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

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.

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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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Exome Sequencing Identifies a Novel Sorting Nexin 14 Gene Mutation Causing Cerebellar Atrophy and Intellectual Disability

Case Reports in Genetics ◽

10.1155/2018/6737938 ◽

2018 ◽

Vol 2018 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

Nadia Al-Hashmi ◽

Mohammed Mohammed ◽

Salim Al-Kathir ◽

Naeema Al-Yarubi ◽

Patrick Scott

Keyword(s):

Intellectual Disability ◽

Gene Mutation ◽

Autosomal Recessive ◽

Cerebellar Atrophy ◽

Facial Features ◽

Loss Of Function ◽

Sorting Nexin ◽

The Family ◽

Cerebellar Ataxias ◽

High Level

The autosomal recessive cerebellar ataxias (ARCA) affect both the central and the peripheral nervous systems. They are also characterized by a relatively high level of genetic heterogeneity with well over 40 genes already implicated. The present study aimed to identify the gene mutation responsible for a complex phenotype comprising cerebellar ataxia and intellectual disability segregating in an Omani consanguineous family. Homozygosity-guided exome data analysis identified a novel frameshift mutation (c.2319_2322del) within the sorting nexin 14 gene (SNX14), which predicts complete absence of the SNX14 encoded protein. Segregation within the family of the sequence variation is consistent with its pathogenic role. Importantly, loss-of-function mutations in SNX14 have recently been described as a cause of a clinically distinguishable recessive syndrome consisting of cerebellar atrophy, ataxia, coarsened facial features, and intellectual disability. This study expands the genetic diversity of ataxia genes in the Omani population and have important implications for the clinical and molecular diagnosis of this condition in affected individuals.

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Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

Journal of Pediatric Genetics ◽

10.1055/s-0040-1721077 ◽

2020 ◽

Author(s):

Yousef Binamer ◽

Muzamil A. Chisti

Keyword(s):

Autosomal Recessive ◽

Common Mechanism ◽

Sequencing Analysis ◽

Loss Of Function ◽

Skin Atrophy ◽

Whole Exome ◽

Infancy And Childhood ◽

Genetics And Genomics ◽

New Feature ◽

Generation Sequencing

AbstractKindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

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Faculty Opinions recommendation of Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1962956.3287063 ◽

2010 ◽

Author(s):

Klaus Klaushofer ◽

Paul Roschger ◽

Nadja Fratzl-Zelman

Keyword(s):

Autosomal Recessive ◽

Hypophosphatemic Rickets ◽

Arterial Calcification ◽

Loss Of Function ◽

Autosomal Recessive Hypophosphatemic Rickets

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Faculty Opinions recommendation of Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1962956.2013054 ◽

2010 ◽

Author(s):

Alan Yu

Keyword(s):

Autosomal Recessive ◽

Hypophosphatemic Rickets ◽

Arterial Calcification ◽

Loss Of Function ◽

Autosomal Recessive Hypophosphatemic Rickets

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Faculty Opinions recommendation of Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727772380.793535929 ◽

2017 ◽

Author(s):

Mitsuhiro Kato

Keyword(s):

Intellectual Disability ◽

Epileptic Encephalopathy ◽

Loss Of Function ◽

Gain Of Function

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Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14

Current Molecular Medicine ◽

10.2174/1566524019666190730095630 ◽

2019 ◽

Vol 19 (9) ◽

pp. 683-687 ◽

Cited By ~ 3

Author(s):

Tawfiq Froukh ◽

Ammar Hawwari

Keyword(s):

Strong Evidence ◽

Autosomal Recessive ◽

Eye Diseases ◽

Initial Reaction ◽

Genetic Contribution ◽

Loss Of Function ◽

Consanguineous Family ◽

Truncated Protein ◽

Threonine Residue ◽

Whole Exome

Background: Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical. Despite the strong evidence of genetic contribution in KC, the etiology of KC is not understood in most cases. Methods: In this study, we used whole-exome sequencing to identify the genetic cause of KC in two sibs in a consanguineous family. The Homozygous frameshift variant NM_001253826.1:c.60delC;p.Leu21Cysfs*6 was identified in the gene Nacetylgalactosaminyltransferase 14 (GALNT14). The variant does not exist in all public databases neither in our internal exome database. Moreover, no database harbours homozygous loss of function variants in the candidate gene. Result: GALNT14 catalyses the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D- galactosamine residue to a serine or threonine residue on target proteins especially Mucins. Conclusion: As alterations of mucin’s glycosylation are linked to a number of eye diseases, we demonstrate in this study an association between the truncated protein GALNT14 and KC.

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