Compound craniosynostosis, intellectual disability, and Noonan-like facial dysmorphism associated with 7q32.3-q35 deletion

Objective Craniosynostosis (CS) is the premature fusion of the cranial sutures, occurring either in isolated or syndromic form. Syndromic CS, which was described in over 180 genetic syndromes, accounts for 15-30% of all CS cases and usually originates from mutations within theFGFR1,FGFR2,FGFR3, andTWIST1genes. However, causative alterations in other genes, or rarely copy number variations (CNVs) were also reported. In this article, we describe a patient with Noonan-like facial dysmorphism accompanied by intellectual disability and compound CS, involving coronal, sagittal, and squamous sutures. Methods We applied karyotyping, copy number variations analysis using array comparative genomic hybridization, and microarray-based genes expresion analysis. Results We have shown that the index carried a large and rare heterozygous deletion, which encompassed 12.782 Mb and mapped to a chromosomal region of 7q32.3-q35 (HG38 - chr7:131837067-144607071). The aberration comprised 109 protein-coding genes, includingBRAF, that encodes serine/threonine-protein kinase B-Raf, being a part of the RAS/MAPK signaling pathway. Discussion The RAS/MAPK pathway plays an essential role in human development; hence, its dysregulation not surprisingly results in severe congenital anomalies, such as phenotypically overlapping syndromes termed RASopathies. To our best knowledge, we report here the first CNV causing haploinsufficiency ofBRAF, resulting in dysregulation of the RAS/MAPK cascade, and consequently, in the phenotype observed in our patient. To conclude, with this report, we have pointed to the involvement of the RAS/MAPK signaling pathway in CS development. Moreover, we have shown that the molecular analysis based on both DNA and RNA profiling, undoubtedly constitutes a comprehensive diagnostic and research strategy for elucidating a cause of genetic diseases.