Molecular Genetics of Frontonasal Dysplasia

Abstract

Frontonasal dysplasias (FND) are facial malformations characterised by the association of hypertelorism, midline facial cleft and nasal abnormalities. They are caused by an abnormal development of the frontonasal process. FND are clinically and molecularly heterogeneous. Molecular bases have been identified in seven FND entities so far: mutations in the X‐linked EFNB1 gene in craniofrontonasal syndrome; biallelic mutations in ALX3 , ALX4 and ALX1 genes in frontonasal dysplasia type 1, 2 and 3, respectively; heterozygous recurrent mutation in ZSWIM6 gene in acromelic frontonasal dysostosis; heterozygous mutations in SPECC1L gene in Teebi syndrome and heterozygous mutations in TWIST1 gene in Sweeney–Cox syndrome. These genes are involved in different pathways. The molecular bases for other clinically described entities such as Pai or oculoauriculofrontonasal syndromes are still unknown despite international efforts to decipher their molecular basis using next‐generation sequencing technologies; almost all affected individuals are of sporadic occurrence. Most patients presenting with FND remain clinically unclassified. The rarity of these disorders and the multiple clinical overlaps account for their challenging and molecular clinical delineation. Key Concepts Frontonasal dysplasia consists of clinically and molecularly heterogeneous entities. Molecular bases are known in a small subset of syndromic FND and still unknown in other clinically described disorders. FND with known molecular bases are dominant, recessive, or X‐linked. An accurate clinical diagnosis is essential for the patients and families management as well as for the identification of the causative molecular bases. The genes involved in FND pathogenesis belong to different cellular pathways; most of their function is still poorly known.