Overview
During The ACMG Genomics Case Conferences, a team from select institutions will present and lead discussions on an intriguing, complex and/or difficult patient case in the area of genomics. The primary focus of these case conferences will be on the adaptation of exome or genome sequencing technology in clinical care.

Session Description
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease and the most common genetic cause of infant mortality, affecting approximately 1 in 10,000 live births. The disease is characterized by progressive symmetrical muscle weakness resulting from the degeneration and loss of anterior horn cells in the spinal cord and brain stem nuclei. The disease is classified on the basis of age of onset and clinical course. SMA is caused by mutations in the telomeric copy of the survival motor neuron 1 (SMN1) gene, but all patients retain a centromeric copy of the gene, SMN2. The homozygous absence of the SMN1 exon 7 has been observed in the majority of patients and is being utilized as a reliable and sensitive SMA diagnostic test. In the majority of cases, the disease severity correlates inversely with an increased SMN2 gene copy number. Carrier detection, in the deletion cases, relies on the accurate determination of the SMN1 gene copies. Since SMA is one of the most common lethal genetic disorders, with a carrier frequency of 1/40-1/60, carrier screening has now been recommended by both ACMG and ACOG. Major progress has also been made by developing therapeutic strategies based on understanding the pathogenesis of the disease. As a result of the recent FDA approval of the antisense therapy (spinraza), support for presymptomatic treatment by newborn screening may become an effective strategy in the future. The webinar attempts to highlight the molecular genetics of SMA with a focus on diagnostics.

Learning objectives

At the conclusion of the series, participants should be able to:

1. Describe the clinical utility of whole exome/whole genome sequencing tests
2. Identify clinical indications for whole exome/whole genome sequencing
3. List determinants used to assess the probability of a variant’s pathogenicity
4. Elaborate on the importance of pre-test counseling and consent

 

Session learning objectives

At the conclusion of this session, participants should be able to:

1. Recognize the different clinical courses of type I, II and III SMA
2. Discuss the genotype/phenotype association for spinal muscular atrophy
3. Recognize the potential role of both carrier screening and newborn screening for SMA
4. Outline the pathogenesis of SMA
5. Provide insight into potential therapies for spinal muscular atrophy

 

 FINANCIAL DISCLOSURES

Planning Committee

Monica Giovanni, MS, CGC

Geisinger Health System, Brookline, MA

Nothing to disclose

 

Liming Bao, MD, PhD, FACMG

Dartmouth-Hitchcock Medical Center

Nothing to disclose

 

Staff - American College of Medical Genetics and Genomics

The following have nothing to disclose.

Jane Radford, MHA, CHCP

Claudia Barnett

Michael Watson, PhD, FACMG

 

Presenters and Disclosures

The following have nothing to disclose.

Thomas W. Prior, Ph.D., FACMG

Professor of Pathology and Neurology

Ohio State University