Hereditary neuropathy or pain disorder

Gene: SAMD9L

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:02 p.m. | Last Modified: 24 Feb 2025, 5:02 p.m.

Panel Version: 6.148

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Green List (high evidence)

Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review.

Created: 4 Nov 2024, 10:37 p.m. | Last Modified: 4 Nov 2024, 10:37 p.m.

Panel Version: 6.79

In OMIM there are associations with Ataxia-pancytopenia syndrome (OMIM:159550) and Monosomy 7 myelodysplasia and leukemia syndrome 1 (OMIM:252270) and a provisional association with Spinocerebellar ataxia 49 (OMIM:619806) all with autosomal dominant inheritance. In Gene2Phenotype there is an association with SAMD9L-related Ataxia-Pancytopenia Syndrome (limited).

3 cases reported with neuropathies being a major phenotypic feature and other cases with some neurological features.

PMID:32808377 - Vaughan et al 2020 - report a 66 year old female with childhood onset of demyelinating neuropathy, initially diagnosed as CMT1, with onset of a progressive cerebellar ataxia in her 50s. A SAMD9L [c.2956C>T p.(Arg986Cys)] variant was identified by WES. No segregation data was available. This missense variant has been reported in other patients with Ataxia pancytopenia (ATPX).

PMID:36553623 - Eggermann et al 2022 - report a mother and daughter with demyelinating neuropathy and a shared missense variant in SAMD9L (NM_152703.5:c.2956C>T; p.(Arg986Cys) that appeared in a low percentage of blood cells (somatic mosaicism). The authors propose this is due to the gain of function variant having an adverse effect on cell proliferation. In the daughter’s peripheral blood sample, another SAMD9L missense variant (NM_152703.5:c.3283A>G; p.(Lys1095Glu)) was also found, but appeared to be of somatic origin and was not present in other tissues. The mother also showed uniparental disomy for chromosome 7.

PMID:31053103 - Thunström and Axelsson (2019) - report a female with transient pancytopenia at 3 months of age and then a slow developing pathology in the peripheral and central nervous system. A de novo variant c.2686 T > G, p.(Phe896Val) in SAMD9L in a patient with The variant was identified by WES. There was no signs of mosaicism.

PMID:27259050 - Chen et al 2016 - report analysis of 2 families with ataxia-pancytopenia syndrome, with a variable phenotype and some neurological features (gait imbalance, horizontal and vertical nystagmus, dysmetria, hyperreflexia, ankle clonus, and sometimes extensor plantar responses) Exome sequencing identified a missense mutation (c.2640C>A, p.His880Gln) in SAMD9L in the first 4-generation family that cosegregated with disease. In vivo hematopoietic mosaicism was observed in 2 individuals. Targeted sequencing of SAMD9L in the second family identified the missense mutation (c.3587G>C, p.Cys1196Ser).


PMID:28202457 - Tesi et al 2017 - 2 families with cytopenias in combination with immunodeficiency, neurological symptoms, and susceptibility to familial myelodysplastic syndrome. Neurological symptoms included balance impairments, lower limb stiffness and weakness, nystagmus, lower limb hyperreflexia, A heterozygous missense variant c.2956C>T (p.Arg986Cys) in SAMD9L was identified by WES in family 1. Two family members who were mildly affected or unaffected also carried this variant plus a rare SAMD9L c.698C>A variant. In the second family targetted sequencing identified a heterozygous SAMD9L c.2672T>C (p.Ile891Thr) missense variant in both affected individuals. Both SAMD9L p.Ile891Thr and p.Arg986Cys variants were found to decrease cell proliferation. Mosaicism was detected in hematopoietic cells.

Created: 4 Nov 2024, 10:32 p.m. | Last Modified: 4 Nov 2024, 10:32 p.m.

Panel Version: 6.75

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Ataxia-pancytopenia syndrome, OMIM:159550; ataxia-pancytopenia syndrome, MONDO:0008038

Publications

• 32808377
• 36553623
• 31053103
• 27259050
• 28202457

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

Sources: Expert list

Created: 19 Oct 2024, 11:23 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
32808377: 36553623 : 31053103: 27259050: 28202457

Publications

• ataxia
• peripheral neuropathy
• pancytopenia