Dominant frontonasal dysplasia with ectodermal defects results from increased activity of ALX4

Alon Peled, Ofer Sarig, Janan Mohamad, Marina Eskin-Schwartz, Dan Vodo, Ron Bochner, Natalya Malchin, Ofer Isakov, Noam Shomron, Gilad Fainberg, Marta Bertolini, Ralf Paus, Eli Sprecher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Frontonasal dysplasia (FND) refers to a group of rare developmental disorders characterized by abnormal morphology of the craniofacial region. We studied a family manifesting with clinical features typical for FND2 including neurobehavioral abnormalities, hypotrichosis, hypodontia, and facial dysmorphism. Whole-exome sequencing analysis identified a novel heterozygous frameshift insertion in ALX4 (c.985_986insGTGC, p.Pro329Argfs*115), encoding aristaless homeobox 4. This and a previously reported dominant FND2-causing variant are predicted to result in the formation of a similar abnormally elongated protein tail domain. Using a reporter assay, we showed that the elongated ALX4 displays increased activity. ALX4 negatively regulates the Wnt/β-catenin pathway and accordingly, patient keratinocytes showed altered expression of genes associated with the WNT/β-catenin pathway, which in turn may underlie ectodermal manifestations in FND2. In conclusion, dominant FND2 with ectodermal dysplasia results from frameshift variants in ALX4 exerting a gain-of-function effect.

Original languageEnglish
Pages (from-to)2806-2812
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Issue number12
StateAccepted/In press - 2023


  • ALX4
  • ectodermal dysplasia
  • frameshift
  • frontonasal dysplasia
  • genodermatosis
  • hypotrichosis


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