ClinGen Dosage Sensitivity Curation Page

AFF2

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
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.
21739600 Stettner (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.
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.

Haploinsufficiency phenotype comments:

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. Additional evidence includes: PMIDs: 17343270 and 11246464 These publications implicate loss of AFF2 with FRAXE syndrome due to deletion or hypermethylation. PMID:?7536393 This publication describes an intragenic deletion involving exon 2-3 that results in a frameshift and premature stop codon, as well as a larger deletion involving the whole AFF2 gene observed in male patients with ID. It is unclear whether the large deletions involves genes other than AFF2. PMID: 17343270 Honda et al. report a female with mild intellectual disability (ID) and a balanced translocation, 46,XX, t(X;15)(q28;p11.2), and a male diagnosed as having mucopolysaccharidosis type II (MPS II or Hunter syndrome) with atypical early-onset ID and a normal male karyotype. Molecular cytogenetic analyses, including fluorescence in situ hybridization and array-based comparative genomic hybridization using an in-house X-tiling array, revealed that first patient to have a breakpoint at Xq28 lying within the AFF2 gene and the second to have a small deletion at Xq28 including part of AFF2 together with the IDS gene responsible for MPS II. PMID: 28263302 Whole genome sequencing of ASD patients revealed 2 LOF variants in AFF2 (Yuen et al., 2017). In addition, as of November 2020, there have been at least 5 LOF AFF2 variants were reported in patients in public databases (three in ClinVar: c.76A>T (p.Lys26Ter);c.3575del (p.Asn1192fs);c.3229C>T (p.Gln1077Ter). Two in LOVD c.613C>T/p.(Gln205Ter);c.3229C>T/p.(Gln1077*).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.