Spinal Muscular Atrophy Carrier Screening Research Articles

Impact of a national population-based carrier-screening program on spinal muscular atrophy births

Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease. Population carrier screening for SMA was introduced in Israel in 2008 through health-care services’ insurance plans and expanded to the entire Israeli population in 2013 by a national health program. The aim of the study was to evaluate the impact of carrier screening on reducing the rate of birth of infants with SMA. All cases of prenatal and postnatal diagnosis of SMA in 2008–2017 were identified from databases of relevant government organizations, genetic laboratories in medical centers, and health care systems in Israel. Since 2013, screening was performed in 309,352 individuals, of whom 5741 were found to be carriers (carrier rate 1:54). Given an average of 180,000 live births annually, the predicted rate of SMA diagnosis was 15 cases per year. Prior to 2013, the average rate of prenatally diagnosed SMA was 4.66 cases per year, compared with 7.75 cases per year following population-wide provision of screening. The annual rate of postnatally diagnosed cases remained steady since 2008, with an average of 7- 7.25 cases per year. Screening has been effective in increasing prenatal detection of SMA but has had no effect on the rate of confirmed postnatal diagnoses. We speculate that screening rates may be affected by social, cultural, and religious factors.

NGS-based spinal muscular atrophy carrier screening of 10,585 diverse couples in China: a pan-ethnic study

In this study, we performed a spinal muscular atrophy carrier screening investigation with NGS-based method. First, the validation for NGS-based method was implemented in 2255 samples using real-time PCR. The concordance between the NGS-based method and real-time PCR for the detection of SMA carrier and patient were up to 100%. Then, we applied this NGS-based method in 10,585 self-reported normal couples (34 Chinese ethnic groups from 5 provinces in South China) for SMA carrier screening. The overall carrier frequency was 1 in 73.8 (1.4%). It varied substantially between ethnic groups, highest in Dai ethnicity (4.3%), and no significant difference was found between five provinces. One couple was detected as carriers with an elevated risk of having an SMA affected baby. The distribution of SMN1:SMN2 genotype was also revealed in this study. Among the individuals with normal phenotype, the exon 7 copy-number ratio of SMN1 to SMN2 proved the gene conversion between them. With NGS-based method, we investigated SMA carrier status in Chinese population for the first time, and our results demonstrated that it is a promising alternative for SMA carrier screening and could provide data support and reference for future clinical application.

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

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.

Carrier Screening and Prenatal Diagnosis for Spinal Muscular Atrophy in 13,069 Chinese Pregnant Women

Spinal muscular atrophy (SMA) is a relatively common, life-shortening, autosomal recessive neuromuscular disease. The carrier frequency of SMA ranges from approximately 0.98% to 2.02%, depending on ethnicity. The American College of Medical Genetics has therefore recommended population screening for SMA carrier status, regardless of race or ethnicity. We performed the largest-scale carrier screening for SMA carriers in mainland China. Carrier screening was offered to 36,470 pregnant women between July 2017 and June 2019, of whom 13,069 women accepted the screening program [35.83%; 95% credibility interval (CI), 35.34%-36.33%]. Copy numbers of exons 7 and 8 in the SMN1 gene were detected by real-time quantitative PCR, and the results were confirmed by multiplex ligation-dependent probe amplification. A total of 231 women were identified as carriers (1.77%; 95% CI, 1.56%-2.01%), indicating a carrier prevalence of approximately 1:56 in the population. After detailed genetic counseling, 207 paternal partners were recalled and tested. Both partners were carriers in 10 couples, of whom prenatal diagnosis was implemented in seven, and one fetus was diagnosed with SMA. Carrier screening could provide couples with informed reproductive choices. Our workflow and experience of carrier screening may facilitate the popularization of SMA carrier screening in mainland China.

Variations in prenatal screening in a US federal healthcare system: Same coverage, different options.

