDX3X patients, and macroglossia, that has never been associated with the syndrome. Conclusions This case expands the knowledge of DDX3X pathogenic variants and the associated DDX3X syndrome phenotypic spectrum.

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The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature

Genes ◽

10.3390/genes12060875 ◽

2021 ◽

Vol 12 (6) ◽

pp. 875

Author(s):

Karlijn Pellikaan ◽

Geeske M. van Woerden ◽

Lotte Kleinendorst ◽

Anna G. W. Rosenberg ◽

Bernhard Horsthemke ◽

...

Keyword(s):

Intellectual Disability ◽

Single Nucleotide Polymorphism Array ◽

Genetic Defect ◽

Missense Variant ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Pituitary Hormone ◽

Negative Effect

Prader–Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader–Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C>T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the ‘Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations’ (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype–phenotype relationship in PWS.

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