1. Vertical transmission of a large calvarial ossification defect due to heterozygous variants of ALX4 and TWIST1.
- Author
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Walters ME, Lacassie Y, Azamian M, Franciskovich R, Zapata G, Hernandez PP, Liu P, Campbell IM, Bostwick BL, and Lalani SR
- Subjects
- Adult, Cerebellar Vermis abnormalities, DNA-Binding Proteins deficiency, Female, Foot Deformities, Congenital genetics, Genes, Dominant, Hand Deformities, Congenital genetics, Heterozygote, Humans, Imaging, Three-Dimensional, Infant, Newborn, Male, Nuclear Proteins deficiency, Pedigree, Pregnancy, Skull diagnostic imaging, Skull embryology, Syndactyly genetics, Thumb abnormalities, Tomography, X-Ray Computed, Transcription Factors deficiency, Twist-Related Protein 1 deficiency, Ultrasonography, Prenatal, Exome Sequencing, Abnormalities, Multiple genetics, Acrocephalosyndactylia genetics, DNA-Binding Proteins genetics, Frameshift Mutation, Loss of Function Mutation, Mutation, Missense, Nuclear Proteins genetics, Osteogenesis genetics, Skull abnormalities, Transcription Factors genetics, Twist-Related Protein 1 genetics
- Abstract
ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss-of-function variants of TWIST1, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in ALX4 and TWIST1. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable ALX4-related EPF phenotype. This report demonstrates comorbid disorders of Saethre-Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic ALX4 variants. To our knowledge this is the first instance of ALX4 and TWIST1 variants acting synergistically to cause a unique phenotype influencing skull ossification., (© 2020 Wiley Periodicals LLC.) more...
- Published
- 2021
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