Exome Sequencing Reveals Novel <i>TTN</i> Variants in Saudi Patients with Congenital Titinopathies

Salih, Mustafa A.; Hamad, Muddathir H.; Savarese, Marco; Alorainy, Ibrahim A.; Al-Jarallah, Abdullah S.; Alkhalidi, Hisham; AlQudairy, Hanan; Albader, Anoud; Alotaibi, Amal Jahz; Alsagob, Maysoon; Al-Bakheet, Albandary; Çolak, Dilek; Udd, Bjarne; Kaya, Namik

doi:10.1089/gtmb.2021.0085

Cited by 4 publications

(5 citation statements)

References 27 publications

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“…Using this, we calculated the recombination rates to calculate a predicted age for the variant. The calculation was performed using published protocols [1,19,32]. This analysis predicted that the variant could To investigate the potential consequence of the missense variant on protein expression, we performed immunoblotting experiments using the index patient's (F1-II-2) fibroblasts.…”

Section: Genetic and Molecular Results Evaluationsmentioning

confidence: 99%

Section: Genetic and Molecular Results Evaluationsmentioning

confidence: 99%

“…Variant filtering and pathogenicity analyses were evaluated according to standard protocols and up-to-date pipelines applied at the King Faisal Specialist Hospital and Research Center as published before [18][19][20]. Briefly, the variants were filtered using different features such as minor allele frequency (MAF, being <1% in control databases), being in known disease-causing genes, protein loss of function, pathogenic or likely pathogenic according to ACMG (American College of Medical Genetics and Genomics) guidelines [21], and homozygosity.…”

Section: Variant Analysis and Bioinformatics Analysismentioning

confidence: 99%

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A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

Aldosary

Alsagob

AlQudairy

et al. 2022

Cells

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The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G<T, p.Val159Phe) in the gene. Clinically affected individuals presented with intellectual disability, encephalopathy, ataxia, optic atrophy, and seizures. Based on whole exome sequencing and confirmatory Sanger sequencing, the variant was fully segregated with the phenotype in the families, absent among large ethnically matching controls as well as numerous in-house exomes, and predicted to be pathogenic by different in silico classifiers. Structural modeling and immunoblot analyses strongly indicated this variant to be pathogenic. Since the families belong to one of the tribal inhabitants of Saudi Arabia, we postulate that the variant is likely to be a founder. We provide the estimated age of the variant and present data confirming the disease-causality of this founder variant.

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Section: Genetic and Molecular Results Evaluationsmentioning

confidence: 99%

Section: Genetic and Molecular Results Evaluationsmentioning

confidence: 99%

Section: Variant Analysis and Bioinformatics Analysismentioning

confidence: 99%

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A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

Aldosary

Alsagob

AlQudairy

et al. 2022

Cells

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“…Biallelic mutations, mainly TTNtv with few non‐truncating variants, cause skeletal muscle diseases with or without a cardiac involvement 5,12–19 . The increasing number of patients diagnosed with a recessive titinopathies is facilitating the delineation of genotype–phenotype correlations 20,21 .…”

Section: Introductionmentioning

confidence: 99%

“…10,11 Biallelic mutations, mainly TTNtv with few non-truncating variants, cause skeletal muscle diseases with or without a cardiac involvement. 5,[12][13][14][15][16][17][18][19] The increasing number of patients diagnosed with a recessive titinopathies is facilitating the delineation of genotypephenotype correlations. 20,21 Finally, non-truncating variants in two specific exons (344 and 364) cause distinct, well-characterized, phenotypes (HMERF and TMD/LGMD2, respectively).…”

Section: Introductionmentioning

confidence: 99%

Use of animal models to understand titin physiology and pathology

Marcello

Cetrangolo

Savarese

et al. 2022

J Cellular Molecular Medi

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In recent years, increasing attention has been paid to titin ( TTN ) and its mutations. Heterozygous TTN truncating variants (TTNtv) increase the risk of a cardiomyopathy. At the same time, TTNtv and few missense variants have been identified in patients with mainly recessive skeletal muscle diseases. The pathogenic mechanisms underlying titin‐related diseases are still partly unknown. Similarly, the titin mechanical and functional role in the muscle contraction are far from being exhaustively clarified. In the last few years, several animal models carrying variants in the titin gene have been developed and characterized to study the structural and mechanical properties of specific titin domains or to mimic patients' mutations. This review describes the main animal models so far characterized, including eight mice models and three fish models (Medaka and Zebrafish) and discusses the useful insights provided by a thorough characterization of the cell‐, tissue‐ and organism‐phenotypes in these models.

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The Meryon Lecture at the 24th annual meeting of the Meryon Society, St. Anne's College, Oxford, UK, 15th July 2022

Salih¹

2023

Neuromuscular Disorders

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Exome Sequencing Reveals Novel TTN Variants in Saudi Patients with Congenital Titinopathies

Cited by 4 publications

References 27 publications

A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families

Use of animal models to understand titin physiology and pathology

The Meryon Lecture at the 24th annual meeting of the Meryon Society, St. Anne's College, Oxford, UK, 15th July 2022

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