Constraints of carrier screening in spinal muscular atrophy: Co-existence of deletion and duplication in SMN1 gene and false negative MLPA result

Sharifi, Zohreh; Forouzesh, Flora; Taheri, Mohammad; Zeinali, Sirous

doi:10.1016/j.genrep.2019.100440

Cited by 4 publications

(2 citation statements)

References 26 publications

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“…In a study by Sharifi et al, where 150 unrelated families with at least one suspected SMA patient in their family were surveyed for SMN gene, they showed false-negative carrier results where individuals had point mutations in the gene and also that heterozygous healthy carriers with two copies of SMN1 in one chromosome may not be identified by the MLPA analysis. 21 Therefore, for prenatal diagnostic, newborn and carrier screening just with this method in such families is risky, at least screening should be done with an additional method, especially for prenatal testing.…”

Section: Discussionmentioning

confidence: 99%

Lessons from Real Life Experience: Importance of In-House Sequencing and Smart Ratio-Based Real-Time PCR Outperform Multiplex Ligation-Dependent Probe Amplification in Prenatal Diagnosis for Spinal Muscular Atrophy: Bench to Bedside Diagnosis

Tuncel,

Sanlıdag,

Dirik

et al. 2023

Glob Med Genet

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Spinal muscular atrophy (SMA) is a rare, recessively inherited neurodegenerative disorder caused by the presence of pathogenic variants in the SMN gene. As it is the leading inherited cause of infant mortality, identification of SMN gene pathogenic variant carriers is important for diagnostic purposes with effective genetic counseling. Multiple ligation probe analysis (MLPA), a probe-based method, is considered as the gold standard for SMA carrier analysis. However, MLPA might give false-negative results in cases with variations in the probe-binding regions. Here, we present a case born to consanguineous SMA carrier parents. Prenatal diagnosis with MLPA failed to detect the compound heterozygous mutant state of the proband and she was born unfortunately with SMA phenotype. Further analysis with a real-time polymerase chain reaction kit was able to detect the compound heterozygous state of the patient and was confirmed with targeted next-generation sequencing technology.

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Section: Discussionmentioning

confidence: 99%

Lessons from Real Life Experience: Importance of In-House Sequencing and Smart Ratio-Based Real-Time PCR Outperform Multiplex Ligation-Dependent Probe Amplification in Prenatal Diagnosis for Spinal Muscular Atrophy: Bench to Bedside Diagnosis

Tuncel,

Sanlıdag,

Dirik

et al. 2023

Glob Med Genet

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“…In addition, in a study conducted in Iran in 2019 with pedigree and STR analysis, it was reported that NAIP deletion also increases the risk of carriage (Shari et al 2019). NAIP gene deletion analysis was performed in twenty-four SMA patients in a Malaysian research to better understand the pathophysiology of the disease, and it was reported that deletion of the NAIP gene was related to disease severity.…”

Section: Discussionmentioning

confidence: 99%

Molecular Analysis of SMN2, NAIP and GTF2H2 Gene Deletions and Relation with Clinical Subtypes of Spinal Muscular Atrophy

Karasu

Acer

Akalın

et al. 2022

Preprint

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SMA (spinal muscular atrophy) is an autosomal recessive neuromuscular disease that causes muscle atrophy and weakness. SMA is diagnosed by homozygous deletion in exon 7 of the SMN1 gene. However, mutations in other genes in the SMA region may contribute to the disease. These include SMN2, which is a pseudogene of SMN1, as well as NAIP and GTF2H2. Within the scope of our study, 58 SMA patients and 40 healthy controls were analyzed in 2018–2021. SMN1 and SMN2 copy numbers were retrospectively included in the study. NAIP gene analyzes were performed by multiplex PCR method and GTF2H2 analyzes were performed by RFLP method respectively. We detected a significant correlation between clinical subtypes (type 2 and type 3) and ambulation status (p = 0.003) and HFMSE scores (p = 0.0063) of 27 pediatric SMA patients compared with separately. Highly differences were determined between SMN2 copy numbers and the SMA subtypes (p = 0.00001). Also, the NAIP gene (p = 0,0095) and the GTF2H2 gene (p = 0,0049) revealed a significant difference between the healthy subjects and SMA subjects, whereas in the SMA subtypes indicated no significant difference. Our investigation is the first to examine the relationship between SMA clinical severity and SMN locus genes in the Turkish population. This small-scale study may be regarded as a pilot study, and it may pave the way for future research to better understand the molecular pathophysiology of SMA disease.

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NAIP Gene Deletion and SMN2 Copy Number as Molecular Tools in Predicting the Severity of Spinal Muscular Atrophy

Abd El Mutaleb,

Ibrahim,

Megahed

et al. 2024

Biochem Genet

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Spinal muscular atrophy (SMA) is one of the most prevalent autosomal recessive illnesses with type I being the most severe type. Genomic alterations including survival motor neuron (SMN) copy number as well as deletions in SMN and Neuronal Apoptosis Inhibitory Protein (NAIP) are greatly implicated in the emergence of SMA. However, the association of such alterations with the severity of the disease is yet to be investigated. This study was directed to elucidate the molecular assessment of NAIP and SMN genomic alterations as a useful tool in predicting the severity of SMA among patients. This study included 65 SMA pediatric patients (30 type I and 35 type II) and 65 healthy controls. RFLP-PCR was employed to determine the genetic polymorphisms of the SMN1, SMN2, and NAIP genes. In addition, qRT-PCR was used to identify the expression of the SMN1 and SMN2 genes, and serum levels of creatine kinase were measured using a colorimetric method. DNA sequencing was performed on some samples to detect any single nucleotide polymorphisms in SMN1, SMN2, and NAIP genes. All SMA patients had a homozygous deficiency of SMN1 exon 7. The homozygous deficiency of SMN1 exons 7 and 8, with the deletion of NAIP exon 5 was found among the majority of Type I patients. In contrast, patients with the less severe condition (type II) had SMN1 exons 7 and 8 deleted but did not have any deletions in NAIP, additionally; 65.7% of patients had multiple copies of SMN2. Analysis of NAIP deletion alongside assessing SMN2 copy number might enhance the effectiveness of the diagnosis that can predict severity among Spinal Muscular Atrophy patients.

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Constraints of carrier screening in spinal muscular atrophy: Co-existence of deletion and duplication in SMN1 gene and false negative MLPA result

Cited by 4 publications

References 26 publications

Lessons from Real Life Experience: Importance of In-House Sequencing and Smart Ratio-Based Real-Time PCR Outperform Multiplex Ligation-Dependent Probe Amplification in Prenatal Diagnosis for Spinal Muscular Atrophy: Bench to Bedside Diagnosis

Lessons from Real Life Experience: Importance of In-House Sequencing and Smart Ratio-Based Real-Time PCR Outperform Multiplex Ligation-Dependent Probe Amplification in Prenatal Diagnosis for Spinal Muscular Atrophy: Bench to Bedside Diagnosis

Molecular Analysis of SMN2, NAIP and GTF2H2 Gene Deletions and Relation with Clinical Subtypes of Spinal Muscular Atrophy

NAIP Gene Deletion and SMN2 Copy Number as Molecular Tools in Predicting the Severity of Spinal Muscular Atrophy

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