Disease | Non-syndromic X-linked intellectual disability |
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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 Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive Source: ClinGen Intellectual Disability and Autism GCEP, accessed 08.07.2023 |
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other | 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: Sources: PMID: 34282157, 8334699, 7977354, 8776586 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.
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.
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Penetrance options Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (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 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. | 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. |
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 | 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 |
BCL-168
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Getting issue details...
STATUS
Andrea Oza, 08.14.2023 |