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Gene-disease assertions not curated here (add link or write note): AD spastic paraplegia (caused by SNVs)

Disease

Increased Risk of Amyotrophic lateral sclerosis

Inheritance

Autosomal dominant

Prevalence

 <1 / 1 000 000

Source: ORPHANET

Rapid or full curation?

  • Rapid
  • Full

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

  • Sporadic ALS patients and controls from Netherlands.

  • Association analysis performed on NIPA1 after excluding C9ORF72 positive cases.

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

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Short tandem repeats - GCG polyalanine repeat (coding region)

  • Increased risk for ALS: >8 repeats

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

    • Meta analysis on 6245 patients with ALS and 5051 controls showed an increased risk of ALS in individuals with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10-5).

  • Gene in ALSoD https://alsod.ac.uk/output/gene.php/NIPA1

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

 Options

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.

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

 Examples

- 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

Case ID, Curator name, Date, Jira ticket link

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