P.38 A novel splice site variant in a patient with spinal muscular atrophy and hypoplastic left heart syndrome

Spinal muscular atrophy (SMA) is an autosomal recessive disorder causing degeneration of motor neurones in the anterior horn of the spinal cord. SMA is caused by homozygous in activation of the SMN1 gene but a highly homologous copy (SMN2), which also produces a small amount of functional SMN protein, can mitigate disease severity. We present a patient with a severe SMA phenotype with hypoplastic left heart syndrome (HLHS), characterize a novel spice-site variant in the SMN1 gene and describe the unusual pathological features in muscle biopsy. The patient was born to consanguineous parents in a national heart center due to antenatal diagnosis of HLHS. Postnatal examination (day 4) revealed decreased tone, a lack of anti-gravity movements, absent deep tendon reflexes but no respiratory distress or feeding problems. Due to the combination of suspected muscle disease and HLHS, together with the results below, treatment was discontinued and the patient died on day 10 of life. Whole genome sequencing (WGS) revealed an apparently homozygous variant in SMN1 located in the donor splice-site between exon 7 and intron 7, c.*3+1G>T (NM_000344.3). MLPA identified one copy of SMN1 and SMN2. Analysis of RNA showed a transcript lacking exon 7 and western blotting of SMN protein from muscle showed reduced levels comparable to other SMA1 patients. Muscle biopsy and subsequent immunohistochemical and immunofluorescence showed unusual expression of embryonic myosin heavy chain in the patient compared to controls and other SMA patients. This case highlights the importance of rapid diagnosis of newborns to allow further treatment decisions to be made. Up to 30% of HLHS patients have associated conditions and the combination with SMA has been previously described, whether this is more than the coincidence of two relatively common conditions is unclear. A severe SMA phenotype has been previously seen in other patients with a splice site variant in intron 7.