TY - JOUR
T1 - Exome sequencing for the differential diagnosis of ciliary chondrodysplasias
T2 - Example of a WDR35 mutation case and review of the literature
AU - Antony, Dinu
AU - Nampoory, Narayanan
AU - Bacchelli, Chiara
AU - Melhem, Motasem
AU - Wu, Kaman
AU - James, Chela T.
AU - Beales, Philip L.
AU - Hubank, Mike
AU - Thomas, Daisy
AU - Mashankar, Anant
AU - Behbehani, Kazem
AU - Schmidts, Miriam
AU - Alsmadi, Osama
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Exome sequencing is becoming widely popular and affordable, making it one of the most desirable methods for the identification of rare genetic variants for clinical diagnosis. Here, we report the clinical application of whole exome sequencing for the ultimate diagnosis of a ciliary chondrodysplasia case presented with an initial clinical diagnosis of Asphyxiating Thoracic Dystrophy (ATD, Jeune Syndrome). We have identified a novel homozygous missense mutation in WDR35 (c.206G > A), a gene previously associated with Sensenbrenner Syndrome, Ellis-van Creveld syndrome and Short-rib polydactyly syndrome type V. The genetic findings in this family led to the re-evaluation of the initial diagnosis and a differential diagnosis of Sensenbrenner Syndrome was made after cautious re-examination of the patient. Cell culture studies revealed normal subcellular localization of the mutant WDR35 protein in comparison to wildtype protein, pointing towards impaired protein-protein interaction and/or altered cell signaling pathways as a consequence of the mutated allele. This research study highlights the importance of including pathogenic variant identification in the diagnosis pipeline of ciliary chondrodysplasias, especially for clinically not fully defined phenotypes.
AB - Exome sequencing is becoming widely popular and affordable, making it one of the most desirable methods for the identification of rare genetic variants for clinical diagnosis. Here, we report the clinical application of whole exome sequencing for the ultimate diagnosis of a ciliary chondrodysplasia case presented with an initial clinical diagnosis of Asphyxiating Thoracic Dystrophy (ATD, Jeune Syndrome). We have identified a novel homozygous missense mutation in WDR35 (c.206G > A), a gene previously associated with Sensenbrenner Syndrome, Ellis-van Creveld syndrome and Short-rib polydactyly syndrome type V. The genetic findings in this family led to the re-evaluation of the initial diagnosis and a differential diagnosis of Sensenbrenner Syndrome was made after cautious re-examination of the patient. Cell culture studies revealed normal subcellular localization of the mutant WDR35 protein in comparison to wildtype protein, pointing towards impaired protein-protein interaction and/or altered cell signaling pathways as a consequence of the mutated allele. This research study highlights the importance of including pathogenic variant identification in the diagnosis pipeline of ciliary chondrodysplasias, especially for clinically not fully defined phenotypes.
KW - Ciliary chondrodysplasias
KW - Exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85029006264&partnerID=8YFLogxK
U2 - 10.1016/j.ejmg.2017.08.019
DO - 10.1016/j.ejmg.2017.08.019
M3 - Article
C2 - 28870638
AN - SCOPUS:85029006264
VL - 60
SP - 658
EP - 666
JO - European Journal of Medical Genetics
JF - European Journal of Medical Genetics
SN - 1769-7212
IS - 12
ER -