Current Status of Y Chromosome Microdeletions: Prevalence, Distribution, Implication and Association with Male Infertility in Indian Men- A Review

Abstract

Introduction: Infertility affects about 15% of couples attempting
pregnancy and in approximately 50% of these cases, male
factors are responsible. Male infertility is clinically characterised
by azoospermia and oligozoospermia depending on the amount
of loss of genetic material and the size of the affected region
on the Y Chromosome Microdeletions (YCM). The majority of
genes located in the Y chromosome are involved in male related
functions such as spermatogenesis in human, in addition to other
endocrine and physiological factors. These microdeletions are
located on q arm of Y chromosome, specifically Azoospermia
Factor (AZF) region, hence called Yq microdeletions. These
deletions are in form of complete/incomplete, recombination;
mutations and Copy Number Variations (CNV) and vary in
frequency depending on region, ethnicity, lifestyles and
other epigenetic factors. Hence, this study is well reviewed
in Indian men with infertility caused by AZF a,b,c and other
partial deletions. So, it is important to the one who is affected
by these mutations and infertile couples who adopt Assisted
Reproductive Technologies (ARTs) after counseling. It is further
useful for prediction of testicular sperm retrieval chances.
Aim: To review the current status of Yq microdeletion frequency
in infertile Indian men with the available data and their correlation
with testicular phenotypes as well as other factors. These
would also reckon as a supportive to other clinical findings for
diagnosis of specific deletion of infertility to adopt ARTs to the
infertile couple.
Materials and Methods: Various studies including our data
were collected to European Molecular Genetics Quality
Network (EMQN) as well as analyse these Yq microdeletions
screened using specific Sequence Tagged Sites (STS) of
available kit like European Academy of Andrology (EAA) and
non-EAAs using Polymerase Chain Reaction (PCR) technology.
Various researchers from various zones of India contributed to
microdeletion screening of Y chromosome using various STS
to AZF locus. These data from 30 study groups were compared
to geographical areas/zones, Indian populations, environment,
selection criteria and other factors in this review.
Results: The data on thousands of Y chromosome analysis
confirmed that the frequency of microdeletions are affected by
sample size, selection criteria of subjects, different geographical
regions, ethnicity, Oxidative Stress (OS), Deoxyribonucleic Acid
(DNA) fragmentation and food styles in addition to genetic defects.
In Indian subcontinent, these deletions contribute to 8.33% from
screening of 5435 Y chromosomes (453/5435). Lower percent
(5.37%) of Yq microdeletions in Western India than other parts
was observed, being highest in South East (20.52%) and North
East zones (17.77%) as mentioned in the present study. These
variations in Yq microdeletions are attributed to geographic region,
foodstyle, other environmental factors and others. AZFc deletions
were more prevalent and correlated to azoospermia (referred/
selected, 66%; deleted 61%) from 30/15 citations respectively
in present cohort over oligospermic and/or severe oligospermic
men followed by b and a sub-regions including b+c, a+b and
others in AZF locus. Amongst 30 study groups, 27 exhibited AZFc
deletions at higher rate.
Conclusion: From these data in India, it was hence noticed
that screening of Yq microdeletion is an important criterion and
its correlation with spermeograms is very necessary to infer
degree of infertility in men. Such cases are strongly suggested
to undergo genetic counselling before adoption of ARTS as
deletions increase risk of genetic anomalies, low birth weight and
congenital malformations in New Births (NB) of Intracytoplasmic
Sperm Injection and Testicular Sperm Ejaculates (ICSI/TESE)
adopted cases. Thus, Y deletion evaluation reckons the
diagnosis of type of male infertility and its prevention in the next
generation propagation through ARTs adopting infertile couples
after counselling..

Full text

Journal of Clinical and Diagnostic Research, 2021 Mar, Vol-15(3): GE01-GE09 11
DOI: 10.7860/JCDR/2021/46154.14604
Genetics Section
Current Status of Y Chromosome Microdeletions:
Prevalence, Distribution, Implication
and Association with Male Infertility
in Indian Men- A Review
Review Article
INTRODUCTION
Cytogenetically, human ‘Y’ chromosome is an acrocentric type
composed of two Pseudoautosomal Regions (PAR1 and PAR2), a
short arm (Yp) and long arm (Yq), that are separated by a centromere
[1]. PARs and short arm Yp are euchromatic while a large portion
of the long qarm is heterochromatic except around centromere
which is euchromatic in nature. The non-recombining region
(NRY) is the locus beyond the PARs which does not recombine
with X-Chromosome during meotic paring [2]. This region has
heterochromatic and euchromatic loci. The heterochromatic
locus of Yq comprises distal Yq containing two highly repetitive
sequences DYZ1 and DYZ2 [1,3]. Variation in this region of the
long arm of Y has been observed [2], whose significance is much
unknown [Table/Fig-1] [4].
The euchromatic region encompasses the pericentromeric region
and the short and long arms of Y which refer to the male specific
region on Y (MSY; [Table/Fig-1]). This region contains genes
for sex determination and regulation of brain functions [1,4,5].
MANDAVA V RAO1, NIDHI P SHAH2, RUTVIK J RAVAL3, POOJA P SOLANKI4,
PARTH S SHAH5, SANDIP C SHAH6
Keywords: Polymerase chain reaction-sequence-tagged site markers, Regional distribution,
Spermeograms, Yq microdeletion screening
ABSTRACT
Introduction: Infertility affects about 15% of couples attempting
pregnancy and in approximately 50% of these cases, male
factors are responsible. Male infertility is clinically characterised
by azoospermia and oligozoospermia depending on the amount
of loss of genetic material and the size of the affected region
on the Y Chromosome Microdeletions (YCM). The majority of
genes located in the Y chromosome are involved in male related
functions such as spermatogenesis in human, in addition to other
endocrine and physiological factors. These microdeletions are
located on q arm of Y chromosome, specifically Azoospermia
Factor (AZF) region, hence called Yq microdeletions. These
deletions are in form of complete/incomplete, recombination;
mutations and Copy Number Variations (CNV) and vary in
frequency depending on region, ethnicity, lifestyles and
other epigenetic factors. Hence, this study is well reviewed
in Indian men with infertility caused by AZF a,b,c and other
partial deletions. So, it is important to the one who is affected
by these mutations and infertile couples who adopt Assisted
Reproductive Technologies (ARTs) after counseling. It is further
useful for prediction of testicular sperm retrieval chances.
