Genetics of low spinal muscular atrophy carrier frequency in sub‐Saharan Africa

Sangaré, Modibo; Hendrickson, Brant C.; Sango, Hammadoun Ali; Chen, Ke-lian; Nofziger, Jonathan H.; Amara, Abdelbasset; Dutra, Amalia; Schindler, Alice B.; Guindo, Aldiouma; Traoré, Mahamadou; Harmison, George G.; Pak, Evgenia; Yaro, Fatoumata N'Go; Bricceno, Katherine V.; Grunseich, Christopher; Chen, Guibin; Boehm, Manfred; Zukosky, Kristen; Bocoum, Nouhoum; Meilleur, K.; Daou, Fatoumata; Bagayogo, Koumba; Coulibaly, Yaya Ibrahim; Diakité, Mahamadou; Fay, Michael P.; Lee, Hee‐Suk; Saâd, Ali; Gribaa, Moez; Singleton, Andrew B.; Maiga, Youssoufa; Auh, Sungyoung; Landouré, Guida; Fairhurst, Rick M.; Burnett, Barrington G.; Scholl, Thomas; Fischbeck, Kenneth H.

doi:10.1002/ana.24114

Cited by 30 publications

(40 citation statements)

References 38 publications

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“…Studies performed on various American population groups, showed an unusually high frequency of multiple copies of SMN1 in the African American population when compared to other populations (Hendrickson et al, 2009;Sugarman et al, 2012). A study performed on unaffected individuals from various sub-Saharan African populations (Kenyan, Malian and Nigerian) confirmed this observation and showed a higher frequency of multiple copies of SMN1 and deletions of SMN2 than European populations (Sangaré et al, 2014).…”

Section: Introductionmentioning

confidence: 78%

“…A major limitation of previous quantitative studies of the SMN region performed in African-American (Hendrickson et al, 2009;Sugarman et al, 2012) and sub-Saharan African populations (Sangaré et al, 2014) was that CNV analysis was performed in unaffected individuals, with the exception of prenatal screening performed by Sugarman et al This study focuses on comparing CNVs in black individuals who are negative for SMA (N/N b ) to identify non-pathogenic CNVs as well as patients with known homozygous SMN1 and SMN2, exon 7 deletions (M 1 /M 1 b and M 2 /M 2 b , respectively) and patients who are clinically suggestive of SMA (U/U b ) to delineate potential pathogenic CNVs.…”

Section: Discussionmentioning

confidence: 99%

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Spinal Muscular Atrophy in the Black South African Population: A Matter of Rearrangement?

et al. 2020

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Spinal muscular atrophy (SMA) is a neuromuscular disorder, characterized by muscle atrophy and impaired mobility. A homozygous deletion of survival motor neuron 1 (SMN1), exon 7 is the main cause of SMA in~94% of patients worldwide, but only accounts for 51% of South African (SA) black patients. SMN1 and its highly homologous centromeric copy, survival motor neuron 2 (SMN2), are located in a complex duplicated region. Unusual copy number variations (CNVs) have been reported in black patients, suggesting the presence of complex pathogenic rearrangements. The aim of this study was to further investigate the genetic cause of SMA in the black SA population. Multiplex ligationdependent probe amplification (MLPA) testing was performed on 197 unrelated black patients referred for SMA testing (75 with a homozygous deletion of SMN1, exon 7; 50 with a homozygous deletion of SMN2, exon 7; and 72 clinically suggestive patients with no homozygous deletions). Furthermore, 122 black negative controls were tested. For comparison, 68 white individuals (30 with a homozygous deletion of SMN1, exon 7; 8 with a homozygous deletion of SMN2, exon 7 and 30 negative controls) were tested. Multiple copies (>2) of SMN1, exon 7 were observed in 50.8% (62/122) of black negative controls which could mask heterozygous SMN1 deletions and potential pathogenic CNVs. MLPA is not a reliable technique for detecting carriers in the black SA population. Large deletions extending into the rest of SMN1 and neighboring genes were more frequently observed in black patients with homozygous SMN1, exon 7 deletions when compared to white patients. Homozygous SMN2, exon 7 deletions were commonly observed in black individuals. No clear pathogenic CNVs were identified in black patients but discordant copy numbers of exons suggest complex rearrangements, which may potentially interrupt the SMN1 gene. Only 8.3% (6/72) of clinically suggestive patients had heterozygous deletions of SMN1, exon 7 (1:0) which is lower than previous SA reports of 69.5%. This study emphasizes the lack of understanding of the architecture of the SMN region as well as the cause of SMA in the black SA population. These factors need to be taken into account when counseling and performing diagnostic testing in black populations.

