ClinGen Dosage Sensitivity Curation Page

OFD1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

Loss of function variants in OFD1 cause orofaciodigital syndrome type I (OFD1), characterized by malformations of the face, oral cavity, and digits. OFD1 is an X-linked dominant condition with lethality in males. The haploinsufficiency score is based on this phenotype. Loss of function variants associated with OFD1 syndrome occur in the first 16 exons. Variants in the OFD1 gene also cause Simpson-Golabi-Behmel syndrome type 2 (GBS2; MIM#300209) and Joubert syndrome-10 (JBTS10; MIM#300804), both of which are X-linked recessive. Truncating variants in exons 20 and 21 have been detected in males with primary ciliary dyskinesia (PMID: 31373179, 31366608)

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.