Disruption of ALX1 Causes Extreme Microphthalmia and Severe Facial Clefting: Expanding the Spectrum of Autosomal-Recessive ALX-Related Frontonasal Dysplasia

YILMAZ, Engin/0000-0001-8873-7645; Akarsu, Nurten/0000-0001-5432-0032; Ozdag, Hilal/0000-0001-7940-2499; Liehr, Thomas/0000-0003-1672-3054; Alanay, Yasemin/0000-0003-0683-9731; von Eggeling, Ferdinand/0000-0002-8062-6999 WOS: 000278045300015 PubMed: 20451171 We present an autosomal-recessive frontonasal dysplasia (FND) characterized by bilateral extreme microphthalmia, bilateral oblique facial cleft, complete cleft palate, hypertelorism, wide nasal bridge with hypoplasia of the ala nasi, and low-set, posteriorly rotated ears in two distinct families. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this clinical entity to chromosome 12q21. In one of the families, three siblings were affected, and CNV analysis of the critical region showed a homozygous 3.7 Mb deletion containing the ALX1 (CART1) gene, which encodes the aristaless-like homeobox 1 transcription factor. In the second family we identified a homozygous donor-splice-site mutation (c.531+1G > A) in the ALX1 gene, providing evidence that complete loss of function of ALX1 protein causes severe disruption of early craniofacial development. Unlike loss of its murine ortholog, loss of human ALX1 does not result in neural-tube defects; however, it does severely affect the orchestrated fusion between frontonasal, nasomedial, nasolateral, and maxillary processes during early-stage embryogenesis. This study further expands the spectrum of the recently recognized autosomal-recessive ALX-related FND phenotype in humans. Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [108S420]; European Research Area Network (E-RARE) [R07197KS] We are grateful to the families for their participation in the study. We thank Han Brunner for critical reading and comments, Ebru Oralli Bircan for illustrations, Hacettepe University Craniofacial Surgery Study Group members Yucel Erk, Emin Mavili, Aycan Kayikcioglu (Plastic and Reconstructive Surgery), Kemal Benli (Neurosurgery), Aysenur Cila (Radiology), Tulin Taner, and liken Kocadereli (Orthodonty) for evaluating the frontonasal malformation cases in the registry. This work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK) (grant numbers 108S420 to N.A.A), and the overall consortium (CRANIRARE) was supported by the European Research Area Network (E-RARE) (project number R07197KS).