The Military Health System (MHS) is a federally funded organization that provides care to active duty service members and their beneficiaries. Our objective was to determine what methods of prenatal screening are used by military treatment facilities (MTFs), assess variations between institutions, and determine how practice patterns align with national recommendations. We surveyed all MTFs offering comprehensive prenatal care (n=49). Departments were asked about aneuploidy screening options, availability of diagnostic testing, and carrier screening. In all, 43 MTFs (88%) completed the survey. Most (39/43) patients were stratified based on risk (predominantly maternal age at delivery and history). The most commonly offered test was combined 1st/2nd trimester screening (59%). Sixty percent routinely offered diagnostic testing, though less than half routinely offered microarrays. The majority offered universal carrier screening for cystic fibrosis (98%) and complete blood count with screening for thalassemias and hemoglobinopathies (88%). At the time of data collection, only five facilities (12%) had implemented spinal muscular atrophy carrier screening. Considerable heterogeneity exists in prenatal aneuploidy testing and carrier screening within the MHS. Standardized guidelines, protocols, and laboratory support would improve processes across the system. Additional resources including genetic counseling support and provider education are needed.

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

Spinal Muscular Atrophy (SMA) is the second most common autosomal recessive genetic disorder. Deletion/duplication changes in SMN1 gene are common features in SMA patients. MLPA (Multiplex Ligation-dependent Probe Amplification) is a robust method for investigation of copy number changes because it not only deals with investigating the SMN1 gene but also adjacent genes such as NAIPE, GTFH2 and SMN2. This study was carried out by MLPA and STR markers to SMA carrier screening on people were referred to Dr. Zeinali's Medical Genetics laboratory. Analysis of 150 unrelated families with at least one affected child suspected of having SMA identified causative mutations in 106 families. Among the nighty-nine patients with a homozygous deletion of SMN1 gene (93.3%), there were ten patients with only one parent showing this deletion as heterozygote, and the other parent had two copies of the gene with normal MLPA result. The results were unexpected findings in an autosomal recessive disorder. Paternity and maternity were tested and confirmed.Further analysis of the grandparents showed that the parents inherited both deletion and duplication from one of their parents. So they have two copies of SMN1 genes in a chromosome and no copy on the other one.Due to high carrier frequency of SMA in highly consanguineous population as Iran, co-existence of deletion and duplication must be highly considered. It seems that performing genetic testing only in patients and parents is not sufficient and investigation of the grandparents or autozygosity mapping is also necessary to have reliable results especially for next pregnancies.

Spinal Muscular Atrophy: Ordering Trends Pre- and Post-ACOG Committee Opinion 691 [17O

INTRODUCTION: Spinal muscular atrophy (SMA) is a leading inherited cause of infant death and is second to cystic fibrosis (CF) as a common, life-limiting autosomal recessive disorder. In March 2017, the American College of Obstetrics and Gynecology (ACOG) released a committee opinion (691) stating that screening for SMA should be offered to all patients considering pregnancy or currently pregnant. METHODS: To assess the uptake of SMA screening following the ACOG recommendations, a retrospective analysis of tests ordered from healthcare practices for single gene carrier screening of SMA and CF was performed. Data were analyzed over two equal time periods pre- and post-March 2017. RESULTS: Data were collected from nearly 4,000 healthcare providers who ordered at least one SMA test in the study period. The average number of monthly tests ordered per practice was six pre-ACOG opinion, and 16.7 post-ACOG opinion. Over 50% of practices did not order SMA testing prior to the ACOG opinion. Among practices regularly ordering testing for CF there was an increase in testing for SMA post-opinion, however, the number of CF tests received was 27% higher than SMA tests received. CONCLUSION: Carrier screening for SMA increased more than two and half times post ACOG opinion, likely due to the new recommendations. Despite the increase in SMA carrier tests, the number of SMA tests post-opinion did not match the number of CF tests from healthcare practices sending both tests to our laboratory. These findings suggest increased adoption of SMA screening guidelines but still not at the level observed for CF.

Carrier frequency of spinal muscular atrophy in Thailand.

Spinal muscular atrophy (SMA) is one of the leading causes of death in infants and young children from heritable diseases. Patients diagnosed with SMA develop symmetrical progressive muscle weakness and atrophy from degeneration of alpha motor neurons. Approximately 95% of patients have a homozygous deletion of survival motor neuron 1 (SMN1) gene in exon 7 and inherited in autosomal recessive pattern. Considering the high prevalence of SMA carrier in many population, it is possible that SMA is one of the most common autosomal recessive disorders in Thailand and Southeast Asia. In this study, we analyzed DNA from peripheral blood of 505 healthy Thai adults using quantitative PCR-based for SMN1 gene exon 7 copy number analysis. Individual samples with heterozygous deletion of SMN1 gene were confirmed with MLPA. The result identified 9 samples (1.78%) with heterozygous deletion and 39 samples as more than 2 copies of SMN1. No homozygous deletion was detected in the samples. In conclusion, we established carrier frequency of SMA in selected Thai population at 1.8% from 505 participants. The prevalence coincides with prevalence in East Asia and Caucasian population. The result could be implemented for SMA carrier screening in couples at risk in the region.

