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Gene-disease assertions not curated here (add link or write note):

Disease

Hereditary spastic paraplegia

Inheritance

Autosomal dominant

Prevalence

 

Source:

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - limited by Cerebral palsy GCEP (but may have underscored). GenCC - Strong (Invitae), Limited (Ambry). Scoring HGMD variants below. Not in Babyseq sheet.

Clinical Validity Scoring Notes and points

RINALDI 2015 PMID: 25751282 - NM_001199753.2(CPT1C):c.109C>T (p.Arg37Cys) - absent gAD v4, REVEL 0.608 - 0.5 variant point

  1. A family with HSP underwent WES on 4 affected individuals with integrated linkage. Sanger used to confirm the variant in the affected and unaffected individuals.

    1. Adult onset, pure spastic paraplegia. Slowly progressive, normal cognition. prolonged central motor conduction time and delayed sensory evoked potentials Peripheral nerve condition velocities were normal.

    2. Fig 1 - 4 affected segs and 1 obligate carrier. 5 affected segs, 7 unaffected segs.

  2. CPT1C localizes to the endoplasmic retriculum, is expressed in motor neurons and interacts with atlastin-1 , an endoplasmic reticulum protein encoded by ATL1, a known HSP gene. Localization and expression via Western in (studies in human induced plueripotent stem cells. Immunoprecipitation study in COS7 cells. EXPERIMENTAL, EXPRESSION (1), INTERACTION (1) - 2 POINTS FUNCTION

  3. The variant alters protein confirmation (via spectroscopy studies) and reduces the number and sizes of lipid droplets on overexpression in cells. +0.5 variant point.

  4. Observed reduction of mean lipid droplets in primary cortical neurons from Cpt1c -/- mice. (suggest this supports dominant negative effect of th Arg37Cys variant). Since this doesn’t recapitulate the genetics observed in humans, only adding 1 point for non-human model organism.

  5. POINT SUMMARY - GENETIC: 1 VARIANT POINT, EXPERIMENTAL: 2 POINTS VARIANT FUNCTION, 1 POINT MODEL ORGANISM = 3 POINTS

D’Amore 2018 PMID: 30564185. NM_001199753.2(CPT1C):

  1. Cohort of patients w/ clinical dx of spastic paraplegia. Targeted panel of 72 genes.

  2. c.2133+1G>A (gnomAD v4 5/1112998, 0.0004%, SpliceAI: 0.990; NMD+. Variant found het in Pt2 (table 2) 2 VARIANT POINTS

  3. c.1802C>T Thr601Met found in pt23. However, frequency for this variant seems much higher - 30/1613960 of total alleles, highest AF 0.01% 11/91086 S. Asian in gAD v4. REVEL Score: 0.886. Due to MAF, not scoring this variant

Hong 2019 PMID: 30911584 NM_001199753.2(CPT1C):c.226C>T (p.Gln76Ter) - 5/1180036 alleles gnomAD v4.

  1. Targeted sequencing NGS panel.

  2. Index patient - Onset in infancy, delayed motor milestones. Spasticity, hyperreflexia, plantar reflex, muscle weakness, progression. Similarly affected younger brother. Mother was asymptomatic but exam revealed high brisk reflexes, positive response of the right Oppenheimer sign. Variant segregated in all 3 individuals. Father and younger brother were normal after exam and were negative for variant. Counting 1 affected, 2 unaffected segs (excluding mom since mild phenotype)

  3. Variant investigated in 293T cells. CPT1C over expressed - significantly decreased expression observed in cells transfected with the c.226C>T variant (fig 2), via fluorescence. Cycloheximide administration rescued expression (cycloheximide inhibits NMD). * this is one area where I don’t follow the GCEPs logic against the cycloheximide experiment. They measured CPT1C transcript expression after treatment with cycloheximide, so if NMD is inhibited, I would think you would expect to see rescued expression (as is shown here)? I will just not score additional functional data but score the variant on its own. 2 VARIANT POINTS

Wang 2023 PMID: 36109173

  1. p.P177Rfs*59 (NMD+) inherited from asymptomatic mother (note they are asymptomatic and not unaffected, similar to family from Hong 2019), downgrade by 1 point due to potential nonseg 1 VARIANT POINT

  2. NM_001199753.2(CPT1C):c.226C>T (p.Gln76Ter) observed in another patient. Inherited from an asymptomatic parent, downgrading for potential non-seg. 1 VARIANT POINT

Segregation total - 6 affected, 9 unaffected - eLOD 3.913, 2 POINTS SEGREGATION

Source:

Clinical Validity Points Total

8.5 GENETIC

3 EXPERIMENTAL

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

Loss of function / Gain of function / Dominant Negative

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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