Aim: To review the current status of Yq microdeletion frequency
in infertile Indian men with the available data and their correlation
with testicular phenotypes as well as other factors. These
would also reckon as a supportive to other clinical findings for
diagnosis of specific deletion of infertility to adopt ARTs to the
infertile couple.
Materials and Methods: Various studies including our data
were collected to European Molecular Genetics Quality
Network (EMQN) as well as analyse these Yq microdeletions
screened using specific Sequence Tagged Sites (STS) of
available kit like European Academy of Andrology (EAA) and
non-EAAs using Polymerase Chain Reaction (PCR) technology.
Various researchers from various zones of India contributed to
microdeletion screening of Y chromosome using various STS
to AZF locus. These data from 30 study groups were compared
to geographical areas/zones, Indian populations, environment,
selection criteria and other factors in this review.
Results: The data on thousands of Y chromosome analysis
confirmed that the frequency of microdeletions are affected by
sample size, selection criteria of subjects, different geographical
regions, ethnicity, Oxidative Stress (OS), Deoxyribonucleic Acid
(DNA) fragmentation and food styles in addition to genetic defects.
In Indian subcontinent, these deletions contribute to 8.33% from
screening of 5435 Y chromosomes (453/5435). Lower percent
(5.37%) of Yq microdeletions in Western India than other parts
was observed, being highest in South East (20.52%) and North
East zones (17.77%) as mentioned in the present study. These
variations in Yq microdeletions are attributed to geographic region,
foodstyle, other environmental factors and others. AZFc deletions
were more prevalent and correlated to azoospermia (referred/
selected, 66%; deleted 61%) from 30/15 citations respectively
in present cohort over oligospermic and/or severe oligospermic
men followed by b and a sub-regions including b+c, a+b and
others in AZF locus. Amongst 30 study groups, 27 exhibited AZFc
deletions at higher rate.
Conclusion: From these data in India, it was hence noticed
that screening of Yq microdeletion is an important criterion and
its correlation with spermeograms is very necessary to infer
degree of infertility in men. Such cases are strongly suggested
to undergo genetic counselling before adoption of ARTS as
deletions increase risk of genetic anomalies, low birth weight and
congenital malformations in New Births (NB) of Intracytoplasmic
Sperm Injection and Testicular Sperm Ejaculates (ICSI/TESE)
adopted cases. Thus, Y deletion evaluation reckons the
diagnosis of type of male infertility and its prevention in the next
generation propagation through ARTs adopting infertile couples
after counselling.

Mandava V Rao et al., Current Status of Y Microdeletions in Indian Infertile Men www.jcdr.net
Journal of Clinical and Diagnostic Research, 2021 Mar, Vol-15(3): GE01-GE09
22
Chromo Domain on Y (CDY1), Golgi autoantigen, golgin subfamily
a 2 likely chondroitin sulfate proteoglycan 4 like Y, Testes Specific
Transcript Y (TTTY)-linked-3, TTTY4 and TTTY17 [28]. Non-Allelic
Homologous Recombination (NAHR) occurs between amplicons
which include deletion, duplication and both leading to Copy
Number Variation (CNV) in this sub region [29]. Hence, this region
is more susceptible for microdeletions. Four partial deletions are
identified viz., b2/b4, gr/gr, b2/b3 and b1/b3 having about 1.6 Mb
[29-31]. Amongst these, gr/gr is the common deletion occurring
due to recombination [32]. The b1/b3 differs from others, as it also
encompasses the part of AZFb and results in loss of RBMY1 and
PRY leading to loss of spermatogenesis in high frequency [27].
However, these partial microdeletions encompassing AZFc and
AZFb regions are important in causing spermatogenic alterations
in male fertility; their importance needs to be answered further. AZF
deletions and semen phenotypes correlate with Yq microdeletions
so, it is appropriate to consider Y deletions as a cause of testicular
semen pathologies. Hence, about 25-55% of males with gonadal
pathologies are related to hypospermatogenesis, arrest of sperm
maturation and SCOS. Amongst, about 5-25% males are with
severe oligospermia to azoospermia [32,33] harboring YCMs. But
depending upon the deletion on AZF locus deleted, the phenotypic
alteration varies [1,16,34]. Accordingly, the patients need to be
suggested for ARTs like Intracytoplasmic Sperm Injection (ICSI) and
Testicular Sperm Ejaculates (TESE).
Mechanisms of AZF Deletions
AZFa deletions are due to homologus intrachromosomal
recombinations between two Human Endogenous Retroviral
(HERV) sequences. AZFb, c deletions result recombination
between palindromes (P5, P1 and P3, P1), respectively. Peculiar
structural organisation of AZFc makes it more prone to structural
rearrangements. Partial deletions occur as a result of recombination
between subamplicons in AZFc. CNV occurs due to various
mechanisms like gene dosage, mutation, deletion or duplication in
AZF locus [1,29,35].
Yq Microdeletions Analysis
Y chromosome deletions are dynamic in addition to other genetic
factors. These microdeletions involve deletions, duplications and
both. Clinically, the Y chromosome changes can be categorised
AZF deletions, partial AZFc deletions and the gene CNVs second to
chromosomal anamolies.
