ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000011.9) (NC_000011.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11137991 Mavrogiannis et al. (2001): 3 distinct ALX4 mutations in 19 individuals from 4 families segregating parietal foramina were described, including two nonsense mutations (418CT encoding Gln140Ter and 736CT encoding Gln246Ter). These nonsense mutations were thought to completely or partially eliminate the DNA-binding homeodomain. The third mutation (653GA encoding Arg218Gln), present in two unrelated families, substitutes a highly conserved residue in the amino-terminal arm of the homeodomain that contacts the minor groove of DNA.
11106354 Wuyts et al. (2000): The authors describe a family affected with parietal foramina with a deletion of a thymidine in exon 2 at position 504 of the cDNA (adenosine of start codon +1), resulting in a premature stop codon after 179 amino acids. Two other families are described in this paper: one with a R272P missense mutation not found in 50 controls, and another with a change deemed a common polymorphism.
16319823 Mavrogiannis et al. (2006): The authors discuss genotype-phenotype correlations between parietal foramina and mutations in ALX4 and MSX2, and describe two additional mutations of ALX4 found in affected families: a heterozygous 10-bp deletion from nucleotides 385 to 394 in the ALX4 gene, resulting in a frameshift and premature truncation of the protein, and nonsense mutation S207X.

Haploinsufficiency phenotype comments:

Incomplete penetrance has been observed (see GeneReviews). Homozygous loss of function mutations in ALX4 have been associated with a different phenotype, frontonasal dysplasia (OMIM #614451). ALX4 is one of the genes deleted in the proximal 11p deletion syndrome (or Potocki-Schaffer syndrome), a contiguous gene syndrome manifesting as parietal foramina, multiple exostoses, and intellectual disability (OMIM #601224).

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

Triplosensitivity phenotype comment:

No evidence found supporting or refuting an association between duplications of the ALX4 gene and a specific phenotype.