I Med Genet 1994;31:187-192 187

Genetic study of indirect inguinal hernia

J Med Genet: first published as 10.1136/jmg.31.3.187 on 1 March 1994. Downloaded from http://jmg.bmj.com/ on January 29, 2021 by guest. Protected by copyright.
Yaoqin Gong, Changshun Shao, Qian Sun, Binxi Chen, Yuan Jiang, Chenhong Guo,
Jianjun Wei, Yishou Guo

Abstract lysis of multiple case families with at least two

We performed a genetic analysis of 280 closely related affected members, we noted the
families with congenital indirect inguinal preferential paternal transmission of the dis-
hernia ascertained in Shandong province. ease gene, suggesting the role of genomic
The multifactorial threshold model and imprinting in the aetiology of this condition.
segregation analysis were applied to these
families to investigate the mode of inherit-
ance of congenital indirect inguinal hernia. Materials and methods
Our results indicate that congenital in- FAMILIES
direct inguinal hernia is not compatible The cases used in this study were identified in
with a multifactorial threshold model, the project "Survey of Major Genetic Diseases
and the frequent vertical transmission and in Shandong Province" which was carried out
high segregation ratio suggest autosomal in the five year period from 1985 to 1990.10
dominant inheritance with incomplete The survey sites were located in 11 prefectures
penetrance and sex influence. Through and covered a population of about one million.
further pedigree analysis of the multiple The work for IIH was carried out in a two
case families with at least two closely stage procedure. During the first stage the
related affected members, we noted patients with IIH were registered by the
preferential paternal transmission of trained village or community doctors. Each
the disease gene, which might suggest the patient identified in the first step was regarded
role of genomic imprinting in the aetio- as a proband (index patient). In the second
logy of this condition. stage, a thorough clinical examination was
conducted on these index patients and their
(JT Med Genet 1994;31:187-192) affected first degree relatives, then the pedi-
gree was drawn. Among 392 index patients, 52
Inguinal hernia (IH) is a common develop- index patients with acquired IIH were
mental anomaly; its incidence has been esti- excluded from further analysis. The 340 pro-
mated to be 6 to 12-5% in the different general bands (319 male, 21 female) had all been
populations studied.' IH can be classified into operated on by 5 years. These probands were
direct inguinal hernia (DIH) and indirect from 280 families. The hernia occurred on the
inguinal hernia (IIH), the latter being far more right side in 138 probands, on the left side in
common than the former. IIH is further sub- 84 probands, and on both sides in the other
divided into congenital and acquired IIH. 118 probands.
Congenital IIH is generally considered to re-
sult from a congenital weakness in the internal
ring and a persistent processus vaginalis and GENETIC ANALYSIS
can be detected during the first months or The observed characteristics of familial ag-
years after birth. gregation of IIH were compared with the
Although there has been considerable evid- expected values based on an MFT model to
ence suggesting the role of genetic factors in discriminate between multifactorial and men-
the aetiology of IH,2' its mode of inheritance delian inheritance."-" These characteristics
remains controversial. Hypotheses proposed include correlations of the proband's sex to the
include (1) autosomal dominant inheritance recurrence risk of relatives, and the severity of
with incomplete penetrance,34 (2) autosomal the proband's defect to the recurrence risk of
dominant inheritance with sex influence,5 (3) relatives. These correlations were evaluated in
Department of X linked dominant inheritance,6 and (4) poly- the first degree relatives of different types of
Medical Genetics, genic inheritance.7-9 probands.
Shandong Medical In a recent survey of major genetic disease in
University, Jinan, Classical segregation analysis was per-
Shandong, P R China the general population of Shandong pro- formed on 341 nuclear families. According
250012 vince,'0 we identified 280 families with con- to the parents' mating type, we divided
Y Gong genital IIH. We applied the multifactorial
C Shao nuclear families into three groups: (1) one
Q Sun threshold (MFT) model and segregation ana- parent affected (U x A matings), (2) both
B Chen lysis to these data to investigate the mode of parents normal with positive family history,
Y Jiang inheritance in congenital IIH. Our results in-
C Guo that is, one parent has a first or second degree
J Wei dicate that congenital IIH is not compatible relative with IIH (U x U(f) matings), and
Y Guo with an MFT model, and the frequent vertical (3) both parents normal (U x U matings). We
Correspondence to transmission and high segregation ratio used the following distributions for the expec-
Dr Gong. suggest autosomal dominant inheritance with tation of families of size s with only one affec-
Received 14 June 1993
Revised version accepted for incomplete penetrance and sex influence in ted sib (1) and with more than one affected sib
publication 11 October 1993 familial IIH. Through further pedigree ana- (2).
188 Gong, Shao, Sun, Chen, Jiang, Guo, Wei, Guo

