Holoprosencephaly 11

A number sign (#) is used with this entry because holoprosencephaly-11 (HPE11) is caused by heterozygous mutation in the CDON gene (608707) on chromosome 11q24.

For a general phenotypic description and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).

Clinical Features

Bae et al. (2011) reported 4 unrelated patients with HPE11. One patient had agenesis of the corpus callosum, hypotelorism, growth hormone deficiency, global developmental delay, and thick eyebrows with synophrys. Another had agenesis of the corpus callosum, alobar HPE, hypotelorism, cleft lip/palate, and absent columella; absent pituitary and polysplenia were noted in this patient at autopsy. Clinical details of the other 2 patients were limited, but 1 had alobar findings.

Molecular Genetics

In 4 unrelated individuals with holoprosencephaly spectrum disorders, Bae et al. (2011) identified 4 different putatively pathogenic heterozygous mutations in the CDON gene (608707.0001-608707.0004). One of the patients had a confirmed de novo mutation. The patients were identified from a cohort of 282 patients screened. Cellular expression and immunoprecipitation studies of the equivalent mutations in rat cDNA indicated that the mutations did not interfere with CDON-SHH (600725) binding, but decreased the ability of CDON to support SHH-dependent signaling by interfering with CDON's ability to interact with certain SHH coreceptors. The findings indicated that CDON must associate with both SHH ligand and other SHH receptor components at the cell surface for proper signaling to occur, and that disruption of these interactions can lead to HPE.