ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

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.