Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation

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,...

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Published in:American journal of medical genetics. Part A 2013-03, Vol.161 (3), p.600-604
Main Authors: Bertola, Débora R, Rodrigues, Melina G., Quaio, Caio R.D.C., Kim, Chong A., Passos‐Bueno, Maria Rita
Format: Article
Language:English
Subjects:
Abnormalities, Multiple - diagnosis
Abnormalities, Multiple - genetics
ALX4
ALX4 gene
Amino Acid Sequence
Child
Congenital Abnormalities - diagnosis
Congenital Abnormalities - genetics
Craniofacial Abnormalities
DNA-Binding Proteins - genetics
dysmorphology
Encephalocele - diagnostic imaging
Encephalocele - genetics
Face - abnormalities
Frameshift Mutation
frontonasal dysplasia
Genetic Association Studies
Humans
Male
Molecular Diagnostic Techniques
Molecular Sequence Data
parietal foramina
Pedigree
Phenotype
Radiography
Sequence Analysis, DNA
Transcription Factors - genetics
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Summary: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. © 2013 Wiley Periodicals, Inc.
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.35762