OR42-4 Increasing the Diagnosis Rate in Patients with Disorders of Sex Development (DSD)

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: OR42-Disorders of Sex Development and Transgender Medicine
Clinical/Translational
Tuesday, June 24, 2014: 9:30 AM-11:00 AM
Presentation Start Time: 10:15 AM
W185 (McCormick Place West Building)
Jill D. Jacobson, MD1, Julie L. Strickland, M.D., M.P.H.1, Laurie Smith, M.D., Ph.D.1, Anna M. Egan, Ph.D.2, Laurel K. Willig, M.S., M.D.3, Emily G Farrow, PhD, CGC1, Carol J. Saunders, Ph.D., FACMG1, Stephen F. Kingsmore, M.B., BAO, ChB, DSc, FRCPath1, Terri L. Luetjen, R.N.1 and John M. Gatti, M.D.1
1Children's Mercy Hospital, Kansas City, MO, 2Children's Mercy Hospital, Kansas City, 3Children's Mercy Hospitals and Clinics, Kansas City, MO
The 2006 Endocrine Society Consensus Statement for Disorders of Sexual Development (DSD) states that only 50% of undervirilized males receive definitive diagnoses, and only about 20% of patients receive molecular diagnoses (1). We established a multidisciplinary DSD clinic (termed GUIDE clinic) at our institution in 2008. One of our objectives was to increase our molecular diagnosis rate.  From 2008 to 2013, we saw 88 patients with DSD in our clinic. We utilized a detailed testing algorithm designed to maximize our molecular diagnosis rate, with a focus on undervirilized males. Upon IRB approval, we identified 36 undervirilized males, 42 overvirilized females, and 10 patients with sex chromosome mosaicism. Eight undervirilized males did not have DNA available. We identified a molecular diagnosis in 18 of 28 (64%) undervirilized males for whom DNA was available. One patient was identified with Klinefelter syndrome by a routine karyotype.  Targeted genetic analysis based on clinical suspicion yielded the following 10 mutations/diagnoses: androgen receptor gene (n=3), NR5A1 (n=2) SOX9 (n=2), Beckwith Wiedeman syndrome (n=1), SRD5A2 (n=1) and a congenital dyserythroblastic anemia gene(n=1). Microarray and/or custom array analysis were performed on the remaining 17 genetic males, resulting in 7 additional diagnoses. Microarray analysis demonstrated duplications or deletions suspected to be associated with genital ambiguity in 4 patients.  Targeted gene panel testing by next generation sequencing (TaGSCAN) identified causative mutations in 3 patients, one in OPHN1, and 2 in NR5A1.  An additional patient was found to have a heterozygous mutation in GNRHR, which is not known to be causative.  The remaining 9 undervirilized males who had DNA available and who had not received molecular diagnoses were offered whole exome sequencing (WES).  Only one undervirilized male has undergone all tests, including WES without receiving a diagnosis.  With respect to virilized females, 25 of 42 (60%) received molecular diagnoses.  Of these, one patient was diagnosed with Down syndrome by a routine karyotype.  Targeted gene analysis yielded the following 23 diagnoses: CAH (n=20), Beckwith Wiedeman syndrome (n=1), Smith Magenis syndrome (n=2). Altogether, including the patients with sex chromosome mosaicism, we achieved a molecular diagnosis rate of 61%.   We conclude that a combination of routine karyotyping, targeted genetic testing, microarray testing, and targeted genome sequencing can provide definitive diagnoses in more than half of patients with DSD.  Whole exome sequencing may be important for undervirilized males who receive no molecular diagnosis despite extensive testing. We anticipate that a higher diagnosis rate can be achieved in DSDs using all currently available genetic tools.  There may remain novel genetic and epigenetic causes for DSD that will be identifiable using emerging tests.

Lee PA, Houk CP, Ahmed F, et al.

Disclosure: JLS: Teacher, Merck & Co.. Nothing to Disclose: JDJ, LS, AME, LKW, EGF, CJS, SFK, TLL, JMG

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