Spinal muscular atrophy carriers with two SMN1 copies

Rochmah, Mawaddah Ar; Awano, Hiroyuki; Awaya, Tomonari; Harahap, Nur Imma Fatimah; Morisada, Naoya; Bouike, Yoshihiro; Saitô, Toshio; Kubo, Yohei; Saito, Kayoko; Lai, Poh San; Morioka, Ichiro; Iijima, Kazumoto; Nishio, Hisahide; Shinohara, Masakazu

doi:10.1016/j.braindev.2017.06.002

Cited by 16 publications

(18 citation statements)

References 30 publications

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“…Simultaneously, c.[271C > T] might be involved in the onset of SMA. In addition, [2 + 0] genotype carriers are two SMN1 copies on one chromosome and with deletion of SMN1 on the other chromosome [ 17 ]. In this article, we found 2 patients (Proband-1 and Proband-2) whose one parent was carriers and the other parent with 3 SMN1 exon7 copies (Proband-1’s mother and Proband-2’s father).…”

Section: Discussionmentioning

confidence: 99%

High-throughput screening reveals novel mutations in spinal muscular atrophy patients

Zhang

et al. 2020

Ital J Pediatr

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Background Spinal muscular atrophy (SMA) is an autosomal recessive hereditary disease associated with severe muscle atrophy and weakness in the limbs and trunk. The discovery of mutated genes is helpful in diagnosis and treatment for SMA. Methods Eighty-three whole blood samples were collected from 28 core families of clinically suspected SMA, and multiplex ligation probe amplification (MLPA) was performed. Afterwards, the complete gene sequence of SMN1 gene was detected. Furthermore, 20 SMA patients were selected from the 28 probands, and 5 non SMA children as controls. The Life Technologies SOLiD™ technology with mate-pair chemistry was utilized to conduct the whole exome high-throughput sequencing. Results Twenty-two probands were SMA patients, 3 probands carriers, and 3 probands normal individuals. Moreover, 2 parents from 2 SMA families were with 3 SMN1 exon7 copies. Six SMN1 single nucleotide variants (SNVs) were identified in the 83 samples, and c.[84C > T], c.[271C > T], c.[−39A > G] and g.[70240639G > C] were novel. Compared with control group, 9102 mutation were selected out in SMA patients. SPTA1 mutation c.[−41_-40insCTCT], FUT5 SNV c.[1001A > G], and MCCC2 SNV c.[−117A > G] were the 3 most frequent mutations in SMA group (95, 85 and 75%, respectively). Conclusions We identified some mutations in both SMN1 and other genes, and c.[271C > T], c.[−41_-40insCTCT], c.[1001A > G] and c.[−117A > G] might be associated with the onset of SMA.

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Section: Discussionmentioning

confidence: 99%

High-throughput screening reveals novel mutations in spinal muscular atrophy patients

Zhang

et al. 2020

Ital J Pediatr

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“…However, this method has limitations. For SMA carrier screening, the silent carriers having two copies of SMN1 on one chromosome but no one on the other, as well as SMN1 intragenic mutations could be missed [ 25 ]. In this aspect of clinical diagnosis, approximately 5% of affected SMA patients with intragenic mutations in the SMN1 gene will not be detected by deletion testing methods, including our method and MLPA [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Accurate diagnosis of spinal muscular atrophy and 22q11.2 deletion syndrome using limited deoxynucleotide triphosphates and high-resolution melting