MATERIALS AND METHODS
Genomic DNA was used for analysing micro deletions with Sequence
Tagged Sites (STS) based on Polymerase Chain Reaction (PCR)
technologies. Thus, these AZF deletions were described by adopting
specific markers of EAA and non EAA STS as suggested by Sen S et
al., [36]. About 18 STS were essentially used for proper identification
of deletions in AZF locus of infertile cases. These include SY746,
SY86, DFFRY, (AZFa), SY113, SY118, SY127, RBM1Y, XKRY, SY134,
SY143 (AZFb), SY153, SY148, SY157, SY255, SY254, SY158,
SY160 (AZFc) in addition to SY14 (SRY). Genomic DNA was used
for PCR assay and was used with necessary reagents for detection
of microdeletions in AZFa, AZFb, AZFc, AZFa+b and AZFb+c sub
regions and others [9,15,36,37] for ensuring optimal results [10,38-
40].
Testing of Yq microdeletions has many applications for correct
diagnosis for the cause of infertility [38,39]. For correlation of
testicular phenotypic manifestations specific guidelines are strictly
followed, while performing spermeogram analysis [41]. Accordingly,
the cases were grouped into azoospermia (obstructive and non-
obstructive) oligozoosospermia (5-15×106/mL), severe oligospermia,
normozoospermia (normal values of sperms in the ejaculate),
These genes are critical in development of gonadal differentiation,
development and function like Sex-Determining Region on Y
Chromosome (SRY), Testis-Specific Protein on Y chromosome
(TSPY), while the longarmed (Yq) has 12 genes and gene
families mainly [1,5,6]. After this discovery, the Y chromosome
is well studied in various species and several functional genes
(approximately 70) are detected [7]. Basically these genes fall in
two categories viz., housekeeping genes homologous to X and
gene families expressed specific to testes, the candidate genes.
The involvement of non-recombining region of Y(NRY) locus
related to Yq in male infertility was coined in 1997, almost 23-year-
ago. However, in 1976, Italian researchers identified detectable
deletions at distal end of band Yq11 in 6 infertile males (6/1170).
Their investigation revealed that deletions are de novo and could
be related to azoospermia [8]. Based on this, the authors proposed
aspermatogenesis factor called the AZF on the Yq locus. With the
advent of molecular maps of the ‘Y’, the studies in AZF region and
male infertility were extensively elaborated [9-11]. Using a panel of
markers, infertile males who had deletions in the Yq 11.23 were
identified [1,12,13]. These studies disclosed in this region, as
three sub regions; proximal, middle and distal defined as AZFa,
AZFb and AZFc, respectively [14]. The Deleted in Azoospermia
(DAZ) gene in AZFc locus was considered as a strong candidate
for male infertility, little is known about other genes in this locus
[12]. This region has the size 0.8 Mb (AZFa), 6.2 Mb (AZFb/P5/
Proximal-P1), 7.7 Mb (AZFb/c; P5/distal P1 and P4/distal P1), 3.5
Mb (AZFc (b2/b4), 1.6 Mb (gr/gr), 1.6 Mb (b1/b3) and 1.8 Mb (b2/
b3) as mentioned in [Table/Fig-1] [1,15,16].
AZFa encodes only single copy genes of four mapped. These genes
are X-homologous genes that escape during inactivation. These are
ubiquitin peptidase 9 Y-linked (USPY9) whose function is beyond
regulation of sperm production. Dead Box on Y Chromosome
(DBY) deletion leads to Sertoli Cell Only Syndrome (SCOS) and
involves also early stages of development Ubiquitously Transcribed
Tetratricopeptide Repeat on Y Chromosome (UTY) gene status in
male infertility is unknown. Same is for thymosine beta 4 Y linked
(Tß4Y). Thus, these candidate genes contribute 5% of deletion [16-
18]. AZFb genes contribute about 16% q deletions in infertile males.
Deletions bring about azoospermia, oligospermia. It also contains
admixture of AZFc locus [Table/Fig-1]. It encodes 5 single copy of
genes and others are more than single copy. These are Cyorf15,
RPS4Y2, E1F1AY, SMCY, XKRY, HSFY, PRY and RBMY. The RBMY
is the most important genes of AZFb involved in spermatogenesis.
Deletion of PRY and RBMY lead to hypospermatogenesis/complete
loss of spermatogenesis [19-23]. Especially, RBMY protein is
involved in all stages of sperm production and male cancers [12].
AZFc locus contributes to 60% of deletions. AZFa and AZFb are
essential for initiating spermatogenesis, while AZFc is necessary
for its completion. The AZFc in most infertile men lead to severe
oligospermia (<5 X 106/mL) to azoospermia [24,25]. It spans 4.5Mb
and codes for 2% candidate genes and in families of transcription
units expressed in testis [26,27]. Thus, it has DAZ, basic protein Y2,
[Table/Fig-1]: Old and new classification of Y chromosome in relation to AZF with
modification [4].

www.jcdr.net Mandava V Rao et al., Current Status of Y Microdeletions in Indian Infertile Men
Journal of Clinical and Diagnostic Research, 2021 Mar, Vol-15(3): GE01-GE09 33
7.31% (3/41) microdeletions [44]. In Mumbai and Nagpur, the
cases were idiopathic type following the classification of World
Health Organisation (WHO) [Table/Fig-3] [41] and their screening
found 3.4% consisting of 56 from 1.636 infertile men, where
AZFc subregion was higher in Mumbai, Maharashtra [36]. From
Nagpur, Ambulkar PS and Pande SS obtained 10.6% deletion
(17/160) from an analysis of oligozoospermia and azoospermia
phenotypes with a dominant of AZFc followed by others [9]. A
study conducted with 88 cases by Nagvenkar P et al., consisting
of (42) oligospermia and (46) severe oligospermia detected only
1.1% microdeletions (1/88) with AZFc [44]. Thus, this Western
region (Gujarat, Maharashtra) constituted only 5.37% (111/2066)
YCM with AZFc dominance [Table/Fig-4].
[Table/Fig-2]: Geographic distribution of Yq microdeletions in Indian infertile man.
