Genetics and Clefting

My assignment for this symposium is to

present an updating of the current status of

the genetics of cleft lip and palate. I will

assume that the two individual entities rec-

ognized by all investigators, cleft lip with or

without a cleft palate and isolated cleft palate,

were both meant to be discussed. These will

be referred to as CL(P) and CP, respectively.

In December of 1978, a workshop sponsored

by the National Institute of Dental Research

was held on the Etiology of Facial Clefting at

Airlie House in Virginia. I would like to pre-

sent some of the ideas and conclusions offered

at that workshop because they most clearly

represent the current status of our knowledge

of the genetics of these two complicated anom-

alies.

In order to discuss the genetics of a disorder,

one must first deal with the difficult problem

of defining the entity to be studied. In this

case, what is the clefting phenotype? Super-

ficially, the definition seems obvious, but it is

becoming increasingly clear to both clinical

and laboratory investigators that the entities

which we have previously considered to be

simple or "garden variety" clefts of the lip

and/or palate are subtly syndromic in nature.

Let us develop the concept of the simple cleft

further. Consider for a moment only clefts of

the primary palate. Within this category we

can recognize a number of syndromes in

which a cleft of the lip (with or without the

palate) is only one of several dysmorphic

events. An example is the EEC syndrome in

Dr. Bixler is affiliated with the Departments of Oral-Facial Genetics and Medical Genetics, Indiana Univer-sity Schools of Dentistry and Medicine, Indianapolis,Indiana.

This paper was supported in part by the Oral-FacialGenetics Training Grant DE 7043.

The paper was a part of a Genetics Panel presented atthe Annual Meeting of the American Cleft Palate Asso-ciation, February, 1979, San Diego, California.

Since this manuscript was submitted, the CleftingWorkshop results referred to have been published:ofFacial Clefting, eds. Melnick, M., Bixler, D. and Shields,E. D., Alan R. Liss Co., 1980, New York.

DAVID BIXLER, D.D.S., Ph.D.Indianapolis, Indiana

which there are missing rays of the hands and

feet, and multiple anomalies of several ecto-

dermal structures and of the lacrimal appa-

ratus. Such syndromes are readily described

by clinicians although their etiologies often

remain obscure. Dr. Gorlin has recently stated

that there are now over 150 recognizable syn-

dromes in which clefts of the lip and/or palate

are but one manifestation of the total clinical

picture. In spite of the lack of evidence on the

etiology of many of these disorders, it is still

convenient and readily acceptable to identify

them as syndromes because they are recurrent

patterns of malformations designated as syn-

dromic cleft lip and palate. No one would

attempt to perform an overall genetic analysis

on these cases because their etiologies are

multiple ranging from simple Mendelian

traits to chromosomal disorders to those that

have no obvious genetic causation and may

be environmentally- or drug-induced. Now,

for this presentation, I am deliberately exclud-

ing all such cases and will not discuss them

but will confine my remarks to what I have

already referred to as the more common or

garden variety of simple cleft lip and palate.

These disorders will be referred to as non-

syndromic CL(P) and non-syndromic CP in

order to avoid confusion.

Let us return to the original point. That is,

the phenotype of the garden variety of non-

syndromic cleft lip and palate is more com-

plicated that was once believed. Let us ex-

amine some of the evidence for this. A number

of reports over the past several years have

appeared in the literature relating to the oc-

currence of fluctuating dermatoglyphic asym-

metries such as variations in ATD angle, ridge

count, and fingerprint patterns in persons

with CL(P) who have a positive family history

of this single malformation. Isolated cases in

families did not show this abnormality. This

was first shown by Adams and Niswander

(1967) and has since been confirmed by Woolf

and Gianas (1976 and 1977). vA large number of published studies have

presented evidence that both the dimensions

and form of the dentition are altered in pa-.

tients with facial clefts. Most of these studies

have not included known syndromic cases of

cleft lip and cleft palate, but there is still a

high prevalance of various tooth abnormali-

ties as reported by Jordan et al. (1966). Adams

and Niswander (1967) also reported dental

abnormalities associated with the familial

cases in their study. No attempt will be made

to review the status of research on microforms

of clefting, but you are all aware that the

literature is full of studies attempting to relate

abnormalities of the eyes, nose, ears, pharynx,

and even the face (Fraser and Pashayan,

1970) to increased genetic liability to clefting.

Collectively, the reports on dermatoglyphics,

teeth, and facial structures suggest that non-

syndromic CL(P) is a malformation complex

of a much broader phenotypic spectrum than

just a simple cleft. More recent reports sup-

port this concept. Rudman et al. (1978) re-

ported a prevalance of growth hormone defi-

ciency in children with cleft lip and palate.

The authors suggested that children with

CL(P) have short stature about four times

more frequently than children of comparable

age without clefts. At the workshop on Etiol-

ogy of Facial Clefting previously mentioned

there was a report by Wilson and Nelson

(1978) on sensory integrative dysfunction

(specific visual-perceptual motor deficits) in

children who have clefts of the lip and palate

without other abnormalities. Also, Weinberg

at Purdue University (1978) has related to me

unpublished information suggesting that chil-

dren with CP may have parents who are not

cleft themselves and who do not show obvious

microforms of cleft palate but may show a

recognizable pattern of articulatory speech

defects.

