124P Hidden in plain sight: genome reanalysis to identify an intragenic novel variant in the SMN locus in a patient with an undiagnosed lower motor neuron disease

Genome sequencing adds an important diagnostic tool for patients with unsolved or atypical phenotypes. Here we describe the diagnostic journey in a patient with an atypical progressive course of riboflavin and thiamine responsive neurodegeneration, who is finally diagnosed with SMA through genome sequencing. The patient is a 28-year-old female presenting at age 4 years with fever, nausea, vomiting and leg pain, followed by itchy lesions on the soles of the feet, burning pain, frequent falls, and foot drop. At age 6-7 years, she developed progressive lower and then upper extremity weakness with loss of independent ambulation at age 10 years. She had scoliosis surgery at age 14 years and developed sudden respiratory failure requiring full-time ventilation via tracheostomy at age 19 years. She had progressive tongue and facial fasciculations with a dramatic response to high dose riboflavin and thiamine supplementation. Family history was significant for an undiagnosed older brother who passed away at age 7 years, who presented with a fever episode at age 2 years followed by progressive difficulty in walking and steppage gait. EMG and muscle biopsy revealed chronic neurogenic changes. Testing for SMN (RT-PCR) was negative. Repeat-SMN testing (MLPA) revealed heterozygous carrier status for the common SMN exon 7 deletion. Three independent WES studies were unrevealing. Research-based genome sequencing with an SMA centric re-analysis tool identified a novel missense variant c.809G>T p.(Ser270Ile) in SMN1, which was previously not recognized as located in SMN1. While exome sequencing did not allow the position of this variant to be unambiguously resolved between SMN1 and SMN2, genome sequencing did unambiguously position the variant on SMN1 via phasing with intronic sequence differences between SMN1 & SMN2. SMN2 copy number was 1. The parental data enabled a determination of compound heterozygosity. Location of intragenic mutations in SMN1 are expected to contribute to clinical severity. In the era of diseases modifying treatments, WGS, followed by direct gene sequencing, ended this diagnostic odyssey lasting more than two decades.