et al. 2018

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BackgroundCopy number variation (CNV) has been implicated in the genetics of multiple human diseases. Spinal muscular atrophy (SMA) and 22q11.2 deletion syndrome (22q11.2DS) are two of the most common diseases which are caused by DNA copy number variations. Genetic diagnostics for these conditions would be enhanced by more accurate and efficient methods to detect the relevant CNVs.MethodsCompetitive PCR with limited deoxynucleotide triphosphates (dNTPs) and high-resolution melting (HRM) analysis was used to detect 22q11.2DS, SMA and SMA carrier status. For SMA, we focused on the copy number of SMN1 gene. For 22q11.2DS, we analyzed CNV for 3 genes (CLTCL1, KLHL22, and PI4KA) which are located between different region-specific low copy repeats. CFTR was used as internal reference gene for all targets. Short PCR products with separated Tms were designed by uMelt software.ResultsOne hundred three clinical patient samples were pretested for possible SMN1 CNV, including carrier status, using multiplex ligation-dependent probe amplification (MLPA) commercial kit as gold standard. Ninety-nine samples consisting of 56 wild-type and 43 22q11.2DS samples were analyzed for CLTCL1, KLHL22, and PI4KA CNV also using MLPA. These samples were blinded and re-analyzed for the same CNVs using the limited dNTPs PCR with HRM analysis and the results were completely consistent with MLPA.ConclusionsLimited dNTPs PCR with HRM analysis is an accurate method for detecting SMN1 and 22q11.2 CNVs. This method can be used quickly, reliably, and economically in large population screening for these diseases.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4833-4) contains supplementary material, which is available to authorized users.

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“…Thus, SMA carriers are usually diagnosed based on their SMN1 copy number, because one SMN1 copy means the heterozygous deletion of SMN1 ([1 + 0] genotype). However, having two SMN1 copies does not always exclude carrier status [32,33]. Some SMA carriers have two SMN1 copies on one chromosome, with the deletion of SMN1 on the other chromosome ([2 + 0] genotype) [32,33].…”

Section: Limitation Of Assigning Sma Carrier Status Based On the Smn1mentioning

confidence: 99%

“…However, having two SMN1 copies does not always exclude carrier status [32,33]. Some SMA carriers have two SMN1 copies on one chromosome, with the deletion of SMN1 on the other chromosome ([2 + 0] genotype) [32,33]. Other carriers may be heterozygous for an intragenic SMN1 mutation ([1 + 1d] genotype; "d" denotes the presence of an intragenic mutation) [32,33].…”

Section: Limitation Of Assigning Sma Carrier Status Based On the Smn1mentioning

confidence: 99%

Assessment of Spinal Muscular Atrophy Carrier Status by Determining SMN1 Copy Number Using Dried Blood Spots

Wijaya

Purevsuren

Harahap

et al. 2020

IJNS

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Spinal muscular atrophy (SMA) is a common neuromuscular disease with autosomal recessive inheritance. The disease gene, SMN1, is homozygously deleted in 95% of SMA patients. Although SMA has been an incurable disease, treatment in infancy with newly developed drugs has dramatically improved the disease severity. Thus, there is a strong rationale for newborn and carrier screening for SMA, although implementing SMA carrier screening in the general population is controversial. We previously developed a simple, accurate newborn SMA screening system to detect homozygous SMN1 deletions using dried blood spots (DBS) on filter paper. Here, we modified our previous system to detect the heterozygous deletions of SMN1, which indicates SMA carrier status. The system involves a calibrator-normalized relative quantification method using quantitative nested PCR technology. Our system clearly separated the DBS samples with one SMN1 copy (carrier status with a heterozygous deletion of SMN1) from the DBS samples with two SMN1 copies (non-carrier status with no deletion of SMN1). We also analyzed DBS samples from SMA families, confirmed SMA in the affected children, and determined the carrier status of their parents based on the SMN1 copy number. In conclusion, our system will provide essential information for risk assessment and genetic counseling, at least for SMA families.

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Spinal muscular atrophy carriers with two SMN1 copies

Cited by 16 publications

References 30 publications

High-throughput screening reveals novel mutations in spinal muscular atrophy patients

High-throughput screening reveals novel mutations in spinal muscular atrophy patients

Accurate diagnosis of spinal muscular atrophy and 22q11.2 deletion syndrome using limited deoxynucleotide triphosphates and high-resolution melting

Assessment of Spinal Muscular Atrophy Carrier Status by Determining SMN1 Copy Number Using Dried Blood Spots

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