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Andrea Oza

Andrea Oza

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Disease

Arthrogryposis

Inheritance

Autosomal recessive / autosomal dominant / X-linked recessive

Prevalence

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titlePossible sources

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

  •  Rapid - curating for molecular mechanism; LOF variant found in case 415904847 SM-MPPFO D-230412920-BH-4196-P-A BH-4196
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clinical Validity Scoring Notes and points

AUTOSOMAL RECESSIVE - meets definitive, LOF established.

PMID: 27653382 - two patients with similar phenotypes: congenital onset, reduced fetal movement, breech presentation, congenital hip dysplasia, poor head control, gross and fine motor delay, scoliosis, normal head and spin MRI. Normal cognition.

  • C.4723C>T p.Arg1575* (0.0003%, 2/84058 S.Asian chr( and c.5053C>T p.R1685* (1 allele gAD) compound het in patient 1. Both variants rare enough for AR disorder - 2x2 points = 4 VARIANT POINTS

  • c.5054G>C p.R1685P (absent gnomAD) and c.5053C>T p.R1685* compound het in patient 2 - 2 VARIANT POINTS

  • Transfected HEK293 cells with mouse Piezo2 - the truncated mouse PIEZO2 proteins were translated but nonfunctional. heterologous expression of Piezo2 constructs in HEK293 cells yielded measurements of mechanically gated inward currents above baseline noise only in cells expressing the wild-type Piezo2 construct. Not sure whether we should really score this since the variant points are increased for LOF variants anyway.

PMID: 27843126 - phenotype in table 1. Congenital respiratory insufficiency, neonatal hypotonia, delayed motor milestones, cognitive delay in some, short stature, limb weakness, absent deep tendon reflexes, dysarthria, scoliosis, arachno/camptodactyly, feet abnormalities.

  • c.5621delT L1874Rfs*5 (absent gnomAD) homozygous in 2 individuals from family A in fig 1. 4 VARIANT POINTS, 1 AR SEG

  • c.3019_3029del p.P1007Lfs*3 homozgyoug in family B. 4 VARIANT POINTS

  • c.1550_1552delGCTinsCGAA p.S517Tfs*48 HOM in two individuals from family C. 4 VARIANT POINTS, 1 AR SEG

AUTOSOMAL DOMINANT - not LOF, likely gain of function.

PMID: 30285720 - missense variant in AD family with distal arthrogryposis (DA)

  • c.8153G > A (p.R2718Q) (absent gnomAD). Per fig 4, segregates in (II2, III1, II5, and I1) - 3 AD SEGREGATIONS, 0.5 VARIANT POINT

  • Most variants in table 3 summary are missense.

PMID: 24726473 - LOF variants:

  • NM_022068.2:c.8238_8245del8 p.Trp2746∗ - de novo in patient B, with CP, short stature, micrognathia, ptosis, scoliosis. VARIANT LOCATED IN LAST EXON

  • NM_022068.2:c.8208delA p.Tyr2737Ilefs*7 - in patient EE with short stature, ptosis, opthalmoplegia. VARIANT LOCATED IN LAST EXON

  • Cites PMID: 23487782 - DA5 is caused by gain of function mutations. Did not curate further.

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Molecular Mechanism

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titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

Penetrance

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titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

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titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

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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

Case ID, Curator name, Date, Jira ticket link

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