Whole exome sequencing identified a novel LAMA2 frameshift variant causing merosin-deficient congenital muscular dystrophy in a patient with cardiomyopathy, and autism-like behavior

Nouri, Zahra; Sarmadi, Akram; Narrei, Sina; Sehhati, Mohammadreza; Tabatabaiefar, Mohammad Amin

doi:10.1016/j.nmd.2022.07.400

Cited by 2 publications

(2 citation statements)

References 43 publications

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“…Also, mutations of LAMA2 have been found in patients with severe childhood epilepsy [34] and malformations of cortical development [35]. Recently, a novel frameshift homozygous variant (p.Tyr1313LeufsTer4) in the LAMA2 gene was found in a patient with congenital muscular dystrophy who had autism-like behavior [36]. A genetic study of schizophrenia discovered that recurrent de novo mutations of LAMA2 were found significantly more often in schizophrenia than controls [37], suggesting that LAMA2 variants may be involved in neuropsychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

Whole Genome Sequencing Revealed Inherited Rare Oligogenic Variants Contributing to Schizophrenia and Major Depressive Disorder in Two Families

Chung

Huang

Fang

et al. 2023

IJMS

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Schizophrenia and affective disorder are two major complex mental disorders with high heritability. Evidence shows that rare variants with significant clinical impacts contribute to the genetic liability of these two disorders. Also, rare variants associated with schizophrenia and affective disorders are highly personalized; each patient may carry different variants. We used whole genome sequencing analysis to study the genetic basis of two families with schizophrenia and major depressive disorder. We did not detect de novo, autosomal dominant, or recessive pathogenic or likely pathogenic variants associated with psychiatric disorders in these two families. Nevertheless, we identified multiple rare inherited variants with unknown significance in the probands. In family 1, with singleton schizophrenia, we detected four rare variants in genes implicated in schizophrenia, including p.Arg1627Trp of LAMA2, p.Pro1338Ser of CSMD1, p.Arg691Gly of TLR4, and Arg182X of AGTR2. The p.Arg691Gly of TLR4 was inherited from the father, while the other three were inherited from the mother. In family 2, with two affected sisters diagnosed with major depressive disorder, we detected three rare variants shared by the two sisters in three genes implicated in affective disorders, including p.Ala4551Gly of FAT1, p.Val231Leu of HOMER3, and p.Ile185Met of GPM6B. These three rare variants were assumed to be inherited from their parents. Prompted by these findings, we suggest that these rare inherited variants may interact with each other and lead to psychiatric conditions in these two families. Our observations support the conclusion that inherited rare variants may contribute to the heritability of psychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

Whole Genome Sequencing Revealed Inherited Rare Oligogenic Variants Contributing to Schizophrenia and Major Depressive Disorder in Two Families

Chung

Huang

Fang

et al. 2023

IJMS

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“…The released row data were converted to the FASTQ le and clean reads were then aligned with the reference human genome sequence (hg19, NCBI Build 38) using the Burrows-Wheeler Aligner (BWA). All the steps were the same as we explained in our previous articles (20,21,23).…”

Section: Es and Bioinformatics Analysesmentioning

confidence: 99%

Clinical and molecular analysis of a novel variant responsive to salbutamol monotherapy during COVID-19 outbreak related to congenital and late-onset of myasthenic syndrome in large kindred

Nouri,

Saffari-Chaleshtori,

Sarmadi

et al. 2024

Preprint

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Background: Congenital myasthenic syndromes (CMSs) are a group of clinically and genetically heterogeneous disorders. Mutations in the DOK7 gene underlie CMS with fatigue and muscle weakness, which would worsen with some conventional treatments but show excellent response to special drugs. Here, we applied exome sequencing (ES) to investigate the etiology of CMS in several patients with congenital and late-onset presentations of the disease. Methods: We ascertained a big pedigree including 3 homozygous and 5 carriers, primary proband was subjected to ES, following immunological, biochemical and neurological evaluations. Molecular dynamics (MD) simulation studies were conducted to investigate the DOK7 proteins' stability. The variant’s pathogenicity was assessed using bioinformatics tools and co-segregation analysis. We adapted the American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation. Results: ES results showed a novel homozygous variant (c.1139-1140delinsA:p.Ala380AspfsTer76) in the DOK7 gene. Co-segregating analysis confirmed the pathogenicity of it based on the ACMG guidelines. Interestingly, the identified variant has shown partial autosomal dominant inheritance. The MD simulation analysis revealed this variant to result in the protein function impairment. Effective treatment with salbutamol was obtained in an 18-months follow-up. Remarkably, therapeutic doses of salbutamol in severe COVID-19 patients prevented recurrence of paralysis or muscle weaknesses that occurred with a mild cold. Conclusion: We found a novel variant in the DOK7 gene, with the newly identified partial autosomal dominant inheritance. The findings were used to administer suitable drugs to the patients with maximum efficiency. Thus, ES creates a unique opportunity to promote personalized medicine.

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Whole exome sequencing identified a novel LAMA2 frameshift variant causing merosin-deficient congenital muscular dystrophy in a patient with cardiomyopathy, and autism-like behavior

Cited by 2 publications

References 43 publications

Whole Genome Sequencing Revealed Inherited Rare Oligogenic Variants Contributing to Schizophrenia and Major Depressive Disorder in Two Families

Whole Genome Sequencing Revealed Inherited Rare Oligogenic Variants Contributing to Schizophrenia and Major Depressive Disorder in Two Families

Clinical and molecular analysis of a novel variant responsive to salbutamol monotherapy during COVID-19 outbreak related to congenital and late-onset of myasthenic syndrome in large kindred

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