Novel mutation in FTHL17 gene in pedigree with 46,XY pure gonadal dysgenesis.

OBJECTIVE:To identify the genetic cause of a pedigree with four patients with 46,XY pure gonadal dysgenesis (PGD). DESIGN:Genetic mutation study. SETTING:Academic medical center. PATIENT(S):Four first cousins, from three households of a Chinese pedigree, affected by 46,XY PGD. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):The patients were studied from clinical and genetic perspectives. Whole-genome sequencing was conducted in family members. RESULT(S):Four first cousins in the third generation were affected by 46,XY PGD. A specific familial characteristic was the prevalence of as high as 100% of gonadal tumors in patients. Whole-genome sequencing identified a new ferritin heavy chain-like 17 (FTHL17) mutation, c.GA442_443TT (p.E148L), which has the potential to interfere with protein function and cause 46,XY PGD. Moreover, the location (Xp21.2) of the FTHL17 gene proves that the family is X-linked recessive. In vitro functional study revealed that the perturbation of FTHL17 caused the decrease of protein expression and cell proliferation. CONCLUSION(S):We describe the first 46,XY PGD pedigree that may be attributed to mutations of the FTHL17 gene. We speculated that the FTHL17 gene is involved in the testis-determining pathway and tumorigenesis.

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