Spinal Muscular Atrophy with Respiratory Distress Type 1 via the IGHMBP2 Gene

Spinal muscular atrophy with respiratory distress type 1 (SMARD1; OMIM 604320) is a disease of the anterior horn cell that most often presents before 6 months of age with intrauterine growth retardation, foot deformities, distal muscle weakness, and respiratory failure due to diaphragmatic eventration and paralysis (Grohmann et al. Nat Genet 29:75-77, 2001). Muscle weakness is progressive and predominately affects the lower distal extremities. Motor nerve conduction velocities, particularly in the legs, are very slow (Pitt et al. Brain 126:2682-2692, 2003). Among a cohort of twenty-nine infants with variant-confirmed SMARD1, Grohmann et al. (2003) found that three-fourths of the patients had IUGR and more than a third were affected by prematurity. The most prominent feature was life-threatening respiratory distress, with stridor or a weak cry being the most common presenting signs. Nearly all patients developed eventration resulting in diaphragmatic paralysis. Muscle weakness was first evident in the lower distal muscles; however, upper limbs were subsequently affected, leading to paralysis of the trunk and limb muscles. Muscle biopsies showed neurogenic changes with myofiber hypertrophy and atrophy.

Spinal muscular atrophy with respiratory distress type 1 is inherited as an autosomal recessive disorder due to variants in the IGHMBP2 gene. IGHMBP2 encodes the immunoglobulin μ-binding protein 2, an ATP-dependent helicase which localizes to neuronal and non-neuronal cells and associates with ribosomes (Guenther et al. Hum Mol Genet 18:1288-1300, 2009). Degeneration of α-motor neurons from the anterior horn is likely related to disruption of protein translation (Guenther et al. 2009). Missense variants appear to be concentrated in the predicted helicase domains (Grohmann et al. Ann Neurol 54:719-724, 2003) while nonsense variants occur throughout the protein. Small deletions and splice site variants are also documented.

The immunoglobulin μ-binding protein l is coded by the IGHMBP2 gene (OMIM 600502) located on chr 11q13.

Respiratory failure between ages 6 weeks and 6 months along with diaphragmatic eventration or, alternatively pre-term birth, is a highly sensitive predictor of IGHMBP2 involvement (Guenther et al. Hum Mutat 28:808- 815, 2007).

This test provides full coverage of all coding exons of the IGHMBP2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).