Exome Sequencing for the Diagnosis of 46,XY Disorders of Sex Development. E. C. Delot1,, R. M. Baxter1, V. A. Arboleda1, H. Lee2, H. Barseghyan1, M. P. Adam3, P. Y. Fechner4, R. Bargman5, K. Keegan6, S. Travers7, S. Schelley8, L. Hudgins8, R. P. Mathew9, H. J. Stalker10, R. Zori10, O. K. Gordon11, L. Ramos-Platt12, A. Eskin1, S. F. Nelson1,2, E. Vilain1 1) Dept Human Genetics, 5301A Gonda Bldg, David Geffen Sch Med at UCLA, Los Angeles, CA 90095; 2) Pathology and Laboratory Medicine, David Geffen Sch Med at UCLA, Los Angeles, CA; 3) Department of Pediatrics, U. Washington, Seattle WA 98195; 4) Department of Endocrinology, Seattle Children's Hospital, Seattle WA 98105; 5) Nassau University Medical Center, East Meadow, NY 11554; 6) Depts of Pediatrics and Human Genetics, Ann Arbor, MI 48109; 7) The Children's Hospital Colorado, Aurora, CO 80045; 8) Division of Medical Genetics, Stanford University, Lucile Packard Children's Hospital, Stanford, CA 94305; 9) TriStar Children's Specialists, Nashville, TN 37203; 10) Division of Pediatric Genetics & Metabolism, U. Florida Gainesville, FL 32610; 11) Cedars-Sinai Medical Center, Los Angeles, CA 90048; 12) Children's Hospital of Los Angeles, Los Angeles, CA 90027.
Disorders of sex development (DSD) are clinical conditions where there is a discrepancy between the chromosomal sex and the phenotypic (gonadal or genital) sex of an individual. Such conditions can be stressful for patients and their families and have historically been difficult to diagnose, especially at the genetic level. In particular, for cases of 46,XY gonadal dysgenesis, once variants in SRY and NR5A1 have been ruled out, there are few other single gene tests available. We used exome sequencing followed by analysis with a list of all known human DSD-associated genes to investigate the underlying genetic etiology of 46,XY DSD patients who had not previously received a genetic diagnosis. We were able to identify a likely genetic diagnosis in more than a third of cases, including 22.5% with a pathogenic finding and an additional 12.5% with likely pathogenic findings. In addition, 15% had variants of uncertain clinical significance (VUS) that may be reclassified as literature evolves. Exome sequencing allowed a remarkable level of genetic diagnostic success in this cohort, especially considering that, for most patients, all other endocrine and genetic testing had been exhausted. Early identification of the genetic cause of a DSD will in many cases streamline and direct the clinical management of the patient, with more focused endocrine and imaging studies and better informed surgical decisions. When unaffected parents are also genotyped there is the additional possibility of identifying novel genes that will further enhance our understanding of these complex conditions and allow for better care and prognostic information for the patients and their families.
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