Fm Ily2 _ Al 716 this method, the fit of a parametric value, say

p, to the data is tested by Xp2= (Up)2/Kpp,
Fm> O with 1 df, where Up is the ML score and
Family A Family B Family C Family D ; Kpp its variance. The iteration procedure

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will lead to the best estimate of the para-
Famil yE meter.14
Figure I Families with multiple cases of IIH.

ANALYSIS OF PARENTAL ORIGIN OF THE DISEASE

GENE
The criteria for the multiple case families used
* to analyse the parental origin of the IIH gene
1 were: (1) there were at least two affected mem-
A , bers; (2) affected members were distributed in
E
l at least two sibships; and (3) the relationship
F G H ; between them was up to third degree. The
K illustration of how these criteria were used are
shown in fig 1. Using these criteria, families B,
Figure 2 Illustration of transmission types. Familiess A C, and D in fig 1 have been included in our
and B, vertical transmission through two generations.
Families C, D, and E, vertical transmission through study, while family A and E have been
three generations. Families F, G, and H, vertical excluded.
transmission through four generations. Family I, vertI ~ical Ac
According to the above criteria, a total of
transmission through five generations. Families _7 and K,
non-vertical transmission. 128 families was identified, of which 70 fami-
lies were selected from the 280 families, the
other 58 families coming from previously pub-
P(r = 1) = {sp[x + (1 -x)qs-l]}/ lished studies,'5 which were ascertained
{sptx +(1 -x) [1 -(1 -p)S]} (1) through 58 probands who underwent opera-
tions in Jinan Children's Hospital during 1989
P(r > 1) = {(1-x) [I1-(I - p7r)s -spirqs-ID to 1991. Phenotypically normal carriers who
{Sp11X + (1x)[l(1 p7 )S],j (2) had carried and transmitted the disease gene to
the next generation were identified by pedigree
where s is the sibship size, r the number of analysis. The sex of each carrier and affected
affected sibs, p the segregation frequency q parent was recorded.
equal to 1 - p, x the frequency of sporaidic
cases, and the probability of ascertainmemnt.
The values of p and x were estimated un der Results
incomplete selection (with n = 0 78) by the PEDIGREE ANALYSES
maximum likelihood (ML) method.14 rith Of the 280 families, there was a positive his-
tory in 78 families (27 85%). In 202 families
(72 14%), the index patient was the only
Table 1 Percentages of different types of families among the multiple case families known affected family member. The illustra-
Transmission No of generations Family type No of families ) tion of different family types is shown in fig 2.
A 23
In 55 of the 78 families with a positive history,
Vertical 2
B 15 the trait was transmitted vertically (table 1).
38 (48 7)
3
Direct male to male transmission was noted in
3 C
D 7 29 families. The vertical and male to male
E 2
12 (15 4)
transmission of the trait in these families
4 F 1 suggests that familial IIH is inherited in auto-
G
H 2
1 somal dominant fashion.
4 (5.1)
5 I 1 (1-3)
Non-vertical J 15
K 8 TEST OF THE MFT MODEL
23 (29 5) In this data set, the sex ratios in probands and
affected subjects were 15 32 (319:21) and 13 36
(374:28), respectively. According to the MFT
Table 2 Risk to first degree relatives by proband's sex* model, when the incidence is higher in one sex
Proband's sex Total Ist degree relatives Affected 1st degree relatives Incidence (%
than in the other, the less affected sex would be
expected to show a higher recurrence risk in
Male
Female
1030
72
64
5
6 21
6-94
their first degree relatives compared to the
more affected sex. However, as is shown in
*
p > 0.05. table 2, the incidence of I IH in the first degree
relatives of female probands was not signific-
Table 3 Risk to first degree relatives by IIH type of probands* antly higher than that of male probands
(p> 005).
IIH type of proband Total 1st degree relatives Affected 1st degree relatives Incidence Another prediction with a similar theoretical
Bilateral 253 16 0.0632 basis is that the more severely affected pro-
Unilateral
509 32 0-0629
bands would be expected to show a higher
Right
Left 340 21 0 0618 risk in their first degree relatives compared to
Total 849 53 0-0624 the less severely affected probands. In this
*p > 0.05. study, the incidence of IIH in the first degree
Genetic study of indirect inguinal hernia 189

