DISP1 deficiency: Monoallelic and biallelic variants cause a spectrum of midline craniofacial malformations

DISP1 encodes a transmembrane protein that regulates the secretion of the morphogen, Sonic hedgehog, a deficiency of which is a major cause of holoprosencephaly (HPE). This disorder covers a spectrum of brain and midline craniofacial malformations. The objective of the present study was to better de...

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Published in:	Genetics in medicine Vol. 26; no. 7; p. 101126
Main Authors:	Lavillaureix, Alinoë, Rollier, Paul, Kim, Artem, Panasenkava, Veranika, De Tayrac, Marie, Carré, Wilfrid, Guyodo, Hélène, Faoucher, Marie, Poirel, Elisabeth, Akloul, Linda, Quélin, Chloé, Whalen, Sandra, Bos, Jessica, Broekema, Marjoleine, van Hagen, Johanna M., Grand, Katheryn, Allen-Sharpley, Michelle, Magness, Emily, McLean, Scott D., Kayserili, Hülya, Altunoglu, Umut, En Qi Chong, Angie, Xue, Shifeng, Jeanne, Médéric, Almontashiri, Naif, Habhab, Wisam, Vanlerberghe, Clemence, Faivre, Laurence, Viora-Dupont, Eléonore, Philippe, Christophe, Safraou, Hana, Laffargue, Fanny, Mittendorf, Luisa, Abou Jamra, Rami, Patil, Siddaramappa Jagdish, Dalal, Ashwin, Sarma, Asodu Sandeep, Keren, Boris, Reversade, Bruno, Dubourg, Christèle, Odent, Sylvie, Dupé, Valérie
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-07-2024 Nature Publishing Group
Subjects:	Adolescent Alleles Anodontia Child Child, Preschool Cleft Lip - genetics Cleft Lip - pathology Cleft Palate - genetics Cleft Palate - pathology Congenital nasal piriform aperture stenosis Craniofacial Abnormalities - genetics Craniofacial Abnormalities - pathology Female Genetics Heterozygote Holoprosencephaly Holoprosencephaly - genetics Holoprosencephaly - pathology Homozygote Humans Incisor - abnormalities Infant Life Sciences Male Membrane Proteins - genetics Midline defects Mutation, Missense - genetics Phenotype SHH Solitary median maxillary central incisor SHH Solitary median maxillary central incisor Midline defects Congenital nasal piriform aperture stenosis Holoprosencephaly solitary median maxillary central incisor holoprosencephaly congenital nasal piriform aperture stenosis midline defects
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Summary:	DISP1 encodes a transmembrane protein that regulates the secretion of the morphogen, Sonic hedgehog, a deficiency of which is a major cause of holoprosencephaly (HPE). This disorder covers a spectrum of brain and midline craniofacial malformations. The objective of the present study was to better delineate the clinical phenotypes associated with division transporter dispatched-1 (DISP1) variants. This study was based on the identification of at least 1 pathogenic variant of the DISP1 gene in individuals for whom detailed clinical data were available. A total of 23 DISP1 variants were identified in heterozygous, compound heterozygous or homozygous states in 25 individuals with midline craniofacial defects. Most cases were minor forms of HPE, with craniofacial features such as orofacial cleft, solitary median maxillary central incisor, and congenital nasal pyriform aperture stenosis. These individuals had either monoallelic loss-of-function variants or biallelic missense variants in DISP1. In individuals with severe HPE, the DISP1 variants were commonly found associated with a variant in another HPE-linked gene (ie, oligogenic inheritance). The genetic findings we have acquired demonstrate a significant involvement of DISP1 variants in the phenotypic spectrum of midline defects. This underlines its importance as a crucial element in the efficient secretion of Sonic hedgehog. We also demonstrated that the very rare solitary median maxillary central incisor and congenital nasal pyriform aperture stenosis combination is part of the DISP1-related phenotype. The present study highlights the clinical risks to be flagged up during genetic counseling after the discovery of a pathogenic DISP1 variant.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1098-3600 1530-0366 1530-0366
DOI:	10.1016/j.gim.2024.101126