Abstract
Frontorhiny is one of the two forms of mid-facial malformations characterized by ocular hypertelorism, wide and short nasal ridge, bifid nasal tip, broad columella, widely separated nares, long and wide philtrum and V-shaped hairline. Sometimes these phenotypes are associated with ptosis and midline dermoid cysts. Frontorhiny inherits in an autosomal recessive pattern. Sequence variants in the Aristaless-like homeobox 3 (ALX3) gene underlying frontorhiny have been reported previously. Here, in the present study, we have investigated four patients in a consanguineous family of Pakistani origin segregating frontorhiny in autosomal recessive manner. Genome scan using 250k Nsp1 array followed by exome and Sanger sequence analysis revealed a novel homozygous nonsense variant (c.604C>T, p.Gln202*) in the ALX3 gene resulting in frontorhiny in the family. This is the first mutation in the ALX3 gene, underlying frontorhiny, in Pakistani population.
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References
Sedano HO, Cohen MM Jr, Jirasek J, Gorlin RJ. Frontonasal dysplasia. J Pediatr. 1970;76:906–13.
Sedano HO, Gorlin RJ. Frontonasal malformation as a field defect and in syndromic associations. Oral Surg Oral Med Oral Pathol. 1988;65:704–10.
Uz E, Alanay Y, Aktas D, Vargel I, Gucer S, Tuncbilek G, et al. Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal recessive ALX1 related frontonasal dysplasia. Am J Hum Genet. 2010;86:789–96.
Ullah A, Kalsoom U-E, Umair M, John P, Ansar M, Basit S, et al. Exome sequencing revealed a novel splice site variant in the ALX1 gene underlying frontonasal dysplasia. Clin Genet. 2017;91:494–98.
Twigg SR, Versnel SL, Nurnberg G, Lees MM, Bhat M, Hammond P, et al. Frontorhiny, a distinctive presentation of frontonasal dysplasia caused by recessive mutations in the ALX3 homeobox gene. Am J Hum Genet. 2009;84:698–705.
Kayserili H, Uz E, Niessen C, Vargel I, Alanay Y, Tuncbilek G, et al. ALX4 dysfunction disrupts craniofacial and epidermal development. Hum Mol Genet. 2009;18:4357–66.
Kayserili H, Altunoglu U, Ozgur H, Basaran S, Uyguner ZO. Mild nasal malformations and parietal foramina caused by homozygous ALX4 mutations. Am J Med Genet Part A. 2011;158:236–44.
Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, et al. The Human Gene Mutation Database (HGMD®): 2003 update. Hum Mutat. 2003;21:577–81.
Zhao GQ, Eberspaecher H, Seldin MF, de Crombrugghe B. The gene for the homeodomain-containing protein Cart-1 is expressed in cells that have a chondrogenic potential during embryonic development. Mech Dev. 1994;48:245–54.
McGonnell IM, Graham A, Richardson J, Fish JL, Depew MJ, Dee CT, et al. Evolution of the Alx homeobox gene family: parallel retention and independent loss of the vertebrate Alx3 gene. Evol Dev. 2012;13:343–51.
Dee CT, Szymoniuk CR, Mills PE, Takahashi T. Defective neural crest migration revealed by a Zebrafish model of Alx1-related frontonasal dysplasia. Hum Mol Genet. 2013;22:239–51.
Seelow D, Schuelke M, Hildebrandt F, Nurnberg P. Homozygosity Mapper an interactive approach to homozygosity mapping. Nucleic Acids Res. 2009;37:593–99.
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: a MapReduce framework for analyzing next generation DNA sequencing data. Genome Res. 2010;20:1297–1303.
Ullah A, Raza SI, Ali RH, Naveed AK, Jan A, Rizvi SD, et al. A novel deletion mutation in the DSG4 gene underlies autosomal recessive hypotrichosis with variable phenotype in two unrelated consanguineous families. Clin Exp Dermatol. 2015;40:78–84.
Perez-Villamil B, Mirasierra M, Vallejo M. The homeoprotein Alx3 contains discrete functional domainsand exhibits cell-specific and selective monomeric bindingand transactivation. J Biol Chem. 2004;279:38062–071.
Ten-Berge D, Brouwer A, el Bahi S, Guenet JL, Robert B, Meijlink F. Mouse Alx3: an (aristaless-like homeobox gene expressed during embryogenesis in ectomesenchyme and lateral plate mesoderm. Dev Biol. 1998;199:11–25.
Beverdam A, Brouwer A, Reijnen M, Korving J, Meijlink F. Severe nasal clefting and abnormal embryonic apoptosis in Alx3/Alx4 double mutant mice. Development. 2001;128:3975–86.
Farlie PG, Baker NL, Yap P, Tan TY. Frontonasaldysplasia: towards an understanding of molecular and developmental aetiology. Mol Syndromol. 2016;7:312–21.
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We highly acknowledge participation of the family members in the present study.
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Ullah, A., Umair, M., e-Kalsoom, U. et al. Exome sequencing revealed a novel nonsense variant in ALX3 gene underlying frontorhiny. J Hum Genet 63, 97–100 (2018). https://doi.org/10.1038/s10038-017-0358-y
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DOI: https://doi.org/10.1038/s10038-017-0358-y
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