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Vertical transmission of a large calvarial ossification defect due to heterozygous variants of ALX4 and TWIST1
Author(s) -
Walters Michelle E.,
Lacassie Yves,
Azamian Mahshid,
Franciskovich Rachel,
Zapata Gladys,
Hernandez Patricia P.,
Liu Pengfei,
Campbell Ian M.,
Bostwick Bret L.,
Lalani Seema R.
Publication year - 2021
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.62036
Subject(s) - intramembranous ossification , mesenchyme , phenotype , ossification , skull , biology , homeobox , anatomy , microbiology and biotechnology , genetics , gene , mesenchymal stem cell , gene expression
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.