Whole‐exome sequencing identified a novel variant in an Iranian patient affected by pycnodysostosis

Abstract

Background Whole‐exome sequencing (WES) has emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. In this study, we aimed to find the potential genetic cause of skeletal disease, a heterogeneous disease, revealing the obvious short stature phenotype. In an Iranian family, we used solo‐WES in a suspected patient to decipher the potential genetic cause(s). Methods A comprehensive clinical and genotyping examination was applied to suspect the disease of the patient. The solo clinical WES was exploited, and the derived data were filtered according to the standard pipelines. In order to validate the WES finding, the region harboring the candidate variant in the CTSK gene was amplified from genomic DNA and sequenced directly by Sanger sequencing. Results Sequence analysis revealed a rare novel nonsense variant, p.(Trp320*); c.905G>A, in the CTSK gene (). In silico analysis shed light on the contribution of the variant to the pathogenicity of pycnodysostosis. This variant was confirmed by Sanger sequencing and further clinical examinations of the patient confirmed the disease. Conclusion The present study shows a rare variant of the CTSK gene, which inherited as autosomal recessive, in an Iranian male patient with pycnodysostosis. Taken together, the novel nonsense CTSK variant meets the criteria of being likely pathogenic according to the American College of Medical Genetics and Genomics‐the Association for Molecular Pathology (ACMG‐AMP) variant interpretation guidelines.

Novel imaging and clinical phenotypes of CONDSIAS disorder caused by a homozygous frameshift variant of ADPRHL2: a case report

“…To begin with, since the pattern of the pedigree was compatible with an autosomal recessive mode of inheritance, only variants that were heterozygous in unaffected parents and homozygous in the proband were considered. The WES data analysis was performed according to the previously reported works [12]. To be on the safe side, the analysis was applied according to the autosomal dominant mode of inheritance too.…”

An enormous Italian pedigree of Marfan syndrome with a novel mutation in the FBN1 gene

“…The mutation nomenclature was established according to the HGVS The genetic conservation of the region harboring the identified mutation was surveyed by comparing that region of the genome in Human, Dog, Rhesus, Mouse, Elephant, Chicken, and several other vertebrates in UCSC and ConSurf databases. [20][21][22] An ABI 3130xl-automated sequencer (Applied Biosystems) was used either to confirm the obtained variant that identified by NGS method and for sequencing the regions which were not covered by the NGS. The NM_000138.4:c.6872-1G > T variant also was sequenced for the familial segregation analysis by using the Sanger sequencing method.…”

“…The genetic conservation of the region harboring the identified mutation was surveyed by comparing that region of the genome in Human, Dog, Rhesus, Mouse, Elephant, Chicken, and several other vertebrates in UCSC and ConSurf databases 20‐22 …”

A First-Case Report of Pycnodysostosis in an Omani Boy

“…Recently, novel CTSK variants were reported in a 4-year-old Afghani boy (c.847T > C, p.Y283H) 6 and in an Iranian boy (c.905G > A, p.Trp320X). 7 We presented here a 9-year-old Omani male child patient with a novel variant of the CTSK gene causing PKND. This is a rarely reported condition in the Middle East and North Africa region and is the first to be reported in the Gulf Cooperation Council (GCC) region with molecular diagnosis.…”