[Table/Fig-3]: Regional zonal distribution of Yq % microdeletions in Indian population.
astherozoospermia (low level of motility, <50%), teratozoospermia
(<30% of normal sperm morphology) and aspermia. Other causes
include cryptorchidism, varicocele, endocrinological, obstruction of
seminal pathways, infection, alcohol and chemotherapy in addition
to genetic defects like cytogenetic disorders, gene mutation, Yq
microdeletion [1,36,42]. Among genetic defects authors revealed
the current knowledge of Yq microdeletions in the genes leading
to infertility and their correlation to the phenotypic manifestations,
implications, their distribution and prevalence in India.
Data Collection
The information, latest was collected using Google on YCMs
and male infertility in India and research paper collected. As
cited earlier this information was categorised for the prevalence
of Yq microdeletion, region wise, phenotype of semen, type
of q deletions, STS markers by PCR-STS method. The data of
Yq deletions were subjected to percent values if necessary,
from chosen 30 study groups of seven Indian Zones; Western
(Gujarat, Maharashtra); Central Zone (Lucknow, Varanasi); North
(Delhi); North-East (Assam); East (West Bengal); South Central
(Hyderabad) and South-East (Tamil Nadu, Kerala), respectively
[Table/Fig-2]. No data was duplicated in this study.
Statistics
The data of 30 group studies were added according to our need
with simple statistics like percentage in this cohort. No duplicate of
data was observed in present study, as it might lead to erroneous
information.
RESULTS AND DISCUSSION
Zonal/Regional Deletion Analysis
In Gujarat Western part of India, screening of Yq microdeletion
[43], reported 141 cases with oligospermia (41) and azoospermia
(100) screen microdeletions. These authors in Anand (Gujarat)
detected 24.11% (34/141) deletion with higher rate of AZFc
deletions [43]. Analysis of oligospermia (3), azospermia (3),
asthenospermia (2), cryptozoospermia (3), oligoasthenospermia
(OAS) (4) and infertile normo-zoospermia (26) totally (41), revealed
In South Eastern (SE) region (Tamil Nadu, Kerala) six groups
studied microdeletions. Abhilash VG et al., from Chennai had
screened 89 cases with 34 azoospermia and 55 oligozoospermia
cases for microdeletions [45]. They reported an average percent
of 24.7% (22/89) consisting high frequency of AZFc. A study from
Tamil Nadu, reported 72 semen samples of oligozoospermia (5),
asthermo (7) and Oligoasthenozoospermia (OAS) (7), exhibited
12.9% deletions (19/72) having AZFc deletions at higher rate
[46] (Sakthivel PJ and Swaminathan M, 2008). Viswambharan N,
et al., documented 13.3% microdeletions (4/30) from their
study cohort [47], Suganthi R et al., [48] from South Eastern
Part of India described 36% deletions (18/50) in oligo and
azoospermia infertile cases with higher frequency of AZFc
S. No. Medical/Clinical term Condition/Definition
1 Aspermia Absence semen upon ejaculate
2 Zoospermia Presence of spermatozoa in the semen
3 Azoospermia A complete absence of sperm in the
semen (both OA and NOA)
4 Normozoospermia All normal semen values in ejaculate
5 Oligozoospermia Presence of an abnormally low number
of sperm in a semen (5-20×106/mL)
6 Severe Oligozoospermia Sperm counts fall between 0 and 5 million
sperm/mL
7 Asthenozoospermia Reduced sperm motility
8 Oligoasthenozoospermia Combination of reduced sperm motility
and low sperm count
9 Teratozoospermia Presence of higher abnormal
morphology in the semen
10 Oligoasthenoteratozoospermia
Condition that includes low number,
poor sperm movement and high
abnormal forms
11 Polyzoospermia Higher than normal values/mL
12 Hematospermia Semen with Red Blood Cell (RBC)
13 Pyospermia Semen with White Blood Cell (WBC)
[Table/Fig-4]: Semen variables according to WHO [41].
OA: Obstructive azoospermia; NOA: Non-obstructive azoospermia

Mandava V Rao et al., Current Status of Y Microdeletions in Indian Infertile Men www.jcdr.net
Journal of Clinical and Diagnostic Research, 2021 Mar, Vol-15(3): GE01-GE09
44
sub-locus. Previous studies by this group [49,50] in 215 and
75 cases documented 11.2% (24/215) and 29.3% (22/75) Yq
microdeletions, respectively. Thus, this zone possessed 20.52%
YCMs (109/531) [Table/Fig-3].
In South Central Zone of India (Hyderabad), the results depicted
in a different pattern. The screening of 20 cases of 10 each of
azoospermia and oligospermic men, the observed deletions in 3
cases was 15% (3/20), with AZFc dominance [51]. Another study
[52] identified in 251 infertile men only 3.98% Yq microdeletions
(10/251) with high percent of AZFc deletions. There were cases of
194 idiopathic infertily and 57 were of varicocele having zoospermia
followed by oligozoospermia, Oligoasthenoteratozoospermia and
teratozoospermia [50]. Swarna M et al., from Hyderabad mapped
4 cases from 50 infertile cases (4/50; 8%) and 9 cases with Yq
deletions (9/70, 12.8%) containing 70 idiopathic infertile cases
of various testicular phenotypic manifestations with high AZFc
deletions and similarly [53,54], Thangaraj K et al., from South India
(Hyderabad) also reported an analysis of 340 azoospermia, where
29 had microdeletion (8.5%) of AZFc >AZFb >AZFa [55]. Thus,
South Central region had the frequency of 7.52% (55/731) deletions
comparatively lower than South East region [Table/Fig-3].
In Eastern region (West Bengal), recent report indicated 5%
microdeletions in a study cohort documented by Ray A et al., in 80
infertile men with 19 azoospermia and 61 oligozoospermia (4/80)
where AZFc was dominated [56]. Sen S et al., reported in their
article, the deletions marked were 8.5% (29/340) [36]. The total
average of Yq in the region remained 7.85% (33/420) [Table/Fig-3].
