Uncommon runs of homozygosity disclose homozygous missense mutations in two ciliopathy-related genes (SPAG17 and WDR35) in a patient with multiple brain and skeletal anomalies.
We describe a patient severely affected with multiple congenital anomalies, including brain malformations and skeletal dysplasia suggestive of cranioectodermal dysplasia (CED) ciliopathy, who unusually carries several homozygosity tracts involving homozygous missense mutations in SPAG17 (exon 8; c.1069G > C; p.Asp357His) and WDR35 (exon 13; c.1415G > A; p.Arg472Gln) as revealed by homozygosity mapping and next generation sequencing. SPAG17 is essential for the function and structure of motile cilia, while WDR35 belongs to the same intraflagellar transport (IFT) gene family whose protein products are part of functional IFT A and B complexes. Formerly, SPAG17 was related - through polymorphic variants - to an influence on individuals' height; more recently, Spag17-/- mice models were reported to present skeletal and bone defects, reduced mucociliary clearance, respiratory distress, and cerebral ventricular enlargement. Homozygous or compound heterozygous mutations in WDR35 have mainly been related to CED2 or short-rib thoracic dysplasia 7, with only three cases showing some brain anomalies. Given that our patient presents these clinical features and the close functional relationship between SPAG17 and WDR35, it is feasible that the combined effects from both mutations contribute to his phenotype. To our knowledge, this patient is the first to harbor a likely pathogenic homozygous mutation in both genes at the same time. Thus, the resulting complex phenotype of this patient illustrates the heterogeneity associated with ciliopathies and further expands the clinical and mutational spectrum of these diseases. Finally, we highlight the combined use of high-throughput tools to diagnose and support the proper handling of this and other patients.
['Córdova-Fletes|Carlos|C|', 'Becerra-Solano|Luis E|LE|', 'Rangel-Sosa|Martha M|MM|', 'Rivas-Estilla|Ana María|AM|', 'Alberto Galán-Huerta|Kame|K|', 'Ortiz-López|Rocío|R|', 'Rojas-Martínez|Augusto|A|', 'Juárez-Vázquez|Clara I|CI|', 'García-Ortiz|José E|JE|']
D000015:Abnormalities, Multiple D000293:Adolescent D001842:Bone and Bones D001927:Brain Diseases D002648:Child D000072661:Ciliopathies D003398:Craniosynostoses D003598:Cytoskeletal Proteins D004476:Ectodermal Dysplasia D005260:Female D053823:Hedgehog Proteins D059014:High-Throughput Nucleotide Sequencing D006720:Homozygote D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D008297:Male D008869:Microtubule-Associated Proteins D020125:Mutation, Missense D010641:Phenotype D011506:Proteins
SPAG17 WDR35 Ciliopathies Exome sequencing LCSH/ROH SNP arrays