Development of a high-resolution Y-chromosome microarray for improved male infertility diagnosis.
OBJECTIVE
To develop a novel clinical test using microarray technology as a high-resolution alternative to current methods for detection of known and novel microdeletions on the Y chromosome.


METHODS
Custom Agilent 8x15K array comparative genomic hybridization (aCGH) with 10,162 probes on an average probe spacing of 2.5 kb across the euchromatic region of the Y chromosome.


METHODS
Clinical diagnostic laboratory.


METHODS
Men with infertility (n = 104) and controls with proven fertility (n = 148).


METHODS
Microarray genotyping of DNA.


METHODS
Gene copy number variation determined by log ratio of probe signal intensity against a DNA reference.


RESULTS
Our aCGH experiments found all known AZF microdeletions as well as additional unbalanced structural alterations. In addition to complete AZF microdeletions, we found that AZFc partial deletions represent a risk factor for male infertility. In total, aCGH-based detection achieved a diagnostic yield of ∼11% and also revealed additional potentially etiologic copy number variations requiring further characterization.


CONCLUSIONS
The aCGH approach is a reliable high-resolution alternative to multiplex polymerase chain reaction for the discovery of pathogenic chromosome Y microdeletions in male infertility.
Program in Genetics and Genome Biology, Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario, Canada.
Ryan K C
RK
Yuen
Program in Genetics and Genome Biology, Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario, Canada.
Anna
A
Merkoulovitch
Program in Genetics and Genome Biology, Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario, Canada.
Jeffrey R
JR
MacDonald
Pathology and Laboratory Medicine, Mount Sinai Hospital Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada.
Matthew
M
Vlasschaert
Division of Urology, Murray Koffler Urologic Wellness Centre, Mount Sinai Hospital, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
Kirk
K
Lo
Division of Urology, Murray Koffler Urologic Wellness Centre, Mount Sinai Hospital, Toronto, Ontario, Canada; Women's College Hospital, University of Toronto, Toronto, Ontario, Canada.
Ethan
E
Grober
Program in Genetics and Genome Biology, Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario, Canada; McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Christian R
CR
Marshall
Division of Urology, Murray Koffler Urologic Wellness Centre, Mount Sinai Hospital, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
Keith A
KA
Jarvi
Pathology and Laboratory Medicine, Mount Sinai Hospital Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: EKolomietz@mtsinai.on.ca.
Elena
E
Kolomietz
Program in Genetics and Genome Biology, Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario, Canada; McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. Electronic address: stephen.scherer@sickkids.ca.
Stephen W
SW
Scherer
D053713:Azoospermia / Q000175:diagnosis* / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods*; D041322:Chromosomes, Human, Y / Q000235:genetics*; D017353:Gene Deletion; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
AZF microdeletion; Y chromosome; comparative genomic hybridization array; male infertility