Carrier screening for spinal muscular atrophy with a simple test based on melting analysis.

Carrier screening of spinal muscular atrophy (SMA) can provide reproductive options for carriers and prevent the birth defects. Here, we developed a simple screening test based on melting analysis. The test comprises a duplex PCR with two primer pairs and three probes to simultaneous amplify SMN1, SMN2, and CFTR. By analyzing the melting profiles, we were able to determine the SMN1/SMN2 ratio and SMN1 + SMN2 copy number to subsequently determine the copy number of SMN1. Samples with one copy of SMN1 were considered as "high risk for carrier," while samples with ≥2 copies of SMN1 were considered as "low risk for carrier." We evaluated the clinical performance of this test using 215 clinical samples with various genotypes that had been previously confirmed by multiplex ligation-dependent probe amplification (MLPA). The test showed high sensitivity (100%) and specificity (97.1%) as well as high positive (97.3%) and negative (100%) predictive value, and was in perfect agreement with the gold standard test, MLPA (k = 0.97). Moreover, it is rapid, inexpensive, and easy to perform and automate, with high reproducibility and capacity. Therefore, we expect this test will advance carrier screening for SMA.

Prenatal Carrier Screening for Spinal Muscular Atrophy.

Introduction Spinal muscular atrophy (SMA), a neurodegenerative genetic disorder, affects 1:5,000 to 1:10,000 infants. Carrier rates are 1:25 to 1:50. We implemented ACOG-endorsed prenatal SMA screening in mid-2014 and sought to assess uptake, observed carrier rate, and providers' knowledge and attitudes toward genetic conditions and carrier screening. Methods Retrospective cohort study of all patients receiving prenatal genetic counseling at our institution from August 2014 to April 2015. Factors associated with screening uptake were assessed. Proportions who accepted screening, were screen-positive, had partners tested, had partners who were screen-positive, and had fetuses tested were calculated. Providers' knowledge and attitudes were assessed using a validated questionnaire. Results Of 1,158 patients offered SMA screening, 224 accepted (19.3%, 95% CI 17.2-21.7). Uptake differed by race, parity, religion, and genetic counselor seen. Five (2.2% or 1:45, 95% CI 0.8-5.3 or 1:19-1:125) women were identified as carriers. Of 3 partners screened, none screened positive (0%, 95% CI 0-5.3). There were no prenatal SMA diagnoses (0%, 95% CI 0-1.4). Of 90 survey respondents, 42% incorrectly answered 1 of 9 knowledge questions. Provider attitudes toward screening were contradictory. Conclusion Despite significant resources utilized, prenatal SMA carrier screening identified no fetal cases. Cost-effectiveness and other barriers should be considered prior to large-scale adoption of more comprehensive genetic screening.

A pilot study of spinal muscular atrophy carrier screening in Saudi Arabia

Spinal muscular atrophy (SMA), an autosomal recessive inherited disease, is a leading genetic killer under the age of two years. This disease is caused by mutation in the telomeric copy of the survival motor neuron gene ( SMN1 ). Most carriers of SMA have one chromosome 5 with a normal SMN1 gene and one with a deleted SMN1 gene. Although no large-scale population-based studies has been done in Saudi Arabia, previous estimations have indicated that incidence of SMA is much higher in Saudi population compared with other ethnic groups, partly because of high prevalence of consanguineous marriages. In this pilot study, we used a highly sensitive quantitative-polymerase chain reaction method to detect SMA carriers. Among 187 normal individuals not related to an SMA patient the carrier frequency was 5%, i.e. one carrier in each 20 persons compared to one in 50–80 in other parts of the world. Based on the results of this pilot study a new project is designed to further analyze the carrier status of SMA in Saudi population. This will shed more light on the magnitude of the problem of SMA in the countries with high rate of consanguinity.

