Abstract
Craniosynostosis (CS) refers to the group of craniofacial malformations characterized by the premature closure of one or more cranial sutures. The disorder is clinically and genetically heterogeneous and occurs usually as an isolated trait, but can also be syndromic. In 30–60% of patients, CS is caused by known genetic factors; however, in the rest of the cases, causative molecular lesions remain unknown. In this paper, we report on a sporadic male patient affected by complex CS (metopic and unilateral lambdoid synostosis), muscular hypotonia, psychomotor retardation, and facial dysmorphism. Since a subset of CS results from submicroscopic chromosomal aberrations, we performed array comparative genomic hybridization (array CGH) in order to identify possibly causative copy-number variation. Array CGH followed by breakpoint sequencing revealed a previously unreported de novo 1.26 Mb duplication at chromosome 1q22-q23.1 that encompassed two genes involved in osteoblast differentiation: BGLAP, encoding osteocalcin (OCN), and LMNA, encoding lamin A/C. OCN is a major component of bone extracellular matrix and a marker of osteogenesis, whereas mutations in LMNA cause several genetic disorders called laminopathies, including mandibuloacral dysostosis (MAD) that manifests with low bone mass, severe bone deformities, and delayed closure of the cranial sutures. Since LMNA and BGLAP overexpression promote osteoblast differentiation and calcification, phenotype of our patient may result from misexpression of the genes. Based on our findings, we hypothesize that both LMNA and BGLAP may be implicated in the pathogenesis of CS in humans. However, further studies are needed to establish the exact pathomechanism underlying development of this defect.
Highlights
Craniosynostosis (CS), the premature fusion of the cranial sutures, occurs in about 1:2000 to 1:2500 live born infants and represents one of the most common congenital craniofacial malformation (Cohen 1979; French et al 1990; LajeunieCommunicated by: Michal WittCS is a clinically and genetically heterogeneous group of disorders that may either occur in rare syndromic forms or, more frequently, as nonsyndromic isolated trait (Wilkie et al 2007)
Other less frequent disorders result from different mutations in the TCF12, EFNB1, MSX2, ALX3, GLI3, IL11RA, and ERF genes (Jabs et al 1993; Twigg et al 2009, 2013; Hurst et al 2011; Keupp et al 2013; Sharma et al 2013; Kutkowska-Kazmierczak et al 2018)
We describe a sporadic male proband affected by complex CS, composed of metopic and lambdoid synostosis, muscular hypotonia, psychomotor retardation, and facial dysmorphism, resulting from a previously unreported de novo 1.26 Mb duplication at chromosome 1q22-q23.1, encompassing two genes involved in osteoblastogenesis: BGLAP encoding osteocalcin (OCN) and LMNA encoding lamin A/C
Summary
CS is a clinically and genetically heterogeneous group of disorders that may either occur in rare syndromic forms or, more frequently, as nonsyndromic isolated trait (Wilkie et al 2007). Syndromic forms comprise over 180 different genetic conditions, in which CS is associated with a broad spectrum of clinical symptoms, including skeletal defects, digital malformations, facial dysmorphism, cardiac and genitourinary defects or other organ abnormalities (Gleeson et al 2006; OMIM). Other less frequent disorders result from different mutations in the TCF12, EFNB1, MSX2, ALX3, GLI3, IL11RA, and ERF genes (Jabs et al 1993; Twigg et al 2009, 2013; Hurst et al 2011; Keupp et al 2013; Sharma et al 2013; Kutkowska-Kazmierczak et al 2018). The pathomechanism of CNVs could be explained by either gene dosage effect leading to overexpression or haploinsufficiency of a gene/genes or by cis-regulatory effect that leads to misexpression of a target gene resulting from change of its regulatory landscape (Klopocki et al 2011)
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