Table 4 Distributions of affected males (r) among male sibs (s) Table 6 Number of sibships with affected or carrier
parent
UXU UXU (f) UXA
Parent Affected Carrier Total
s/r 1 2 Total slr 1 2 3 Total s/r 1 2 Total
Father 58 66 124

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1 114 114 1 44 44 1 21 21 Mother 2 33 35
2 49 5 54 2 20 9 29 2 5 2 7 Total 60 99 159
3 27 2 29 3 12 2 14 3 4 4
4 10 1 11 4 5 1 6 4 1 1 2
5 2 2 5 2 1 3 5 1 1 2
Total 202 8 210 83 11 2 96 32 4 36

Table 7 Number of sibships with affected and carrier

relatives of bilateral probands was not signific- grandparents
antly higher than that of unilateral probands Grandparent Affected Carrier Total
(table 3). A similar result was observed in the
comparison of probands with right IIH and Grandfather
Grandmother
32
2
3
1
35
3
left IIH. Total 34 4 38

SEGREGATION ANALYSIS
The above analyses suggest that dominant
inheritance may be more likely in these fami- Table 8 The parental origin of the IIH gene by
lies. As noted in table 4, we have 36 nuclear pedigree analysis
families with one parent affected and 306 fami- Group Male affected Female affected
lies with both parents unaffected, of which 96 Total 177 11
had a positive family history; thus complete Paternal 140 (79-1%) 6 (54-5%)
penetrance can be ruled out for the dominant Affected father
Carrier father
68
72
3
3
transmission model. As most cases of IIH are Maternal 37 (20 9%) 5 (45-5%)
males, segregation analyses were performed on Affected mother
Carrier mother
1
36
0
5
male sibships only. The results of segregation
analyses for the three groups are summarised
in table 5.
Since the proportion of sporadic cases, if from the carrier mother. A striking difference
any, may be unique for the families with one exists in the sex distribution of the affected
parent affected, p and x were simultaneously parents and carriers (table 6).
estimated from the data. The iteration proced- Data on the grandparental generation are
ure resulted in the final estimates of p = 0-225 shown in table 7. Though not complete, they
and x = 0 013, showing that among non-spora- show a similar tendency of distorted sex ratio
dic cases the segregation frequency is 0-225. If to that of the parental generation.
these families were considered as representing The results described above suggest that the
dominant inheritance, the penetrance is 0 225/ affected persons might have inherited the IIH
0-5 = 0.45. gene more frequently from their father than
For the sibships of UXU (f), p = 0-225 and from their mother. Therefore, the parental
x = 0 013 have an excellent fit to the data, with origin of the IIH gene was determined separ-
Xp2 = 0-032 and xx2 = 0041. This is consistent ately for affected males and females. The re-
with the speculation that familial IIH shows sults show that the majority of the affected
dominant inheritance with incomplete pene- males (79-1%, table 8) inherited the IIH gene
trace. from their father (p < 0 01). However, the fact
For those families with a negative family that females rarely develop IIH means that
history, the proportion of sporadic cases is far there are more families with an affected father
from zero (Xx2= 13 28, p<001). The best es- than with an affected mother and makes it
timate of x is 0 599 for this group of families. invalid to compare the number of affected
fathers with the number of affected mothers to
determine the origin of the IIH gene. We
PARENTAL ORIGIN OF THE IIH GENE therefore compared only the numbers of car-
A total of 159 sibships with affected or carrier rier fathers and carrier mothers. Of the 108
parents was included in the 128 pedigrees affected males with a carrier parent, 72 had a
selected. In 58 of 60 sibships the father was the carrier father and 36 had a carrier mother, the
affected parent, while the mother was affected former being far more than the latter
in only two sibships. In 66 of 99 sibships the (X2 = 12-00, p < -05). Unfortunately, the female
phenotypically normal father carried and affected sample is too small to be analysed.
transmitted the disease gene; in the other 33
sibships the disease genes were transmitted
Discussion
Table 5 Segregation analyses of IIH families Most cases of IIH arise from retention or
imperfect obliteration of the processus vagina-
Group No of families p x XP2 xx2 lis, the embryological outpocketing of perito-
UxU 210 0-225 0 12 26 13-28 neum that precedes testicular descent into the
210 0-225 0-599 0-04 0 scrotum. The testes originate along the uro-
U x U(f) 96 0-5 0 23-12 31-02
96 0-225 0-013 0-03 0-04 genital ridge in the retroperitoneum and mi-
UxA 36 05 0 7-54 7-27 grate caudally during the second trimester of
36 0 225 0-013 0 0
pregnancy to arrive at the internal inguinal
190 Gong, Shao, Sun, Chen, Jiang, Guo, Wei, Guo