In North East (NE), the results varied where Mahanta R et al., [57]
screened only 100 infertile cases with 5% YCM (5/100) where
AZFc was dominant. In a study of Barbhuiya PN et al., published
25.30% Yq deletions in Assam (43/170) [58]. These 170 infertile
men had various types of semen. They reported high frequency of
AZFa and c in inferstitial deletion of AZF locus. The total deletions
were of 17.17% (48/270) [Table/Fig-3].
In Lucknow and Varanasi (Central Indian Zone), various reports are
available contributing 5.65% YCMs (39/690) from various groups
[Table/Fig-3]. Ambasudhan R et al., detected 5% microdeletions
from 177 infertile men with various phenotype manifestations in
Varanasi (9/177) with high frequency of c deletions [59]. Khan FH
et al., in their cohort, 100 infertile cases consisting of azoo, oligo
and asthenozoospermia had 10% Yq deletions (10/100) [60].
Mainly, they found AZFa and AZFc including b+c types. The study
reported by Pandey LK et al., had 64 infertile men with 3.3%
deletions (2/64), where AZFc was dominant in their semen types
[61]. Similarly, Singh K and Raman R in their study obtained 4.8%
(13/270) in azoo- and oligospermic men with infertility possessing
of AZFc and AZFd deletions [62]. In Lucknow Mittal RD et al., in
79 infertile men, with oligo (25), azoospermia (54), screened for
Y Chromosome Microdeletion (YCM), who reported 6.5%(5/79)
with AZFc and AZFb deletions followed by b+c types [63].
In Northern Part of India (Delhi), Dada R et al., documented
6% deletions in a study having oligo and azoospermia (8/133)
[64]. Earlier study by these researchers in 70 infertile cases
with varicocele, 11.4% microdeletions was reported (8/70) [65].
Mitra A et al., in their study group containing 14 azoospermia
with Klinefelter Syndrome (KFS) had 4 cases of AZFa and AZFc
deletion (4/14; 28.6%) [66]. In another study with 119 azoo
and 51 oligospermia cases had 5.29% microdeletions (9/170),
spanning AZFc followed by b+c a and b deletions [67]. Recently,
Dada R et al., analysed 140 cases of oligo-and azoo with
varicocele and found 5.7% deletions (8/140) [68]. They observed
AZFc and a+b are higher than b and b+c deletions. Sachdeva K
et al., claimed that out of 200 infertile cases with spermatogenic
failure at testicular level had deletions 10.5% (21/200) [69]. The
protocol for identification of Y deletions in their cases was of Non
Obstructive Azoospermic (NOA) and oligospermic men. Hence,
in north zone, the average YCMs are 7.97% (58/727) having
dominance of AZFc subregion [Table/Fig-3].
This mapping of Yq microdeletions in Indian studies of these
30 groups/citations indicated a range from 1.1 to 28.6% with
an average frequency of 8.33% from total analysis of 5435
chromosomes (453/5435). It includes different groups, region
and diverse classes of infertile men. Sub continent analysis of
large databases has earlier revealed the percent of microdeletions
ranged from 8-10% [70], in support of the observations.
But reports presented by Sen S et al., had significantly lower
frequencies (3.4%, 56/1636; 5.8% 215/3647) than the data
(8.33%) [Table/Fig-3] [36].
AZF Locus Microdeletions
AZF microdeletions and semen phenotypic correlations are
well appreciated in relation to infertility by several authors
[1,17,37,71]. Overall 25-55% males with testicular pathologies
like hypo spermatogenesis, sperm maturation arrest, Sertoli Cell
Only Syndrome (SCOS) and about 5-25% males are affected by
SOS or azoospermia harbouring YCMs as indicated earlier [32].
In this cohort more azoospermia cases (referred/selected 66%;
affected 61%) in 30 and 15 study groups, respectively, than
oligo-and others are attributed to AZFc locus [Table/Fig-2,3].
The sub-region microdeletions delivered in present study were
AZFc (37.66%; 29/77), AZFa and AZFb (19.48%; each15/77),
AZFb+c (10.39%; 8/77), AZFa+b (5.19%; 5/77), AZF a+c and
AZFa+b+c (2.6%;each 2/77) and 1.3% each of AZFd and DAZ
(1/7) respectively in a total of 77 deletions in present study
[Table/Fig-5].
[Table/Fig-5]: Summary of percent (%) AZF sub region micro deletions (77) in our
study.
AZFa Microdeletions and Phenotype Correlation
Microdeletions in this region contributed to 5%, as it contains
only 4 single copies of genes [16,17]. Mostly these infertile cases
have spermotogenic failure and restricted to SCOS [33,72,73].
Few workers believe it is related to oligospermia [33]. In present
study, few study groups (7/30) mapped high rate of AZFa deletion
and related to oligo/severe oligospermia. Thus, this region
deletion depends on amount of genetic material deleted ranging
from azoospermia to normozoospermia [74,75]. Present study
review data thus had indicated low frequency of microdeletion
contributing to testicular pathology [Table/Fig-6] as seven group
had AZFa deletions at higher rate.
AZFb Deletion and Phenotypes
This region is also comparatively smaller than c region containing
3.2 Mb spanning few genes [76] that are single and multiple copies of
DNA repeats and 14 amplicons and contributes about 16% deletions.
This region is important for early stages of spermatogenesis and
frequently responsible for hyperspermatogenesis [77]. In present

www.jcdr.net Mandava V Rao et al., Current Status of Y Microdeletions in Indian Infertile Men
Journal of Clinical and Diagnostic Research, 2021 Mar, Vol-15(3): GE01-GE09 55
Sr.