Evaluation and characterization of a high-resolution melting analysis kit for rapid carrier-screening test of spinal muscular atrophy

Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans, caused by the homozygous absence of the survival motor neuron gene 1 (SMN1). SMN2, a copy gene, influences the severity of SMA. Several assays have been described for molecular diagnosis or carrier screening of SMA. A newly developed tool based on a high-resolution melting analysis (HRMA) that enables high-throughput screening without sophisticated protocols but low costs reveals itself to be powerful. We evaluate the performance of an HRMA-based kit for a carrier-screening test of SMA that was designed to detect the substitution of a single nucleotide in SMN1 exon 7. Carriers were identified in 453 participants by quantifying the SMN1 gene and compared with denaturing high-performance liquid chromatography (DHPLC) assay. An HRMA-based kit had a higher sensitivity (100%) for carrier testing than the DHPLC assay (93%), with the added advantage that some homozygous sequence alterations could be identified. The HRMA kit is a new, fast, and highly reliable quantitative test for the SMA molecular carrier test.

Comparison of three methods for the genetic diagnosis of spinal muscular atrophy

Objective To evaluate the value of PCR-restriction fragment length polymorphism (PCR-RFLP), real-time PCR and multiplex ligation-dependent probe amplification (MLPA) in the genetic diagnosis of spinal muscular atrophy (SMA) and make laboratory support accessible to clinicians for the molecular diagnosis of SMA. Methods Methodological evaluation. Forty-one suspected SMA cases and 359 control individuals received in Shanghai Children′s Medical Centre from March 2013 to June 2014 were detected for the deletion of exon 7 and 8 in the survival motor neuron gene 1 (SMN 1) by PCR-RFLP, real-time PCR and MLPA, respectively. Then the results of the three methods were compared and the benefits and limitations of the three methods were evaluated. Results The result of real-time PCR was in complete agreement with that of MLPA, showing that 29 suspected cases harbored homozygous deletions of SMN1 and 1 case possessed heterozygous deletion. Among the homozygous deletions, 27 patients demonstrated absence of exon 7 and 8, and 2 cases demonstrated only the absence of exon 7. Meanwhile, both PCR-RFLP and MLPA analysis showed the same results that only 5 out of 395 control cases carried heterozygous deletion. As for cases without heterozygous deletions, PCR-RFLP demonstrated the same result with real-time PCR and MLPA but it missed all the heterozygous ones. Conclusions PCR-RFLP, the conventional SMA gene diagnosis method, was only capable of detecting homozygous deletion of exon 7 and/or 8 of SMN1, but was not as sensitive as to find out the carriers with heterozygous deletions. MLPA could detect the deletion and quantify the copy numbers of exon 7 and 8 of SMN1, efficiently, while the price was relatively high, which brings challenges for its application in the carrier screening of SMA. Compared with these two methods, real-time PCR with high throughput and low input was a rapid, accurate and economic method for the genetic diagnosis of SMA and carrier screening in large populations. (Chin J Lab Med, 2015, 38: 16-20) Key words: Spinal muscular atrophies of childhood; Polymorphism, restriction fragment length; Real-time polymerase chain reaction

SMA carrier testing: a meta-analysis of differences in test performance by ethnic group.

Spinal muscular atrophy (SMA) is a severe autosomal recessive genetic disease that occurs in about one in every 10 000 births. Prenatal carrier testing is available for SMA, and the utility of universal screening is actively debated. The aim of this study was to perform a systematic review and meta-analysis of SMA genotype frequency, carrier frequency, and carrier test performance in different ethnic groups. We performed a systematic review of the literature for studies on SMA carrier screening test performance. Ethnicity-specific allele frequencies, carrier rates, and screening test performance were determined from data of 169 000 individuals in 14 published studies. Pooled estimates were calculated for each ethnic group using a random effects meta-analysis. The detection rate of SMA screening in the non-Black population was 87-95%; however, detection rates fell to 71% among the Black population. These results highlight that although SMA carrier testing generally performs well and could be considered as a routine prenatal screen, SMA testing should be used cautiously in the Black population.

