title: Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation.
abstract: Frontonasal dysplasias (FND) comprise a spectrum of disorders caused by abnormal median facial development. Its etiology is still poorly understood but recently frontonasal dysplasia phenotypes were linked to loss-of-function mutations in the ALX homeobox gene family, which comprises the ALX1, ALX3, and ALX4 genes. All ALX-related frontonasal phenotypes till date had been compatible with an autosomal recessive mode of inheritance. In contrast, heterozygous loss-of-function mutations in ALX4 had been only associated with isolated symmetrical parietal ossification defects at the intersection of the sagittal and lambdoid sutures, known as enlarged parietal foramina. We report a family with vertical transmission from mother to son of mild frontonasal dysplasia phenotype caused by a novel ALX4 gene mutation (c.1080-1089_delGACCCGGTGCinsCTAAGATCTCAACAGAGATGGCAACT, p.Asp326fsX21).This is the first report of a frontonasal phenotype related to a heterozygous mutation in ALX4. This mutation is predicted to cause the loss of the aristaless domain in the C-terminal region of the protein and preserves the homeodomain. We speculate that a different mechanism, a dominant-negative effect, is responsible for the distinct phenotype in this family.
authors: Instituto da Criança - HC/FMUSP, São Paulo, Brazil. debora.bertola@icr.usp.br
authors: Débora R
authors: DR
authors: Bertola
authors: Melina G
authors: MG
authors: Rodrigues
authors: Caio R D C
authors: CR
authors: Quaio
authors: Chong A
authors: CA
authors: Kim
authors: Maria Rita
authors: MR
authors: Passos-Bueno
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics; D000595:Amino Acid Sequence; D002648:Child; D000013:Congenital Abnormalities / Q000175:diagnosis* / Q000235:genetics; D019465:Craniofacial Abnormalities; D004268:DNA-Binding Proteins / Q000235:genetics*; D004677:Encephalocele / Q000000981:diagnostic imaging* / Q000235:genetics; D005145:Face / Q000002:abnormalities; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D011859:Radiography; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C416676:ALX4 protein, human; D004268:DNA-Binding Proteins; D014157:Transcription Factors