Successful Application of whole Exome Sequencing in Identification of the Underlying Genetic Cause in A Family with Infertility in Both Sexes

سال انتشار: 1398
نوع سند: مقاله کنفرانسی
زبان: انگلیسی
مشاهده: 283

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شناسه ملی سند علمی:

RROYAN20_245

تاریخ نمایه سازی: 29 مهر 1398

چکیده مقاله:

Background: The most severe phenotypes of infertility in women are premature ovarian insufficiency (POI) and non-ob-structive azoospermia (NOA) in men. POI is characterized by premature amenorrhea reflecting an early depletion of the fol-licular reserve in the ovaries of women under the age of 40. Non obstructive azoospermia is defined as lack of spermatogenesis or mature spermatozoa in the testes, low testicular volume and high follicle stimulating hormone values. Due to the absence of sperm in testis and follicles in the ovaries, these two disorders are considered similar in terms of the phenotype. POI and NOA are heterogeneous diseases caused by a variety of mechanisms however, there is a strong genetic component for both as fami-lies with multiple affected children exist. Despite many studies into the genetics of POI and NOA few genes have been identified that can explain a substantial proportion of cases leaving many cases idiopathic. Here, our objective is to identify the genetic cause of NOA and POI in six affected members of a consanguineous Iranian family.Materials and Methods: Whole exome sequencing (WES) was performed the affected and their parents. In silico analy-sis was also used to predict the effect and pathogenicity of the discovered variants followed by Polymerase Chain Reaction (PCR) and Sanger sequencing to validate the segregation of the variant with the disease in the pedigree.Results: Given the consanguinity of the pedigree, high priority was given to homozygous variants observed in the affected of both sexes. A final list of pathogenic variants was prepared and one specific variant in a highly conserved domain of a gonad specific protein was confirmed to be mutual among the affected. Conclusion: With the application of WES we identified a path-ogenic variant in Iranian family with multiple instances of POI and NOA. Our finding reinforces the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases for which conventional genetic approaches have previously failed to provide a molecular diagnosis.

نویسندگان

K Padidar

Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.

A Akbari

Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.

M Totonchi

Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.. Department of Stem Cells and Developmental Biology, Cell Sci-ence Research Center, Royan Institute for Stem Cell Biology

N Almadani

Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.