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Andrea Oza

Andrea Oza

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  1. DEVELOPMENTAL DELAY.

    1. PMID: 35224839 - associates asserts that LOF variants are associated w / developmental delay, but only describe missense variant. Describes p.Leu137Phe missense variant in 1 child, de novo, with mild to moderate developmental delay. Overexpressed variant in HEK293 cells, observed variant displayed no catalytic activity. Gene is not missense constrained, has a moderate LOEUF score of 0.78. At most 1.1 point (adding functional 0.5, de novo 0.5, missense common disease 0.1 points). Another variant c.421A>G (p.Thr141Ala) de novo in patient with possible developmental delay. Not scoring this because the phenotype is vague/unclear.

    2. PubMed: 33057194 - c.284G>A p.R95Q de novo in patient 20399, but multiple de novo variants found, see supplemental table 1

    3. PMID: 35982159 0 supplemental data 3; same patient as 33057194

  2. Agenesis of corpus callosum and ventriculomegaly (fetal imaging) -

    1. PMID: 36307859 and 36307859 (overlapping authors, likely same fetus). In Supplement, classified as VUS, described as de novo. Agenesis of the corpous callosum is a feature of Lenz-Majewsky dwarfism (PMID 29341480)

    2. Deletion hg19 arr8q22.1(97 214 184–98 480 468) × 1 in fetus with Macrocephaly, mild VM, dysplastic CC, signs of MCD, overgrowth. Deletion impacts at least 7 other genes.

Disease

Lenz-Majewski syndrome

Inheritance

Autosomal dominant

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

  VERY RARE

Source:

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

No ClinGen curation. GenCC conflicting w/ US labs: Strong by Invitae, limited by Ambry. HGMD variants curated in Clinical Validity scoring. This is the only phenotype listed for this gene in OMIM.

Clinical Validity Scoring Notes and points

It appears the phenotype is so specific that several studies only sequenced this gene. Did not penalize the scoring for this reason.

PMID: 24241535 author overlap with PMID 29341480 . See supplement table 1

  • c.1058A>G p.Q353R recurrent variant, identified in patients 2-4. Confirmed de novo in patient 3 and 4. Variant injected into zebrafish embryo and showed craniofacial abnormalities. (0.5 variant/patient points x 3)+(2 de novo x 0.5) = 2+0.5 functional evidence = 3 points.

  • c.805C>T p.Pro269Ser in Patient 1 - confirmed de novo. Variant injected into zebrafish embryo and showed craniofacial abnormalities. 1.5 point.

  • c.794T>C p.Leu265Pro in patient 5 same patient described and counted in PMID: 29341480. Variant injected into zebrafish embryo and showed craniofacial abnormalities. 0.5 POINT

PMID: 29341480

  • Sequencing of PTDSS1 only.

  • NM_014754.3:c.794T>C (p. Leu265Pro) in patient 1 (exon 7). Same patient as patient previously reported in PMID:24241535

    • parents not available. REVEL Score: 0.877, absent gnomAD.

  • NM_014754.3:c.284G>T(p.Arg95Leu) mutation in exon3 in patient 2

    • parents not available. REVEL Score: 0.778. Absent gnomAD 0.5 POINTS

  • NM_014754.3:c.806C>T (p.Pro269Leu) in exon 7 in patient 3

    • de novo inheritance was confirmed. REVEL 0.819. Absent gnomAD - 1 POINT

PMID: 31403251

  • NM_014754.3:c.284G>T(p.Arg95Leu) (reported in 9341480) in a patient with Lenz-Majewski syndrome. Reportedly de novo. Sequencing of PTDSS1 gene only. 1 POINT

Source:

Clinical Validity Points Total

Source: 7.5

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

At least MODERATE.

(I stopped curation at this point because the variant I am working on will only reach VUS as LOF is not a mechanism of disease)

Source: 24241535, 29341480, 31403251.

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Likely Gain of function / Dominant Negative

PMID: 29341480 - caused by activating de novo variants (per text)Sources: 24241535, 27044099

Gene has moderate LOEUF score of 0.78.

No high frequency SV deletions in gnomAD.

PMID: 24241535 - supports GOF mechanism by functional evidence. Summary from abstract: “Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1.”

  • Patient fibroblasts showed higher incorporation of radiolabel into phosphatidylserine and phosphatidylserine-derived phosphatidylethanolamine compared to control cells, indicating increase in phosphatidylserine sythesisphosphatidylserine synthesis.

  • Patient fibroblasts showed incorporation of 3H serine into phosphatidylserine and phosphatidylethanolamine that was resistant to inhibition by phosphatidylserine

  • Therefore, patient mutations render the enzyme PSS1 resistant to feedback inhibition by phosphatidylserine.

PMID: 27044099

  • HEK293 cells. Expression of mutant PSS1 enzymes showed a significant increase in PS synthesis and accumulates in the ER. They showed significantly reduced levels of PI4P both in the Golgi and the PM by activating the Sac1 phosphatase.

  • Inhibitors of PI4KA blocked PS synthesis and reduced PS levels by 50% in normal cells, but mutant enzymes alleviated the PI4P dependence of PS synthesis.

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)

Congenital

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.

Severe

Clinical Features

Cutis laxa

Facial dysmorphism

Severe growth retardation

Hypoerostotic skeletal dysplasia

Intellectual disability

Sources: 9341480

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

The PTDSS1 gene is associated with autosomal dominant Lenz-Majewski syndrome, a rare disease that is characterized by craniofacial, dental, cutaneous, and limb anomalies. Intellectual disability is also a feature (PMID: 24241535, 29341480, 31403251). Pathogenic variants are typically found to be de novo missense variants, and the molecular mechanism is likely gain-of-function (PMID: 24241535, 27044099). Variants in this gene have also been reported in individuals with developmental delay and/or autism; however, evidence supporting this gene-disease association is limited (PMID: 35224839, 33057194).

Case ID, Curator name, Date, Jira ticket link

SDSM-VS, AO, 11/6/2024