No. Author
Phenotypes selected
AZF locus detected
Deleted/Total
cases
Percent
deletion (%) Locations
Indian
zonesAzoo Oligo/SOS Others
1Nailwal M and Chauhan JB
[43] 41 100 - AZFc, AZFb, AZFa 34/141 24 Anand
Western
2 Sen S et al., [36] 992 600 44 AZFc, b+c, a, b, a+b,
a+c, a+b+c 56/1636 3.4 Mumbai
3 Shah PS et al., [42] 3 3 35 AZFc, AZFa 3/41 7.3 Ahmedabad
4 Ambulkar PS and Pande SS [9] 90 70 - AZFc, b+c, b, a, a+b 17/160 10.6 Nagpur
5 Nagvenkar P et al., [44] 40 48 - AZFc 1/88 1.1 Mumbai
6 Babu SR et al., [51] 10 10 - AZFc 3/20 15 Hyderabad
South
central
7 Rao L et al., [52] 104 90 57 AZFc, a=b+ 10/251 3.89 Hyderabad
8 Swarna M et al., [54] 15 55 - AZFc 9/70 12.8 Hyderabad
9 Swarna M et al., [55]+++ 10 40 - AZFc 4/50 8 Hyderabad
10 Thangaraj K et al., [55] 340 - - AZFc, b, a 29/340 8.5 Hyderabad
11 Suganthi R et al., [48] 30 20 - AZFc, b+c, a=b+ 18/50 36 Tamil Nadu
South east
12 Suganthi R et al., [49] 215 infertile cases AZFc, b,
b+c, a+b+c, a+c, a 24/215 11.2 Tamil Nadu
13 Suganthi R et al., [50] 75 infertile cases - 22/75 29.3 Tamil Nadu
14 Vishwambaran N et al., [47] 17 13 - AZFc, a=b+ 4/30 13.3 Tamil Nadu
15 Sakthivel PJ and Swaminathan
M [46]
72
infertile
cases
AZFc, a 19/72 12.9 Coimbatore
16 Abhilash VG et al. [45] 34 54 - AZFc 22/89 24.7 Chennai
17 Sen S et al., [36] 340 infertile cases - 29/340 8.5 West Bengal
Eastern
18 Ray A et al., [56] 19 6 - AZFc 4/80 5 West Bengal
19 Mahanta R et al., [57] 100 infertile cases AZFc 5/100 5 Assam
North east
20 Barbhuiya PN et al., [58] 50 82 38 AZFc, d 43/170 25.3 Assam
21 Khan FH et al., [60] 100 infertile cases AZFa, c, b+c 10/100 10.0 Varanasi
Central
22 Pandey LK et al., [61] 64 infertile cases AZFc 2/64 3.48 Varanasi
23 Singh K and Raman R [62] 270 infertile cases AZFc, DAZ, AZFb 13/270 4.80 Varanasi
24 Mittal RD et al., [63] 54 24 - AZFc, b 5/79 6.3 Lucknow
25 Ambasudhan R et al., [59] 142 33 2 AZFc 9/177 5.1 Varanasi
26 Mitra A et al., [66] 14 infertile cases AZFa, c 4/14 28.6 New Delhi
North zone
27 Mitra A et al., [67] 119 51 - AZFc, a=b+, b+c 9/170 5.3 New Delhi
28 Dada R et al., [65] 40 30 - AZFc, b, a+b 8/70 11.4 New Delhi
29 Dada R et al., [64] 133 infertile cases AZFc, b, a, a+b 8/133 6 New Delhi
30 Dada R et al., [68] 114 16 - AZFc, a+b, b, b+c 8/140 5.7 New Delhi
31 Sachdeva K et al., [69] 200 infertile cases AZFc, a,b, b+c 21/200 10.5 New Delhi
Total (30)@Deletion types 453/5435 8.33% All zones (7)
[Table/Fig-6]: Summary of referred/screened phenotypes cases vs AZF locus with percent deletion in Indian population. @ Sr. No. 2 and 17: Same but Indian Zones are
compared from this citation.
Deletion frequencies in study groups (30):AZFc*(27)>AZFb**(9)>AZFa***(7). Numbers in parenthesis indicate study groups in the [Table/Fig-3] (1-30); *:1-16, 18, 19, 20, 22-25, and 27-31 (27 study groups)
**:1, 4, 10, 12, 23, 24, 28-30 (9 Study groups); ***: 2, 3, 15, 21, 26, 31 (6 Study groups); +=equal.: Total deletion=77; Referred/Selected cases (21 Groups); Azoospermia=66%(2264/3445);OS/SOS=30%
(1045/3445); Others=4%(136/3445); ΨSOS: Severeoligozoospermia
review report, AZFb microdeletions exhibited high frequency of
these deletions found relatively in 9 study groups (9/30) [Table/
Fig-6]. Phenotypes range from spermatogenic anomalies and
oligo- spermia/hypo-oligospermia [42,76]. The deletions hence in
this AZFb, however had more than AZFa types in infertility cases
with oligo to SOS [Table/Fig-6] [11,36].
AZFc Deletions and Phenotype Correlation
The AZFc region comprises of repeated sequences and
palindromes making it suitable for deletions with partial types.
Hence, these deletions correlated with testicular phenotypes
ranging from severe oligospermia to azoospermia [27,78,79].
Patients having these deletions show progressive decline in sperm
counts from oligo to severe and absence of sperm [80-83]. In our
cited study groups (30) [Table/Fig-6], more (66%) infertile men
were referred for screening and affected (61%) were azoospermia
followed by oligospermia correlating with high frequency of AZFc
deletions comparatively. Colaco S and Modi D; Sen S et al.,
and Shah PS et al., and several researchers also noticed high
prevalence of AZFc microdeletions due to its complex structure
[1,36,42]. Twenty seven study groups (27/30) delivered high rate
of AZFc microdeletions amongst all 30 groups [Table/Fig-6].
Other Microdeletions and Phenotypes
Few study groups in our cohort reported AZFb+c, AZFa+b,
AZFa+c, AZFa+b+c, AZFd and DAZ having other double and
triple deletions that are related to hypospermetogenesis and other
testicular pathologies. These deletions were low in frequency as
compared to AZFc, a and b types and are depicted in [Table/Fig-6].
