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

Disease

Non-syndromic X-linked intellectual disability

Inheritance

X-linked Recessive

Prevalence

 1-9 / 1 000 000

Source: orphanet

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD

ClinGen Intellectual Disability and Autism GCEP, accessed 08.07.2023

Clinical Validity Scoring Notes and points

AFF2 variants were first reported in relation to X-linked non-syndromic intellectual disability in 1993 (PMID:8334699). This gene encodes a putative transcriptional activator involved in speckle biogenesis. AFF2, previously referred to as FMR2, is associated with the folate-sensitive fragile X E locus on chromosome X. An expansion of the GCC trinucleotide repeat in this gene leads to Fragile XE syndrome, or FRAXE, a form of X-linked intellectual disability. Individuals with variants in AFF2 commonly present with intellectual disability, seizures, behavioral manifestations, and mild dysmorphic facial features.

AFF2 is highly constrained for LoF variants (gnomAD v2.1.1). The repeat expansion, c.-460_-458GCC(6_25), is reported in at least six probands in three publications (PMIDs: 8334699, 8023854, 21739600) and is included in this curation. One additional missense variant (PMID:21739600) is included in this curation.

This gene-disease relationship is also supported by functional expression experimental evidence, a drosophila rescue, mouse model, protein interaction, biochemical function, and patient cell alteration evidence (PMIDs: 9299237, 11171404, 11923441, 19136466, 23562910).

In summary, there is a definitive gene-disease relationship between AFF2 and X-linked non-syndromic intellectual disability. This classification was originally approved by the Intellectual Disability and Autism Gene Curation Expert Panel on October 20, 2017. As of June 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.

Source:

Clinical Validity Points Total

12

Source:

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Source:

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

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)

Congenital

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

Pathogenic variants are short tandem repeat expansions of CCG in the 5' untranslated region.

  • Normal range 6-30

  • Intermediate/grey-zone 31-60

  • Premutation range 61-200

  • Pathogenic range ≥200

Source: PMID: 34282157

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-dsiease relationship is limited

Case ID, Curator name, Date, Jira ticket link

BCL-168 - Getting issue details... STATUS

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