Disease | Increased Risk of Amyotrophic lateral sclerosis |
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Inheritance | Autosomal dominant |
Prevalence | <1 / 1 000 000 Source: ORPHANET |
Rapid or full curation? | - Rapid Partial (for STR cutoffs)
- Full
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ClinGen / GenCC / BabySeq / HGMD / OMIM | CLINGEN - None. GenCC - Strong/Moderate. GenCC - none (strong/moderate for spastic paraplegia) |
Clinical Validity Scoring Notes and points | Tazelaar 2019 PMID: 30342764 meta-analysis on 6245 patients w/ ALS and 5051 controls showed an overall increased risk of ALS in those w/ expanded (>8) GCG repeat length. (odds ratio = 1.50, p = 3.8×10−5, 95% CI [1.24, 1.82]) repeating the analysis by excluding 322 C9orf72 repeat carriers yielded a p value of 7.7×10−5 for the fixed-effects meta-analysis (OR = 1.49, 95% confidence interval [CI] = 1.22‒1.81) and a p value of 1.0×10−4 for the multivariate logistic regression analysis (OR = 1.47, 95% CI = 1.21‒1.78). Exclusion of an additional 171 samples (133 cases and 38 controls) carrying a nonsynonymous or loss-of-function mutation in SOD1, FUS, or TARDBP did not alter the results (fixed-effects meta-analysis p value = 7.5 ×10−5, OR = 1.49, 95% CI = 1.22‒1.81).
Hilde Van Daele 2023 PMID: 37043475 large cohort of 6013 sporadic ALS patients and 2411 matched controls Used cutoff of 10 repeats for NIPA1. Expansions in this gene were considered risk factors. Expansions were observed in patients all of whom had a variant in another ALS-related gene, see supplement: C9orf72 expansion (5 cases, 1 control); SOD1 (1 case, 0 controls); C9ORF72 sv (1 case, 0 controls); CHMP2B (1 case, 0 controls); NEK1 (1 case, 0 controls); SYNE1 (1 case, 0 controls), UNC13A (22 cases, 9 controls); ATXN1 expansion (1 case, 0 controls), ATXN2 (1 case, 0 controls); C9ORF72 + SYNE1, FUS + UNC13A, SPG11 + UNC13A
Dekker 2016 PMID: 26777436 Blauw 2012 PMID: 22378146 2292 ALS patients and 2777 controls from Netherlands, Germany, Belgium. Sequenced NIPA1 and analyzed for the polyalanine tract. Found an effect on ALS susceptibility in individuals with >8 repeats (P¼ 1.6×1024, OR¼1.71, 95%CI¼1.30–2.26 Does not appear other genes were ruled out per methods.
Source: |
Clinical Validity Points Total | Source: |
Clinical Validity Classification | Expand |
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| title | Classifications (pts) |
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| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
| Source: |
Molecular Mechanism | Expand |
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| Loss of function Gain of function Dominant negative Unknown Other |
| Short tandem repeats - GCG polyalanine repeat (coding region) Review STRchive: Normal: 6-10. Pathogenic 11-56. "age_onset":"Typical: 44-60 (PMID: 26777436); Range: 25 (PMID: 22378146) - 77 (PMID: 26777436)", gnomAD Normal ≤ 10, Pathogenic ≥ 11 Nirvana - normal 0-8, expanded 9-inf (WILL FLAG MANY CASES AT 9 OR HIGHER) STRipy - Normal 6-10, pathogenic ≥ 11 PMID: 30342764 Gene in ALSoD https://alsod.ac.uk/output/gene.php/NIPA1
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Penetrance | Expand |
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| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | Source: |
Age of Onset | Expand |
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| Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | |
Severity | Expand |
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| Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers. |
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Clinical Features | Sources: |
HPO Terms https://hpo.jax.org/app/ | |
Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary | Expand |
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| - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited |
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Case ID, Curator name, Date, Jira ticket link | |