Ewelina Bukowska-Olech1,2, Monika Dmitrzak-Węglarz3, Dawid Larysz4, Bartosz Wojciechowicz5, Dorota Simon6, Joanna Walczak-Sztulpa1, Aleksander Jamsheer1,6. 1. Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland. 2. Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland. 3. Department of Genetics in Psychiatry, Poznan University of Medical Sciences, Poznan, Poland. 4. Department of Radiotherapy, The Maria Skłodowska Curie Memorial Cancer Centre and Institute of Oncology, Gliwice, Poland. 5. Perlan Technologies Sp. z o.o., Puławska 303 Street, 02-785, Warsaw, Poland. 6. Centers for Medical Genetics GENESIS, Dąbrowskiego 77A Street, 60-529, Poznan, Poland.
Abstract
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 the FGFR1, FGFR2, FGFR3, and TWIST1 genes. 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, including BRAF, 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 of BRAF, 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.
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 the FGFR1, FGFR2, FGFR3, and TWIST1 genes. 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, including BRAF, 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 of BRAF, 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.
Authors: Ewelina Bukowska-Olech; Anna Sowińska-Seidler; Dawid Larysz; Paweł Gawliński; Grzegorz Koczyk; Delfina Popiel; Lidia Gurba-Bryśkiewicz; Anna Materna-Kiryluk; Zuzanna Adamek; Aleksandra Szczepankiewicz; Paweł Dominiak; Filip Glista; Karolina Matuszewska; Aleksander Jamsheer Journal: Front Mol Biosci Date: 2022-04-28