ClinGen Dosage Sensitivity Curation Page

AFF2

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.