SETX

Inheritance Pattern: AR

Disease ID:MONDO:0018996

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011223

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0011223

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0018996

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0018996

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0011223

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0018894

Submitter: ClinGen

​​SETX encodes senataxin, an RNA/DNA helicase; it is involved in transcriptional regulation, resolution of RNA/DNA hybrids (R-Loops), DNA damage response, regulation of autophagy, among other functions. Senataxin is ubiquitously expressed, it was shown to be present in human brain and spinal cord (Chen et al, 2004, PMID: 15106121) as well as throughout the mouse brain, with the highest expression levels in the cerebellum and hippocampus (Chen et al, 2006, PMID: 16644229). The gene was first mapped to chr9q34 in a large Maryland family with autosomal dominant juvenile onset amyotrophic lateral sclerosis, initially reported as a variant of Charcot- Marie-Tooth (CMT) (Chance et al, 1998, PMID: 9497266; Blair et al, 2000, PMID: 11085590). Around the same period, linkage analysis and homozygosity mapping of families with ataxia with oculomotor apraxia mapped the AOA2 locus to the same genomic region (Nemeth et al, 2000, PMID: 11022012; Bomont et al, 2000, PMID: 11175288). Testing of additional families allowed the identification of the human ortholog of yeast Sen1p, SETX, as the causative gene in patients with the recessive form of ataxia with oculomotor apraxia type 2 (AOA2) and the dominant juvenile form of amyotrophic lateral sclerosis type 4 (ALS4) (Moreira et al, 2004, PMID: 14770181; Chen et al, 2004, PMID: 15106121). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, clinical presentation, as well as molecular mechanism. Therefore, the disease entities have been split into Distal hereditary motor neuropathy with pyramidal features aka ALS4 (OMIM: 602433) and Spinocerebellar ataxia with axonal neuropathy aka AOA2 (OMIM: 606002) and will be assessed separately. Patients with ALS4 present during childhood or adolescence, with distal muscle weakness and atrophy, pyramidal signs. They exhibit a combination of upper and lower motor neuron degeneration; respiratory musculature is usually spared, with no bulbar involvement, slow progression and normal life expectancy in most reported patients. Although the gene is very polymorphic, only few well established causative missense variants were reported in patients with ALS4. Some of these variants segregated within families (Chen et al., 2004, PMID: 15106121; De Jonghe et al, 2002, PMID: 12023320; Drew et al, 2015, PMID: 25802885; Ma et al, 2018, PMID: 30052327; Avemaria et al, 2011, PMID: 2143876; Rudnik-Schöneborn et al, 2012, PMID: 22088787; Grunseich et al, 2020, PMID: 31957062); while others were sporadic (Saiga et al, 2012, PMID: 2257723; Grunseich et al, 2020, PMID: 31957062; Hadjinicolaou et al, 2021, PMID: 34922620). The gene-disease association is also supported by experimental evidence. Two mouse models were generated, a transgenic mouse (PrP-SETX-R2136H) and a knock-in mouse (Setx-L389S). The mutant mice displayed motor neuron degeneration and neuron toxicity with no detectable evidence for sensory abnormalities and key ALS features of TDP-43 nuclear clearance and cytosolic mislocalization. These findings were consistent with ALS4 patient pathology (Bennett et al, 2018, PMID: 29725819). The mechanism of pathogenicity is reported to be gain-of-function. By altering R-loop levels, the senataxin mutation in ALS4 leads to disruption of transcription and abnormal TGFβ signaling as shown in patient derived cells (Grunseich et al, 2018, PMID: 29395064; Grunseich et al, 2020, PMID: 31957062). In summary, there is [definitive evidence/Strong evidence] to support the relationship between SETX and [distal hereditary neuropathy/ALS4]. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.