A mixed methods exploration of families' experiences of the diagnosis of childhood spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease with a carrier frequency of 1 in 41 in Australia. Childhood SMA is classified into three types based on the age at which children present with symptoms and the clinical severity. Families' experiences leading up to the diagnosis have not been described, but are important when considering the potential for a diagnostic odyssey. Using a mixed methods approach, data were collected from interviews and a national survey of families of children with SMA to explore their experiences of this journey. The combined findings (n=28) revealed that the journey to receiving a diagnosis was protracted. The time from first noticing symptoms to finally receiving a diagnosis was emotional and frustrating. Once parents or other family members became aware of symptoms, almost all had consulted with multiple different health professionals before the diagnosis was ultimately made. Not surprisingly, receiving the diagnosis was devastating to the families. The nature of the information and the way it was given to them was not always optimal, particularly because of the difficulties predicting clinical severity. Most felt that their child could have been diagnosed earlier and, although there were mixed views around the benefit of this for their child, they felt it may have reduced the emotional impact on families. Overall, families were more in favour of population carrier screening for SMA when compared with newborn screening of the population. Despite an increasing awareness of SMA, the diagnostic delay continues to have negative impacts on families.

Carrier screening for spinal muscular atrophy in 4719 pregnant women in Shanghai region

Spinal muscular atrophy (SMA) is a common and fatal autosomal recessive disorder. Approximately 94% of SMA patients are caused by homozygous deletion of SMN1 gene. SMA carrier screening is recommended considering the high carrier frequency (1 in 35-50) as well as severity of the disease. A prospective population-based cohort study was carried out on 4719 pregnant women from Shanghai region. Copy numbers of SMN1 and SMN2 genes were effectively determined with denaturing high performance liquid chromatography (DHPLC) technique. The method has detected 94% of SMA cases with deletion or conversion of the SMN1 genes. Ninety SMA carriers with only one copy of the SMN1 gene were identified among the 4719 pregnant woman. The carrier rate was 1.9%. Respectively, 1.2% and 0.6% of the carriers were caused by SMN1 gene deletion and SMN1 gene conversion. Through this study, we have determined the frequency of SMA mutation carriers in a population of pregnant women. The result may provide a basis for genetic counseling in order to reduce the rate of SMA affected births.

An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy

Spinal muscular atrophy is a common autosomal-recessive disorder caused by mutations of the SMN1 gene. Spinal muscular atrophy carrier screening uses dosage-sensitive methods that determine SMN1 copy number, and the frequency of carriers varies by ethnicity, with detection rates ranging from 71 to 94% due to the inability to identify silent (2 + 0) carriers with two copies of SMN1 on one chromosome 5 and deletion on the other. We hypothesized that identification of deletion and/or duplication founder alleles might provide an approach to identify silent carriers in various ethnic groups. SMN1 founder alleles were investigated in the Ashkenazi Jewish population by microsatellite analysis and next-generation sequencing. An extended haplotype block, specific to Ashkenazi Jewish SMN1 duplications, was identified by microsatellite analysis, and next-generation sequencing of SMN1 further defined a more localized haplotype. Of note, six novel SMN1 sequence variants were identified that were specific to duplications and not present on single-copy alleles. The haplotype was also identified on SMN1 duplication alleles in additional ethnic groups. Identification of these novel variants in an individual with two copies of SMN1 significantly improves the accuracy of residual risk estimates and has important implications for spinal muscular atrophy carrier screening.

