Inheritance

X-linked Recessive

Prevalence

 1-9 / 1 000 000

Source: orphanet

Rapid or full curation?

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: ClinGen Intellectual Disability and Autism GCEP, accessed 08.07.2023

Clinical Validity Classification

Definitive

Source: ClinGen Intellectual Disability and Autism GCEP, accessed 08.07.2023

Molecular Mechanism

Loss-of-function (Due to LOF variants or triplet repeat expansion that results in methylation)

Triplet repeat expansions:

• Location and motif - CCG in the 5’UTR https://stripy.org/database/AFF2

• Repeat Ranges:

  • Normal 6-30

  • Grey zone 31-60

    • These alleles may vary slighly upon transmission but aren’t expected to expand to a full mutation (PMID: 9063737)

  • Premutation 61-200

  • Pathogenic expansion >200

• Sources: PMID: 34282157, 8334699, 7977354, 8776586, 9063737

• Review notes:

  • 34282157 - Validation study for TP-PCR, uses the above cutoffs for repeat ranges.

  • 8334699 - One of the first studies describing expansions in AFF2. Normal individuals had 6-25 copies of the repeat. Affected males had >200 and have methylation. Carrier females also had 200 copies

  • 7977354 - segregation observed in several families. The ID can be mild and affected males may have affected daughters. Affected males had repeats of 800 to far >1000 bp in length (ie ~260 to >330 repeats). Normal females had 900bp, 800bp and 400bp bands. They also describe contraction of an enlarged repeat of ~400 repeats in a mother to only 25 in the daughter. Transmission through a female resulted in an expansion of the repeat in 12/15 of the cases, whereas after transmission through males a decrease in length was found in all 3 cases tested. Apart from mild intellectual disability, affected males and females did not show a specific clinical phenotype. overlap with the PMID 8334699 authors.

  • 7783162 - Segregation across several families, overlap with the PMID 8334699 authors.

  • 8776586 - Population survey of boys with learning difficulties and their mothers to determine the repeat lengths for normal, premutation and full mutations. This is the study where most of the repeat ranges cited in other papers come from. There was one expansion observed from a mother who had 66 repeats present.

  • 9063737 - defined the common/stable range as 0-30. Intermediate range was 31-60, and had three observations of unstably transmitted repeats in this range.

LOF Sources: PMID: 22065534, 21739600, 8673085, 17343270, 11246464

• Curated as haploinsufficient by ClinGen dosage sensitivity (last evaluated 12/08/2020). Evidence summary:

• PUBMED: 22065534 Sahoo (2011): Report of two male patients with focal deletions involving AFF2 who had features consistent with FRAXE syndrome. Patient 1 had a maternally-inherited deletion resulting in loss of exons 2-4. Maternal phenotype is not reported. Patient 2 had a deletion resulting is loss of exons 1-3 and the 343 kb region upstream of AFF2, inheritance was not known. Patient 2 also had a 358 kb duplication at 1q21.1 that overlapped the TAR syndrome critical region.

• PUBMED: 21739600Stettner (2011): Report of two brothers with features consistent with FRAXE syndrome who had a maternally-inherited deletion in AFF2 resulting in loss of exon 3. The mother was phenotypically normal and an affected maternal uncle was also found to carry the deletion.

• PUBMED: 8673085 Gecz (1996): Characterization of a deletion found in a boy with features consistent with FRAXE syndrome that had been reported previously (PMID: 7536393). The deletion was 982 kb and resulted in loss of exons 2 and 3 and a premature truncation. It was maternally-inherited.

• Loss of function variants in the AFF2 gene have been observed in individuals with FRAXE type X-linked intellectual disability (OMIM: 309548). This condition can also be caused by GCC repeat expansion in the promoter region of AFF2 gene. When males carry more than 200 copies of GCC repeat, methylation at the CpG island occurs and AFF2 gene expression is suppressed. The clinical presentation of affected males includes developmental delay, speech delay, intellectual disability, ADHD, autism and seizures/epilepsy. The potential phenotypic spectrum seen in female carriers is not fully understood. PMIDs: 17343270 and 11246464 These publications implicate loss of AFF2 with FRAXE syndrome due to deletion or hypermethylation.

Penetrance

(list source/PMID)

Unknown

Source: Expansions are rare, ID is milder than FMR1 Fragile X, affected males have been observed to transmit to affected daughters. Incomplete penetrance in which carrier females are unaffected have been observed; however, affected females have also been reported (see references in molecular mechanism above)

Age of Onset

(list source/PMID)

Congenital

Severity

Moderate

Clinical Features

Nonsyndromic intellectual disability, both affected males and females observed.

Sources: 7783162, 7977354

HPO Terms

https://hpo.jax.org/app/

HP:0001249 Intellectual disability

Gene SOPs & Notes

Both LOF deletions and short tandem repeat expansions of CCG in the 5' untranslated region have been observed.

• Location and motif - CCG in the 5’UTR https://stripy.org/database/AFF2

• Repeat Ranges:

  • Normal 6-30

  • Grey zone 31-60

  • Premutation 61-200

  • Pathogenic expansion >200

• Sources: PMID: 8334699, 8776586, 7977354, 8776586

Curation Summary

The AFF2 gene is associated with X-linked intellectual disability. While this condition primarily affects males, affected females have been observed. This condition is caused by both loss-of-function variants and CCG repeat expansions in the 5' untranslated region (PMID: 8334699, 8776586, 7977354, 8776586).

Case ID, Curator name, Date, Jira ticket link

https://broadinstitute.atlassian.net/browse/BCL-168 Andrea Oza, 08.14.2023