Targeted exome sequencing identified a novel frameshift variant in the PGAM2 gene causing glycogen storage disease type X

Nayab, Anam; Alam, Qamre; Alzahrani, Othman R.; Khan, Ranjha; Sarfaraz, Sara; Albaz, Alrayan Abass; Rafeeq, Misbahuddin M; Sain, Ziaullah M; Waqas, Ahmed; Umair, Muhammad

doi:10.1016/j.ejmg.2021.104283

Cited by 9 publications

(8 citation statements)

References 13 publications

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“…In this study, in silico methodology such as homology modeling for wild-type and mutant was carried out. The 3D structure of ALKBH8 was modeled by the I-TASSER server ( Nayab et al, 2021 ). The predicted structure of ALKBH8 has a good degree of accuracy.…”

Section: Resultsmentioning

confidence: 99%

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability

Waqas

Nayab

Shaheen³

et al. 2022

Front. Genet.

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Intellectual disability (ID) has become very common and is an extremely heterogeneous disorder, where the patients face many challenges with deficits in intellectual functioning and adaptive behaviors. A single affected family revealed severe disease phenotypes such as ID, developmental delay, dysmorphic facial features, postaxial polydactyly type B, and speech impairment. DNA of a single affected individual was directly subjected to whole exome sequencing (WES), followed by Sanger sequencing. Data analysis revealed a novel biallelic missense variant (c.1511G>C; p.(Trp504Ser)) in the ALKBH8 gene, which plays a significant role in tRNA modifications. Our finding adds another variant to the growing list of ALKBH8-associated tRNA modifications causing ID and additional phenotypic manifestations. The present study depicts the key role of the genes associated with tRNA modifications, such as ALKBH8, in the development and pathophysiology of the human brain.

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Section: Resultsmentioning

confidence: 99%

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability

Waqas

Nayab

Shaheen³

et al. 2022

Front. Genet.

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“…The 3D Structure of mutated protein was generated by MODELLER, version 9.19 16 . MODELLER helps to predict 3D structure of proteins by meeting spatial restraints 17 . The model was selected from the models produced by MODELLER based on the MODELLER evaluation score.…”

Section: Methodsmentioning

confidence: 99%

“…The selected structure was optimized through 1000 steps of steepest-decent 13 and 1000 steps of conjugate-gradient 14 MODELLER helps to predict 3D structure of proteins by meeting spatial restraints. 17 The model was selected from the models produced by MODELLER based on the MODELLER evaluation score.…”

Section: Sanger Sequencingmentioning

confidence: 99%

Overlapping neurological phenotypes in two extended consanguineous families with novel variants in the CNTNAP1 and ADGRG1 genes

Khan

Umair

Abbas

et al. 2023

The Journal of Gene Medicine

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BackgroundPopulation diversity is important and rare disease isolates can frequently reveal novel homozygous or biallelic mutations that lead to expanded clinical heterogeneity, with diverse clinical presentations.MethodsThe present study describes two consanguineous families with a total of seven affected individuals suffering from a clinically similar severe syndromic neurological disorder, with abnormal development and central nervous system (CNS) and peripheral nervous system (PNS) abnormalities. Whole exome sequencing (WES) and Sanger sequencing followed by 3D protein modeling was performed to identify the disease‐causing gene. RNA was extracted from the fresh blood of both families affected and healthy individuals.ResultsThe families were clinically assessed in the field in different regions of Khyber Pakhtunkhwa. Magnetic resonance imagining was obtained in the probands and blood was collected for DNA extraction and WES was performed. Sanger sequencing confirmed a homozygous, likely pathogenic mutation (GRCh38: chr17:42684199G>C; (NM_003632.3): c.333G>C);(NP_003623.1): p.(Trp111Cys) in the CNTNAP1 gene in family A, previously associated with Congenital Hypo myelinating Neuropathy 3 (CHN3; OMIM # 618186) and a novel nonsense variant in family B, (GRCh38: chr16: 57654086C>T; NC_000016.10 (NM_001370440.1): c.721C>T); (NP_001357369.1): p.(Gln241Ter) in the ADGRG1 gene previously associated with bilateral frontoparietal polymicrogyria (OMIM # 606854); both families have extended CNS and PNS clinical manifestations. In addition, 3D protein modeling was performed for the missense variant, p.(Trp111Cys), identified in the CNTNAP1, suggesting extensive secondary structure changes that might lead to improper function or downstream signaling. No RNA expression was observed in both families affected and healthy individuals hence showing that these genes are not expressed in blood.ConclusionsIn the present study, two novel biallelic variants in the CNTNAP1 and ADGRG1 genes in two different consanguineous families with a clinical overlap in the phenotype were identified. Thus, the clinical and mutation spectrum is expanded to provide further evidence that CNTNAP1 and ADGRG1 are very important for widespread neurological development.

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“…Primer's sequence will be provided on request. Sanger sequencing data was analyzed using BIOEDIT, version 7.2 9,10 …”

Section: Methodsmentioning

confidence: 99%

A novel biallelic variant in the Popeye domain‐containing protein 1 (POPDC1) underlies limb girdle muscle dystrophy type 25

et al. 2022

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POPDC1 also known as BVES, is a highly conserved transmembrane protein, important for striated muscle function and homeostasis. Pathogenic variants in the POPDC1 gene are associated with limb‐girdle muscular dystrophy type 25 (LGMDR25). In the present study, we performed trio‐whole exome sequencing (WES) followed by Sanger sequencing on a single family having LGMD clinical features. Protein modeling of all POPDC1 missense variants (POPDC1Pro134Leu, POPDC1Ile193Ser, and POPDC1Ser201Phe) associated with LGMDR25 were performed using Molecular Dynamics (MD) simulation. We identified a homozygous missense variant (c.401C>T; p.Pro134Leu) in the POPDC1 gene. Altered 3D structure, disruptive fluctuation, less compactness, and instability were observed in all the three variants of POPDC1 protein models. In comparison, POPDC1Ser201Phe protein dynamics were more unstable than other variants. Functional study of newly identified variant would add key answers to underlying mechanisms of the disease.

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Targeted exome sequencing identified a novel frameshift variant in the PGAM2 gene causing glycogen storage disease type X

Cited by 9 publications

References 13 publications

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability

Case Report: Biallelic Variant in the tRNA Methyltransferase Domain of the AlkB Homolog 8 Causes Syndromic Intellectual Disability

Overlapping neurological phenotypes in two extended consanguineous families with novel variants in the CNTNAP1 and ADGRG1 genes

A novel biallelic variant in the Popeye domain‐containing protein 1 (POPDC1) underlies limb girdle muscle dystrophy type 25

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