Clinical and Laboratory Standards Institute NBS13—Newborn Screening for Spinal Muscular Atrophy describes newborn screening (NBS) laboratory tests and screening strategies used to identify newborns at increased risk of developing spinal muscular atrophy (SMA). SMA is a serious condition that causes weakness, motor decline, and death in otherwise cognitively normal children. Early detection and intervention are critical to improving the strength and survival of newborns with SMA, allowing them to live healthier and more productive lives. SMA is caused by loss of function of the survival of motor neuron (SMN) gene, with about 95% of SMA cases characterized by a homozygous deletion in SMN1 exon 7, leading to deficiency of the SMN protein and degeneration of motor neurons followed by progressive muscle weakness. The severity of the disease is typically inversely correlated to the number of SMN2 copies. CLSI NBS13 describes the various methods used for SMN1 exon 7 deletion testing and SMN2 copy number analysis, validation of assays, integrating SMA NBS into NBS laboratory operations, interpreting and reporting screening results, as well as short-term and long-term follow-up.

CLSI NBS13 discusses the detection of 5q spinal muscular atrophy (SMA) by population-based newborn dried blood spot (DBS) screening and preanalytical, analytical, and postanalytical aspects of newborn screening (NBS) for SMA. It focuses on analytical methods to detect the homozygous absence of SMN1 exon 7, which accounts for approximately 95% of SMA cases, as well as methods for SMN2 copy number analysis. CLSI NBS13 describes:

• Background information on the biological and clinical features of SMA, and the value of the SMN2 copy number in predicting disease severity

• Preanalytical considerations, including population education and issues of consent before screening

• Analytical methodologies for detecting the homozygous absence of SMN1 exon 7, including:

– Real-time quantitative PCR (qPCR)

– High-resolution melting analysis (HRMA)

– Multiplex ligation-dependent probe amplification (MLPA)

– Digital PCR (dPCR)/droplet digital PCR (ddPCR)

– Capillary electrophoresis

– Mass spectrometry

• Analytical methodologies for SMN2 copy number analysis, including real-time qPCR, dPCR, and capillary electrophoresis

• Screening strategies and laboratory screening algorithms, cutoff value determinations, case definition, and risk assessment for NBS programs to consider when implementing SMA NBS

• Postanalytical short-term follow-up (STFU) and long-term follow-up (LTFU) procedures, including case tracking, diagnostic testing needed to confirm an SMA diagnosis, and recent treatments available for SMA

The intended users of CLSI NBS13 include NBS laboratories, follow-up and program personnel, public health program administrators, diagnostic medical laboratories, SMA treatment centers, health care providers (HCPs; eg, primary care providers, neonatologists, pediatricians, neurologists), regulatory agencies, public health policy makers, and manufacturers of instruments, reagents, and related products used for NBS.

CLSI NBS13 does not include:

• Details of carrier screening

• Details of confirmatory diagnostic laboratory testing

• Details of clinical treatments and monitoring

• Comparative cost information