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Section: Introductionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Spinal Muscular Atrophy in the Black South African Population: A Matter of Rearrangement?

et al. 2020

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“…SMA is an autosomal recessive disease and is a leading genetic cause of infant death worldwide with an incidence of 1 in 6000–10,000 births (Pearn, 1978; Cuscó et al., 2002). The carrier frequency for SMA is 1:25–50 in most populations (Ben-Shachar et al., 2011; Su et al., 2011; Sugarman et al., 2012; Lyahyai et al., 2012) though it is lower for some ethnicities (Zaldívar et al., 2005; Labrum et al., 2007; Hendrickson et al., 2009; Sangaré et al., 2014). SMA results from the loss or mutation of SMN1 ( survival motor neuron 1 ; OMIM #600354) on chromosome 5q13 (Lefebvre et al., 1995).…”

Section: Introductionmentioning

confidence: 99%

SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR

Stabley

Harris

Holbrook

et al. 2015

Molec Gen & Gen Med

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Proximal spinal muscular atrophy (SMA) is an early-onset motor neuron disease characterized by loss of α-motor neurons and associated muscle atrophy. SMA is caused by deletion or other disabling mutation of survival motor neuron 1 (SMN1). In the human genome, a large duplication of the SMN-containing region gives rise to a second copy of this gene (SMN2) that is distinguishable by a single nucleotide change in exon 7. Within the SMA population, there is substantial variation in SMN2 copy number; in general, those individuals with SMA who have a high SMN2 copy number have a milder disease. Because SMN2 functions as a disease modifier, its accurate copy number determination may have clinical relevance. In this study, we describe the development of an assay to assess SMN1 and SMN2 copy numbers in DNA samples using an array-based digital PCR (dPCR) system. This dPCR assay can accurately and reliably measure the number of SMN1 and SMN2 copies in DNA samples. In a cohort of SMA patient-derived cell lines, the assay confirmed a strong inverse correlation between SMN2 copy number and disease severity. Array dPCR is a practical technique to determine, accurately and reliably, SMN1 and SMN2 copy numbers from SMA samples.

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“…It is a leading genetic cause of infant and early childhood mortality across the world with an incidence of 1 in ~10,000 live births (Pearn 1978; Cuscó et al 2002; Sugarman et al 2012). The carrier frequency for SMA ranges from 1:25 to 1:50 (Zaldívar et al 2005; Labrum et al 2007; Hendrickson et al 2009; Ben-Shachar et al 2011; Su et al 2011; Sugarman et al 2012; Lyahyai et al 2012; Sangaré et al 2014). While SMA is primarily a disorder affecting motor neurons, other cells are affected by this disease (Shababi et al 2014).…”

Section: Spinal Muscular Atrophymentioning

confidence: 99%

Using Systems Biology and Mathematical Modeling Approaches in the Discovery of Therapeutic Targets for Spinal Muscular Atrophy

Butchbach

2018

Advances in Neurobiology

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Systems biology uses a combination of experimental and mathematical approaches to investigate the complex and dynamic interactions with a given system or biological process. Systems biology integrates genetics, signal transduction, biochemistry and cell biology with mathematical modeling. It can be used to identify novel pathways implicated in diseases as well as to understand the mechanisms by which a specific gene is regulated. This review describes the development of mathematical models for the regulation of an endogenous modifier gene, SMN2, in spinal muscular atrophy—an early-onset motor neuron disease that is a leading genetic cause of infant mortality worldwide—by cAMP signaling. These mathematical models not only can aid in understanding how SMN2 expression is regulated but they can also be used to examine the best ways to manipulate cAMP signaling to maximally increase SMN2 expression. These models will lead to the development of therapeutic strategies for treating SMA. This systems biology approach can also be applied to other neurological diseases, particularly those in which a disease-causing gene or a modifier gene has been identified.

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Genetics of low spinal muscular atrophy carrier frequency in sub‐Saharan Africa

Cited by 30 publications

References 38 publications

Spinal Muscular Atrophy in the Black South African Population: A Matter of Rearrangement?

Spinal Muscular Atrophy in the Black South African Population: A Matter of Rearrangement?

SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR

Using Systems Biology and Mathematical Modeling Approaches in the Discovery of Therapeutic Targets for Spinal Muscular Atrophy

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