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Andrea Oza

Andrea Oza

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Disease

KIF1A-related autosomal recessive spastic paraplegia

Inheritance

Autosomal recessive

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Mentioned in ClinGen Intellectual Disability curation. GenCC - Strong by Ambry

Clinical Validity Scoring Notes and points

Klebe et al. (2012)

  • FSP546 - Homozygous c.1048C>G p.R350G (1 allele European gAD v4, 0.0001%; REVEL 0.930). Het in both parents, HOM in 4 affected (3 segs), wt or het in 5 unaffected sibs. (0.25^3)*(0.75^5)= 0.003707885 0.5 VARIANT POINTS

  • FSP1079 - homozygous c.764C>T Ala255Val (absent gAD, REVEL=0.814) mutation in affected members of a consanguineous Palestinian family with SPG30. Age at onset ranged from 10 to 39 years, and patients had spastic gait with axonal sensorineuropathy after long disease duration. None had cerebellar signs. Appears to be a different family from Erlich, pedigree is different and no author overlap. There are 5 affected segregations per fig 1 (Not including the affected HOM dad), and one het unaffected sib. (0.5^5)*(0.5^1)= 0.015625 likelihood. 0.5 VARIANT POINTS

Erlich 2011 PMID: 21487076 - c.764C>T Ala255Val (absent gAD, REVEL=0.814) A Palestinian family (parents from same village, but no known consanguinity), with HSP. Genotyping to find ROH performed, then candidate genes were reviewed and selected KIF1A for sequencing via Sanger. Three sibs homozygous, parents and four unaffected heterozygous. (0.25^2)*(0.75^4)= 0.019775 0 points seg, 0.5 VARIANT POINTS.

Lee 2023 PMID: 37001573 - NM_001244008.1:c.2751_2753delGGA Glu917del absent gnomAd Korean family with mild HSP underwent WES. Variant has high freq in gnomAD did not review further. https://gnomad.broadinstitute.org/variant/2-241696840-ATCC-A?dataset=gnomad_r2_1

YONEKAWA 1998 - PMID 9548721 - KO MOUSE, showed motor and sensory disturbances, died within a day of birth. In nervous system of mutant mice, the transport of synaptic vesicle precursors showed a specific and significant decrease. marked neuronal degeneration and death occurred both in KIF1A mutant mice and in cultures of mutant neurons. 2 points mouse model

LEE 2015 PMID: 25265257 - FIG 4. Recessive variants A255V and R350M, both variants showed increased proximal distribution compared to WT. +0.5 experimental points for both variants - 1 POINT.

Calculating segregation manually due to family FSP1079 - 0.015625*0.019775*0.003707885= 0.00000114 likelihood, 3 points seg per https://docs.google.com/spreadsheets/d/1ynxrqsKevXAUMOkEK22Fflse_Ql2u_W_PXhR-LX6ua4/edit#gid=1134334

Clinical Validity Points Total

7.5

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

MODERATE

Molecular Mechanism

UNKNOWN

Penetrance

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

Expand
titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

Expand
titleOptions

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

Expand
titleExamples

- 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

SEE ABOVE

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 11.28.2023 D-190115360-BH-4000-P-A