(abdominal) ring at about the sixth month of of reduced penetrance. Third, the finding that
intrauterine life. During the last trimester, affected males are much more numerous than
they proceed through the abdominal wall via affected females suggests that the trait is
the inguinal canal and descend into the scro- influenced by sex. This sex influence could

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tum, the right slightly later than the left. The be attributed to the anatomical difference
processus vaginalis then normally disappears between males and females.
postnatally except for that portion surround- Segregation analyses also support autosomal
ing and serving as a covering for the testis. dominant inheritance of IIH. The estimated
Failure of this obliterative process results in segregation ratio and penetrance were 0 225
congenital IIH. Acquired IIH probably re- and 0 45, respectively. As expected, the pro-
sults from the stress of muscular activity and portion of sporadic cases was unique for A x U
the increase in intra-abdominal pressure forc- and U x U (f) matings. In U x U matings,
ing open a previously imperfectly obliterated sporadic cases were estimated to account for
processus vaginalis. However, it is not clear at most cases.
this time whether congenital and acquired IIH It is interesting to compare IIH with two
are basically different from one another, or other common and extensively investigated
whether they can be considered to be different congenital malformations, cleft lip with or
manifestations of the same or a similar defect without cleft palate and neural tube defects,
affecting different parts of the inguinal region. which also result from incomplete closure of
Therefore, only the probands with congenital the organs involved. Although previous stud-
IIH were included in this study. ies have shown that these two conditions have
Previous population studies have suggested multifactorial inheritance, S-8 recent analyses
that congenital IIH is inherited under a multi- have provided evidence of involvement of
factorial threshold model.7"9 In order to assess major genes.'925 Thus it is plausible to specu-
whether the multifactorial threshold model late that morphorgenesis may be determined
can explain IIH clustering in this data set, two by single genes and complicated by environ-
predictions were tested. mental factors. If the IIH gene has a "suscep-
First, IIH occurs more commonly in males tibility to the environment", it is quite likely
than in females. This is because of the defect in that incomplete penetrance or variable pheno-
the abdominal wall occasioned by the descent of copies or both may be present in IIH, and then
the testes into the scrotum in the male and also analyses will result in non-mendelian estimates
perhaps because of the protection to the inside of the transmission probabilities. This should
of the lower ventral abdominal wall afforded by not necessarily be interpreted as evidence
the uterus in females. Under the multifactorial against the major gene hypothesis.26
threshold model, when incidence is different in In summary, these data, regardless of the
one sex from the other, risk in relatives depends analytical approach, indicate that there is
on the sex of the probands. Contrary to this strong statistical evidence that familial IIH is
expectation, the present series shows that inherited in an autosomal dominant fashion
the proband's sex was independent of the with a reduced penetrance and sex influence.
recurrence risk to the first degree relatives. As mentioned above, IIH occurs more fre-
Second, the right testis descends later than quently in males than in females, so families
the left and the processus vaginalis is therefore with an affected father and son(s) should be
obliterated later on the right side than on the expected to be more common than those with
left side; hence hernia is more frequent on an affected mother and son(s). In the group of
