Year: 2024
Type: article
Study design: Case Report
Abstract: Spinocerebellar ataxia with axonal neuropathy (SCAN) is a group of conditions characterized by progressive cerebellar ataxia with peripheral neuropathy. SCAN2 is one such condition associated with juvenile onset of ataxia, increased serum alpha-fetoprotein (AFP), oculomotor apraxia (OMA) and biallelic mutations in the gene SETX. This entity was previously known as AOA2, but given the inconsistent finding of OMA, it is more accurate to refer to the condition as SCAN2. Here we present the case of a young adult male with SCAN2 and a unique combination of difficult to detect variants, highlighting the combined value of whole genome sequencing (WGS) and RNA sequencing (RNASeq) in solving undiagnosed diseases where other approaches have failed. The proband, 29-year-old male, presented to the NIH Undiagnosed Diseases Program (UDP) with a 10-year history of progressive gait instability and peripheral neuropathy. He had normal development throughout childhood and was active without any concerns. At 20-years-old, he noticed increased weakness and difficultly balancing. He suffered numerous falls and injuries and began to lose sensation in his hands and feet. He also reported progressive dysarthria and difficultly with fine motor control. At age 24, an EMG confirmed an axonal sensory motor polyneuropathy. A brain MRI showed moderate diffuse pancerebellar atrophy and although his AFP was normal, he received a diagnosis of SCAN. Despite extensive investigations including family exome sequencing, a comprehensive ataxia panel, repeat expansion testing, and mitochondrial sequencing, no molecular explanation had been uncovered. As part of his UDP evaluation, the family underwent a quartet whole genome sequencing (WGS) study which identified compound heterozygous variants in SETX including a 5.55kb deletion involving the penultimate exon of SETX and an intronic variant likely to affect mRNA splicing. The detrimental impact of both variants was established by showing absence of normal SETX protein expression on fibroblasts and demonstrating that the intronic variant resulted in aberrant mRNA splicing leading to skipping of exon 16. This case highlights the power of WGS, RNASeq and protein expression studies in solving undiagnosed diseases emerging from unusual structural and cryptic splicing variants.
Source: Genetics in Medicine Open
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,200
OpenAlex ID: W4392606631