ClinGen Dosage Sensitivity Curation Page

11p11.2 (Potocki-Shaffer syndrome) region (includes ALX4, EXT2)

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
15852040 Wakui et al. (2005) compare deletion size and phenotype in 10 individuals affected with Potocki-Shaffer syndrome (PSS). Full spectrum of PSS is seen in individuals with deletions at least 2.1 Mb (chr11:43894800-46152450 [hg19]), including both ALX4 and EXT2. ALX4 haploinsufficiency results in parietal foramina and EXT2 haploinsufficiency results in exostoses.
16319823 Mavrogiannis et al. (2006) describe mutations in homeobox genes ALX4 and MSX2 causing craniosynostosis. In this study, they identified a three-generation family with a deletion on chr11:40406581-44924293 [hg19], which includes the ALX4 and EXT2 genes manifesting enlarged parietal foramina and exostoses of the long bones. This family did not have intellectual disability, and by STR and FISH mapping the deletion of this family against other reported deletions in the literature, the authors propose that the gene(s) involved in this phenotype are proximal to EXT2 in PSS subjects.
20140962 Swarr et al. (2010) provide a comprehensive clinical description of PSS based on meta analysis of 6 individuals with cytogenetically defined 11p deletions and review of the literature. While the deletions were of various sizes and linear positions, all included ALX4 and EXT2, accounting for the cardinal features of craniofacial anomalies, enlarged parietal foramina, and exostoses of the long bones. The authors also make evaluation and maintenance recommendations for PSS individuals based on the primary clinical findings.

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.