the right than on the left side. If IIH were unaffected carrier parents, however, the carrier
inherited under a multifactorial threshold fathers are also over-represented although the
model, a higher threshold would be expected opposite would be expected. Their inheritance
for those subjects with left IIH, and con- pattern is apparently inconsistent with autoso-
sequently a higher risk would be expected in mal dominant inheritance. This observed pre-
relatives of left IIH than in relatives of right ponderance of paternal transmission calls for
IIH. Similarly, a higher risk would also be new explanations. We discuss two possibilities
expected in the first degree relatives of bi- here.
lateral probands than in relatives of unilateral First, ascertainment bias might be respon-
probands. This was not the case for either sible as affected paternal relatives may be more
comparison. easily identified since they are more familiar
Tests of the predictions of the MFT model with each other. However, in the other dis-
do not support the assumption of multifactor- eases we surveyed by the same methods used
ial inheritance in IIH; rather, we consider for the selection of IIH families, such prepon-
autosomal dominant inheritance with incom- derance was observed in different sexes for
plete penetrance and sex influence more likely, different diseases. For example, an excess of
based on the strong evidence provided by maternal transmission was noted in the multi-
pedigree and segregation analysis. ple case families with epilepsy, while an excess
In families with familial IIH, three import- of paternal transmission occurred in the multi-
ant criteria for the model mentioned above are ple case families with cleft lip with or without
satisfied. First, vertical and male to male trans- cleft palate (Gong et al, unpublished data).
mission of the trait establish the autosomal The fact that male/female ratios of transmit-
dominant pattern. Second, some parents of ters (normal and affected) shift towards dif-
affected subjects are not affected, but they ferent sexes in different diseases argues against
obviously carried and transmitted the deleteri- a significant bias of ascertainment in our
ous gene. This can be considered as evidence sample.
Genetic study of indirect inguinal hernia 191

Second, sex specific genomic imprinting imprinting. One such example is Wiedeman-
could account for the preferential paternal Beckwith syndrome (WBS), which is charac-
transmission of the IIH gene. We assume that terised by macroglossia, gigantism, earlobe
the IIH gene is not expressed or expressed at a pits or creases, abdominal wall defects, and an

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low level if it is transmitted from the mother increased risk for the development of tumours.
(this kind of imprinting has been referred to as In WBS the paternally transmitted alleles at
maternal imprinting27) in contrast to paternal the WBS locus were supposed to be func-
imprinting in which the paternal homologue is tionally inactivated to account for the rarity of
inactivated or expressed weakly in the off- transmitting males.'6
spring. In conclusion the fact that most affected
Homologous chromosomes may undergo males had inherited the IIH gene from their
different modifications when they segregate father implicates a role of genomic imprinting
during gametogenesis. These modifications or in the aetiology of the IIH phenotype. Further
their effects may persist through embryogene- follow up of the familial IIH families will allow
sis and distinguish the maternal and paternal testing of this hypothesis. Our findings for IIH
alleles or regions until adult stage. Such represent a step towards understanding the
imprinted information can apparently result in developmental basis of this common human
differential activity of parental alleles. In genetic disorder.
mammals, the first convincing experimental
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