ClinGen Dosage Sensitivity Curation Page

OFD1

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
11179005 Ferrante et al. (2001) described 3 frameshift, one nonsense and one splice-site variant in females with oral-facial-digital type 1 (OFD1) syndrome. One familial variant, a 19 basepair deletion in exon 3 of the OFD1 gene leading to a frameshift, was shown to segregate with disease. This variant was detected in an affected mother and daughter but absent in an unaffected daughter and son. Variants described were not found in 90 normal X chromosomes.
11950863 Rakkolainen et al. (2002) describe two frameshift and one splice variant in OFD1. The splice variant in intron 5 was detected in a family with affected females in three successive generations. A second family carried a 2 basepair insertion in exon 16 that was detected in an affected mother and two affected daughters. The variant were not found in 50 control individuals.
18546297 In a cohort of 120 individuals clinically diagnosed with OFD1 syndrome Prattichizzo et al 2008 detected 57 loss of function variants including 36 frameshift, 11 splice-site and 11 nonsense variants. All variants were located in exons 1-16 (out of 23 exons).
23033313 Bisschoff et al 2013 detected 27 loss of function variants in female probands from a cohort of 61 families with suspected OFD1 syndrome. The mothers of 18 probands were tested and the variants were found to be inherited from an affected mother in 6/18 cases.

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.