Ambulkar PS and Pande SS and Suganthi R et al., detected high
rate of AZFc microdeletions comparing to abnormal semen types
in comparison to a and b deletions [9,37]. Dada R et al., in their
studies revealed high rate of AZF a+b over AZFb micro deletions
[Table/Fig-6] [65,67].

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Journal of Clinical and Diagnostic Research, 2021 Mar, Vol-15(3): GE01-GE09
66
Sr.
No Author
Semen types deleted Deleted/Total
Azoo oligo/SOS Others
1 Sen S et al., [36] 34 22 - 56/1636 (3.4%)
2 Shah PS et al., [42] 1 2 - 3/41 (7.3%)
3 Suganthi R et al., [48] 10 8 - 18/50 (36%)
4 Barbhuiya PN et al., [58] 13 18 12 43/170 (28.3%)
5 Ambasudhan R et al., [59] 8 - 1 9/177 (5%)
6 Nagrvenkar P et al., [44] 1 - - 1/88 (1.1%)
7Nailwal M and Chauhan
JB [43] 20 14 - 34/141 (24.11%)
8 Rao L et al., [52] 5 4 1 10/25 (3.89%)
9Ambulkar PS and Pande
SS [9] 10 7 - 17/160 (10.6%)
10 Thangaraj K et al., [55] 34 - - 34/25 (8.5%)
11 Swarna M et al., [53] 2 1 1 4/80 (8%)
12 Swarna M et al.. [54] 4 1 4 9/70 (12.8%)
13 Dada R et al., [64] 7 1 - 8/133 (6.0%)
14 Dada R et al., [68] 6 2 - 8/140 (5.7%)
15 Athalye AS et al., [94] 8 3 1 12/100 (12%)
Total (15 Groups) 163 83 20 266/3036 (8.76%)
[Table/Fig-7]: Semen types deleted vs deletion correlation in 15 groups of Indian
population. Azoospermia cases (163/266=61%) were affected than others.
Partial Microdeletions and Phenotypes
The AZFc has partial deletions viz b2/b4, b1/b3, b2/b3 and gr/gr,
where b1/b3 combination of AZFb and AZFc regions in addition
to CNV. Among, gr/qr the most common type that are due to
homologous recombination. These partial microdeletions are
highly variable in multiple studies reported and are controvertial
[1,28]. Similarly few reports are documented regarding to CNVs [1].
In present report, these are not well screened by any group and
require further elucidation.
Prevalence and Distribution of Yq Microdeletions in India
Overall distribution of microdeletion screening notified that
AZFc region has high frequency as it is a complexed structure.
Most of the testicular phenotype cases with azoospermia
followed by oligospermia possessed deletion of AZFc only. It is
overall followed by AZF region of a, b, b+c and others [Table/
Fig-6] to support the data of previous authors [36,37] in Indian
infertile men.
In our review cohort, further South East (20.52%), North East
(17.77%), North (7.97%), East (7.85%) and South Central (7.52%)
contained comparatively high frequency of Yq deletions followed by
Western (5.37%) and Central (5.65%) regions, respectively. Thus
these YCM are minimum in Western and Central Indian Zones [Table/
Fig-2,3]. This could be due to geographic regions, ethnicity, sample
size, population, food styles, STS-kits used and other epigenetic
factors. Such results with other authors are also documented in
Indian population in related to prevalence and distribution of Yq
microdeletions [36,42].
IMPLICATIONS
Yq Microdeletions Analysis and Methodologies in Future
It is suggested that analysis of Yq microdeletions involve use of
multiple STS markers spanning various AZF loci [37]. Authors
used EAA and non-EAA markers of 4 to 30, but it is better to use
a good number of markers to detect Yq microdeletions. Further,
EAA and EMQN strongly recommend two, STS which is specific
to DAZ gene in the P2 and P1 palindromes. Partial deletions
cited to b2/b4 pattern can also be analysed using Sy 160 STS
markers. Conventional PCR is to be upgraded to multiplex
PCR, which is less costlier less time and advantageous than
former [23]. Commercial kits such as Diachem/Bird, Euroclone
are available [84]. Bunyan DJ et al., reported a method for
the detection of partial AZFc deletions and Multiplex Ligation
dependant Probe Amplification (MLPA) probe mix (P360) known
as MLPA assay [85]. Microarray developed by Osborne EC et
al., for microdeletions are also recommended for these studies
with better reproducible results to infertile men [86].
Microdeletions and ARTs
Mapping of microdeletions of Yq in infertile men correlates to
phenotype of testis which is a good predictor of sperm retrieval
during Testicular Sperm Ejaculates (TESE). Microdeletions in
infertile cases carry them to offspring born after ICSI. Further,
testing of sperm for microdeletions, which are useful for sperm
banks related to ARTs. Sperm carrying higher microdeletions
may lead poor quality embryos [87] after using ICSI. Further,
patients with AZFc microdeletions presented high sperm
recovery from testis than cases with AZFa and AZFb deletions
who presented a poor prognosis [88]. Simoni M et al.,; Nailwal M
and Chauhan JB also supported azoospermic cases with AZFc
deletions are better for ICSIs [15,75]. Genetic counselling is
adapted to couples undergoing such ARTs. Moreover, prediction
of prognosis of male infertility with Yq microdeletion is also
important for recovery of testicular phenotypes. Testing of AZF
region for deletions/CNVs may also be essential for detecting
testicular tumours. Additionally, microdeletions causing infertility
in males undergoing ARTs through genetic counselling are also
strongly associated with neuropsychiatric disorders [1].
Y-Deletion and DNA Damage
DNA fragmentation increases with Oxidative Stress (OS) in a
sperm cell. This OS occurs in sperm of infertile cases by several
factors such as heavy metals, free radicals, caspases during
apoptosis. Such induced OS upsets oxido-redox ratios leading
to DNA damage and mutations. Hence, it is proved that DNA
Fragmentation Index (DFI) shoots up in sperm of infertile men due
to reduced recombination repair, DNA package anomaly [17,89].
