Partial DAZ deletions in a family with ﬁve
Judith Gianotten, M.D.,
Marie¨ tte J. V. Hoffer, Ph.D.,
Jan W. A. De Vries, Ph.D.,
Nico J. Leschot, Ph.D.,
Jan Gerris, Ph.D.,
and Fulco van der Veen, Ph.D.
Academic Medical Center, Amsterdam, The Netherlands
Objective: To study the genetic cause of infertility in a family with ﬁve infertile brothers.
Design: Case report.
Setting: Center for reproductive medicine at a university medical center.
Patient(s): Five brothers presenting with primary infertility due to severely impaired spermatogenesis; also,
their parents and two other paternally related family members.
Intervention(s): Fluorescence in situ hybridization and sequence family variant analysis was performed in
leukocyte DNA to determine the number of deleted in azoospermia (DAZ) genes. Linkage analysis was
performed for X chromosome inheritance, and mitochondrial DNA (mtDNA) was screened for mutations.
Main Outcome Measure(s): DAZ gene copy number, X chromosome linkage, and mtDNA sequence.
Result(s): With conventional polymerase chain reaction (PCR) analysis, no deletions of the AZFc region were
found, but with ﬂuorescence in situ hybridization and sequence family variant analysis, only two DAZ genes
instead of four were detected in all individuals tested. The ﬁve brothers did not share an identical X
chromosomal locus, and no mutations were found in the mtDNA of the index patient.
Conclusion(s): A reduced copy number of the DAZ genes is found in ﬁve infertile brothers with severely
impaired spermatogenesis, as well as in their normospermic father and in two other fertile paternally related
family members. This illustrates that the phenotype associated with a reduced copy number of the DAZ genes
can be extremely variable. (Fertil Steril 2003;79(Suppl 3):1652–5. ©2003 by American Society for Repro-
Key Words: Male infertility, DAZ gene, familial clustering, spermatogenesis, microdeletions, AZFc
The molecular etiology of male factor sub-
fertility due to impaired spermatogenesis is still
unknown in the majority of cases. Structural
and numerical chromosomal abnormalities are
found in approximately 4% of patients with
azoospermia or oligozoospermia (1).
Deletions of any of the Y chromosomal
regions azoospermia factor a, b, or c (respec-
tively, AZFa, AZFb, and AZFc) are also a fre-
quent cause of spermatogenic defects. Dele-
tions of the AZFc region are most frequently
found, that is, in 2%–10% of azoospermic or
severely oligozoospermic men (2–7). The
AZFc region spans 3.5 Mb and contains seven
gene families that are all thought to be involved
in spermatogenesis (7). One of these gene fam-
ilies is the deleted in azoospermia (DAZ) gene
family, which consists of four nearly identical
copies divided into two clusters with two genes
each (7, 8). Although most deletions involve a
deletion of all four DAZ genes, absence of only
two of the DAZ genes also is associated with
impaired spermatogenesis (9–11).
Most cases of male factor subfertility are
individual cases, and the genetic aberrations
found are usually de novo events. However,
clustering of male subfertility in families has
been described (12–14), and several case re-
ports with multiple affected family members
have been published (15–23), indicating that it
is a potentially heritable condition.
In this article, we present a unique family
with ﬁve brothers who are infertile because of
severely impaired spermatogenesis. To eluci-
date the genetic basis for the infertility in this
family, we screened all ﬁve brothers as well as
their parents and two other paternally related
family members for known genetic causes of
impaired spermatogenesis. In addition, we per-
Received July 11, 2002;
revised and accepted
October 24, 2002.
Reprint requests: Judith
Gianotten, M.D., Center for
Department of Obstetrics
Academic Medical Center,
Meibergdreef 9, 1105 AZ
Netherlands (FAX: 31-20-
Center for Reproductive
Department of Clinical
FERTILITY AND STERILITY
VOL. 79, SUPPL. 3, JUNE 2003
Copyright ©2003 American Society for Reproductive Medicine
Published by Elsevier Inc.
Printed on acid-free paper in U.S.A.