Nothing About Us Without Us: Guidelines for Genetic Testing

Guidelines for genetic testing developed by professional societies may be more centered on the concerns of society members than the needs of the individuals and families that may undergo testing. This could be considered appropriate because it will be the healthcare provider who will assess whether to test; when to test; whom to test; and how to provide the right support, interpretation, and follow-up to the individual or family tested. Genetic testing requires guidelines because of the complexity of testing for the individual and his or her family. It also requires flexibility because context matters a great deal in genetics. For this very reason, multiple stakeholders should be involved in guideline development. Professional societies have a deliberative process for their members, and those closely associated with their practice, to engage in discourse that leads to guidelines. We believe that the testing guidelines should reflect more than the professionals’ perspective. Ultimately, the ramifications of testing guidelines do not exist in isolation from the whole healthcare experience of the individual. This means that the perspectives of other providers, the individuals, and families should be a part of the deliberative process. One might ask why the advocacy organizations don’t establish guidelines themselves. We believe that multiple stakeholder groups should be involved. A striking example of where two groups of professionals create difficulties for each other and the people they serve is the guidelines for spinal muscular atrophy (SMA) carrier screening. Obstetricians disagree with geneticists about carrier testing for this condition. Geneticists believe that carrier testing for SMA should be offered to the general population, and obstetricians do not believe it should be offered broadly. In statements made by the two societies, the contrast is clear, but from the point of view of the patient, it is confusing. The American College of Obstetricians and Gynecologists’ Committee on Genetics concludes: ‘‘[The committee] agrees that preconception and prenatal screening for SMA is not recommended in the general population at this time’’ (American College of Obstetricians and Gynecologists, 2009). The American College of Medical Genetics, on the other hand, concludes: ‘‘Because SMA is present in all populations, carrier testing should be offered to all couples regardless of race or ethnicity. Ideally, the testing should be offered before conception or early in pregnancy. The primary goal is to allow carriers to make informed reproductive choices’’ (Prior 2008). As a result of these two guidelines, obstetricians, midwives, geneticists, nurses, nurse practitioners, pediatricians, genetic counselors, and potential parents do not have a clear guideline on which to base a decision. It does not appear that either professional society engaged the other stakeholders from the ‘‘medical home’’ to any great degree, particularly in the guideline articulation. It is not apparent that either society invited the very individuals whose lives are affected by the decision into the process of creating guidelines. This case of SMA carrier screening is also a good example because of the complexity of the issue for parents as well. There are parents of children with SMA who desperately wish carrier screening had been available to them before they had to witness their baby die of the condition. There are also parents of children with the condition, albeit a milder form, who are very concerned that carrier screening might limit the number of children born with the condition. This might decrease appreciation for these children and perhaps reduce research activity and funding for the condition. The American College of Medical Genetics recently released guidelines for genetic testing in children (American College of Medical Genetics, 2013). This is a revision of a statement they made more than 10 years ago, so it was a welcome addition to current considerations for all of the stakeholders. It is not apparent that the deliberative process included parents of children affected by genetic conditions. It did not include advocates of the various disease advocacy organizations. Although it would be much more difficult to come to consensus with multiple stakeholders, doing so is a worthy endeavor. The silos that exist in medicine, from basic discovery through translational science to delivery of services, severely limit progress. The learning healthcare system (Institute of Medicine, 2011) requires that all stakeholders be involved in the entire process. Starting with clinical questions emerging from clinical care and the lived experience of individuals and families with disease will help accelerate diagnostic and treatment development. Engaging clinicians (of all specialties) and citizens in formulating basic research plans will help to make discovery more relevant to translational science. Empowering communities, whether geographic, ethnic, or disease affinities, to be responsible for characterizing cohorts will stitch together a national clinical research network of engaged communities (Seifer S, 2013). Learning from the people who

A pilot study on spinal muscular atrophy carrier screening in Shanghai region using real-time PCR

To develop a screening program for spinal muscular atrophy (SMA) carriers, and to assess the carrier frequency and detection rate in Shanghai region. Quantitative analysis of the SMN1 gene by real-time PCR was developed using specimens from 15 SMA patients and 76 SMA parents from 38 affected nuclear families. A pilot screening was carried out for 1741 asymptomatic pregnant women. Frequencies of SMN1 alleles were determined with the Hardy-Weinberg equilibrium. Forty five out of the 1741 women were identified as SMA carriers by the presence of single copy of SMN1. The frequencies of no copy, 1 copy, 2 copy and 3 copy alleles were 1.37 U+00D7 10-2, 9.45 U+00D7 10-1, 2.80 U+00D7 10-2 and 1.27 U+00D7 10-2, respectively. The adjusted SMA carrier frequency was 1:35 with a detection rate of 94.49%. For those with a negative screening result, individuals with 3 copies carried a higher residual risk. The incidence of SMA carriers in Shanghai region is similar with that in Caucasian populations. Carrier screening has high detection efficiency. An effort should be made to further distinguish SMN1 gene copy numbers for those with more than 2 copies, since accurate determination of 2 and 3 copy allele frequencies is essential for post-screening genetic consulting.

Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72 400 specimens

Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ∼1 in 10 000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n=72 453) and prenatal diagnosis (n=121) for this condition. Our analysis of large-scale population carrier screening data (n=68 471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11 000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA.