Exome sequencing for the diagnosis of 46,XY disorders of sex development.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
Samples were either submitted to the research laboratory or submitted as clinical samples to the UCLA Clinical Genomic Center. Sequencing data were filtered using a list of genes known to be involved in DSD.


RESULTS
We were able to identify a likely genetic diagnosis in more than a third of cases, including 22.5% with a pathogenic finding, an additional 12.5% with likely pathogenic findings, and 15% with variants of unknown clinical significance.


CONCLUSIONS
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. Exome sequencing proved an efficient method toward such a goal in 46,XY DSD patients.
Departments of Human Genetics (R.M.B., V.A.A., H.B., A.E., S.F.N., E.D., E.V.) and Pathology and Laboratory Medicine (V.A.A., H.L., S.F.N.), David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California 90095; Department of Pediatrics (M.P.A.), University of Washington, Seattle, Washington 98195; Department of Endocrinology (P.Y.F.), Seattle Children's Hospital, Seattle, Washington 98105; Nassau University Medical Center (R.B.), East Meadow, New York 11554; Departments of Pediatrics and Human Genetics (C.K.), Ann Arbor, Michigan 48109; The Children's Hospital Colorado (S.T.), Aurora, Colorado 80045; Division of Medical Genetics (S.S., L.H.), Stanford University, Lucile Packard Children's Hospital, Stanford, California 94305; TriStar Children's Specialists (R.P.M.), Nashville, Tennessee 37203; Division of Pediatric Genetics and Metabolism (H.J.S., R.Z.), University of Florida, Gainesville, Florida 32610; Cedars-Sinai Medical Center (O.K.G.), Los Angeles, California 90048; Children's Hospital of Los Angeles (L.R.-P.), Los Angeles, California 90027; and Departments of Pediatrics (A.P.-H., E.D., E.V.) and Urology (E.V.), David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California 90095.
Ruth M
RM
Baxter
Valerie A
VA
Arboleda
Hane
H
Lee
Hayk
H
Barseghyan
Margaret P
MP
Adam
Patricia Y
PY
Fechner
Renee
R
Bargman
Catherine
C
Keegan
Sharon
S
Travers
Susan
S
Schelley
Louanne
L
Hudgins
Revi P
RP
Mathew
Heather J
HJ
Stalker
Roberto
R
Zori
Ora K
OK
Gordon
Leigh
L
Ramos-Platt
Anna
A
Pawlikowska-Haddal
Ascia
A
Eskin
Stanley F
SF
Nelson
Emmanuèle
E
Délot
Eric
E
Vilain
D058490:Disorder of Sex Development, 46,XY / Q000175:diagnosis* / Q000235:genetics; D059472:Exome; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D010641:Phenotype