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 variants in 19 individuals from 4 families segregating parietal foramina (PFM) including those families linked to 11p region (region that includes proximal 11p deletion syndrome)were described. Family 1 nonsense variant c.418 C->T (p.Gln140Ter) that was inherited (affected IV-1 from affected father III-3); another affected paternal relative was also found to carry the variant, for a total of 2 segregations in this family. Family 2 nonsense variant c.736 C->T (p.Arg18Gln) also segregated with disease in several affected members of the family (for example, proband IV-4 inherited from III-6, II-3, I-2). However, there was also at least one individual in this family with the variant and a normal skull radiograph; this individual did go on to have two affected children (individuals III-7 and III-8). In all, this family demonstrated 6 segregations between genotype+/phenotype+ individuals. These nonsense variants were thought to completely or partially eliminate the DNA-binding homeodomain.
11106354 Wuyts et al. (2000): Mutational analysis of the ALX4 gene in three unrelated Foramina parietalia permagna (FPP) families without MSX2 variants were analyzed. Family 1 identified a c.504delT in proband inherited from affected father. The authors noted that this variant results in a premature stop codon.
16319823 Mavrogiannis et al. (2006): The authors discuss looked at 20 unrelated families with an established diagnosis of enlarged parietal formina (PFM) or cranum bifidum (CB), 14 were familial cases and 6 were sporadic cases. Family 10 was identified as having a c.620c->A(p.S207X). The variant was detected in all 5 affected individuals with PFM, absent or malpositioned teeth, short an broad thumbs/halluces, and mild facial dysmorphism. Three siblings, the father and paternal grandfather were tested. Family 11 was identified as having frameshifting deletion c.385_394del (p.C129PfsX49). The unaffected parents were not tested in family 11.

Haploinsufficiency phenotype comments:

PMID: 29215649 Lee et al. (2018) designed a 20 gene panel based on genes associated with craniosynostosis through retrospective testing of an Australian and New Zealand cohort of 233 individuals.Two ALX4 gene variants were identified c.94del (p.Ser32Argfs*149) seen in a patient with parieto-occipital skull defect and a c.712T>G (p.Tyr238Asp). Parietal foramina also occur as part of the Potocki-Shaffer syndrome ( OMIM: 601224), a contiguous gene syndrome caused by a deletion on chromosome 11p11.2 that includes the ALX4 gene. Biallelic ALX4 variants (autosomal recessive) cause frontonasal dysplasia-2 (FND2; 613451), which is also associated with parietal foramina but has more severe frontonasal defects.

  • 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.