Thus, OS is implicated for DNA damage inturn relating to Yq
microdeletions in infertile cases. Hence, OS DNA damage and
deletion in Y chromosome are related in infertile males [71,90-
93], but such couples with affected males need to be treated
with antioxidants and evaluated and such cases are also to be
counselled prior to adopt ICSI and other IVF techniques in future
[34,37,42,94,95]. [Table/Fig-7] shows semen types deleted vs
deletion correlation in 15 groups of Indian population. Azoospermia
cases (163/266=61%) were affected than others types.
YCMs in Indian Scenario
Published data earlier showed the frequency of microdeletions
in Indian population ranged from 3 to 29.34% with an average
frequency of 8.1% [37,42,47,61,65]. Thangaraj K et al., proposed
8.5% YCMs from the study of 340 azoospermia infertile cases
[55]. In another study, it is reported that it increased to 9.63%
[65]. Only Sen S et al., [36] documented to 3.4% frequency
of deletions in Indian population of 1636 cases, which is
significantly lower than others. Same group had also mentioned
low frequency 5.8% deletions, but present study cohort
exhibited 8.33% deletions from 5435 Y chromosomes analysed
supporting the data of Thangaraj K et al., Pandey LK et al., and
Dada R et al., [55,61,64]. Recently, Shah PS et al., and Rao
MV, also reported similar data falling in range of 8-10% [16,42]
and Waseem AS et al., in India these deletions ranged from
0.59-32.62% with an average of 13.48% [95], but his own data
delivered only 10.02% deletion frequency. This variation could be
due to ethnic background study protocol and other factors. The
Indian population further is affected by AZFc deletion followed by

www.jcdr.net Mandava V Rao et al., Current Status of Y Microdeletions in Indian Infertile Men
Journal of Clinical and Diagnostic Research, 2021 Mar, Vol-15(3): GE01-GE09 77
AZFb and AZFa in most of the testicular phenotypes as reported
by others [37]. The azoospermia cases thus considered to be
mostly affected than oligo/severe oligospermia and others. The
AZFc deletions containing such azoospermic cases are better
suitable than other pathologic phenotypes as suggested above
[75,88,95] for associated reproductive technologies in present
and future of Indian Scenario.
Limitation(s)
Male infertility caused by genetic factor needs to be assessed
with proper genetic tests. Significance of microdeletions/
partial deletions are to be communicated to couples. Accurate
methodology is to be developed for full success rate of deletions.
Congenital malformations, genetic defects, loss of birth weight
and its propagation to offspring are to be limited successfully.
CONCLUSION(S)
This study cohort clearly enumerates the Yq microdeletion
(8.33%) leading to male infertility mainly falling in the range of
8-10% in India. Correlation between these types of deletions
and associated testicular phenotypes provide identification
of infertility type, detecting the prognosis of infertile males,
treatment and other defects like cancer. Azoospermic men are
affected with high frequency of AZFc deletions in present study
having more percent in Eastern region of India. Herewith, it
also provides opportunities for counseling the couple adopting
ARTs, where male partner carries these specific deletions. Y
chromosome deletion analysis is also necessary in sperm banks
to curtile multiple abnormal embryo yield after ICSI and TESI,
since the prevalence and distribution, of these complete and
partial deletions vary region wise, population groups, ethnicity,
sample size, STS marker used, selection criteria, haplotypes,
environment and other epigenetic factors.
Further, hereby these studies definitely take forward new direction
to evaluate infertile males possessing Yq deletions for correct
treatment clinically. These advancements allow more widespread
of this deletion screening and its implication in infertility clinics,
IVF and andrology laboratories in our country and also around the
globe in future.
Acknowledgement
Author would like to thank all staff of the Neuberg-Supratech
Laboratory, Ahmedabad, especially to Ms. Nirali C Thakker and Mr.
Rahul Yadav for their assistance in the technical work.
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www.jcdr.net Mandava V Rao et al., Current Status of Y Microdeletions in Indian Infertile Men
Journal of Clinical and Diagnostic Research, 2021 Mar, Vol-15(3): GE01-GE09 99
PARTICULARS OF CONTRIBUTORS:
1. Research Director, Department of Genomic Medicine, Neuberg-Supratech Referral Laboratory, Ahmedabad, Gujarat, India.
2. Senior Geneticist, Department of Genomic Medicine, Neuberg-Supratech Referral Laboratory, Ahmedabad, Gujarat, India.
3. Junior Scientist, Department of Genomic Medicine, Neuberg-Supratech Referral Laboratory, Ahmedabad, Gujarat, India.
4. Bioinformatician, Department of Genomic Medicine, Neuberg-Supratech Referral Laboratory, Ahmedabad, Gujarat, India.
5. Chief Scientist Genomic Medicine, Department of Genomic Medicine, Neuberg-Supratech Referral Laboratory, Ahmedabad, Gujarat, India.
6. Laboratory Director, Department of Genomic Medicine, Neuberg-Supratech Referral Laboratory, Ahmedabad, Gujarat, India.
PLAGIARISM CHECKING METHODS: [Jain H et al.]
• Plagiarism X-checker: Aug 01, 2020
• Manual Googling: Jan 06, 2021
• iThenticate Software: Jan 13, 2021 (2%)
ETYMOLOGY: Author Origin
NAME, ADDRESS, E-MAIL ID OF THE CORRESPONDING AUTHOR:
Dr. Sandip C Shah,
Neuberg-Supratech Referral Laboratory, Paldi, Ahmedabad, Gujarat, India.
E-mail: sandip.shah@supratechlabs.com
Date of Submission: Jul 31, 2020
Date of Peer Review: Sep 19, 2020
Date of Acceptance: Jan 16, 2021
Date of Publishing: Mar 01, 2021
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? NA
• For any images presented appropriate consent has been obtained from the subjects. No
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