The purpose of this brief discussion of the

phenotypic definition of CL(P) and CP is to

point out the considerable difficulty in defin-

ing precisely the phenotype of CL(P) and CP.

Obviously, without that precise definition,

genetic studies of these two entities are loaded

with pitfalls, and any data collected must be

interpreted with caution.

Let us recognize two major groups ofCL(P)

and CP based on the previous phenotypic

discussion as syndromic types and non-syn-

dromic types. I would now like to present our

recently published data regarding the genetics

of the non-syndromic forms of CL(P) and CP

Bixler, GENETICS AND CLEFTING 1 1

. while recalling the caveat of phenotype defi-

nition.

The data reported here have been drawn

from the Danish population with the cooper-

ation of Dr. Poul Fogh-Andersen, who oper-

ates on all cleft patients in Denmark, and -

Professor Jan Mohr of the Institute ofMedical

Genetics in Copenhagen. With their assist-

ance, we have been able to ascertain some

5500 cleft persons or 95+% of all cleft individ-

uals born in Denmark between 1933 and

1973. Thus, we have acheived a near total

population ascertainment. The isolated cleft

palate data represent the doctoral thesis work

of Dr. Ed Shields (McGill University in Mon-

treal), who spent part of a fellowship in Co-penhagen studying this program. The cleft lip

and palate data analysis represents the collec- ©

tive efforts of Dr. Michael Melnick (Univer-

sity of Southern California) while he was a

postdoctoral fellow at Indiana University and

myself.

In 1941, Fogh-Andersen published his the-

sis on a genetic study of 704 Danish probands

with CL(P) and CP. This study has been

widely quoted, and one of its most important

conclusions was that CL(P) is genetically and

epidemiologically different from CP. Further-

more, Fogh-Andersen proposed from his data

that CL(P) is inherited as a conditioned dom-

inant trait meaning that the expression of the

mutant gene is considerably modified by the

genetic milieu. However, even allowing for

variable expression and incomplete pene-

trance of any such gene in nonsyndromic

cases, he anticipated the possibility that there

could be more than one genetic type of CL(P)

and so predicted. By comparison, isolated cleft

palate was demonstrably familial in only a

small number of cases, and he proposed the

mode of inheritance of CP to be one of simple

dominance with variable gene expression and

incomplete penetrance. It is remarkable that

essentially these same conclusions could be

drawn from most human material published

today. For some 20 years, these genetic con-

clusions have been employed essentially un-

altered, and it was only in the early 60's that

researchers began to consider other genetic

explanations for clefts of the lip and palate.

The motivation for this was apparently two-

fold: (1) CL(P) and CP clearly did not con-

form to Mendelian inheritance patterns. (2)

New schools of thought were developing to

provide explanations for such non-Mendelian

12 Cleft Palate Journal, January 1981, Vol. 18 No. 1

types of inheritance. In 1965, Falconer pro-

posed a mathematical model to describe the

inheritance of discontinuous phenotypic

traits, such as clefts of the lip and palate

which are not transmitted in any simple man-

ner. This model is based on the concept that

there is an underlying liability for that partic-

ular trait which encompasses both genetic and

environmental factors. In order to convert this

continuous variable of liability into a recog-

nizable dichotomous phenotype (affected or

normal), he imposed a threshold ofexpression.

In this mathematical model the genetic com-

ponent is considered to be quantitative, po-

lygenic, and presumably additive in nature.

The incidence of the trait in near relatives of

a proband will vary according to the degree

of genetic relationship. From the observed

incidence of the trait in relatives, Falconer

described how one can make an estimate of

the heritability of this liability, a parameter

commonly determined for traits of such a

threshold nature. Although Falconer did not

apply this model to the phenotypes CL(P)

and CP, it was soon done by several authors.

Carter (1969, 1976), particularly, was instru-

mental in proposing this model as a descriptor

of the etiology of the common major congen-

ital malformations of man including CL(P)

and CP. Based upon these publications, sev-

eral predictions could be made for any such

multifactorial-threshold (MF-T) trait. These

are summarized in Table 1.

Major criticisms have been leveled at this

model and its predictions. The relationship

between increasing risk with increasing num-

ber of affected in nuclear families (Prediction

No. 1) has been discounted since the cumu-

lative or additive nature of the genetic ele-

ments in cleft lip and palate has yet to be

demonstrated (Morton et al., 1970; Thomp-

son 1975 and; Seegmiller and Fraser, 1977).

Prediction No. 5 has been discounted as useful

since it has been pointed out by Fraser (1976)

and others that too large a change in popu-

lation incidence is needed to produce an al-

tered risk to siblings of probands. Some au-

thors have commented that any analysis of

variance which attempts to identify and em-

ploy a correlation of trait incidence between

relatives (Prediction No. 6) is inappropriate

since it disregards the biologic fact of gene-

environment interrelationships (Lewontin,

1974; Moran, 1973; and Feldman and Le-

wontin, 1975). Finally, several authors (Mor-

ton et al., 1970; Smith, 1971; and Melson,

1974) have commented on how multifactorial,

monogenic, and even environmental etiologic

models simulate each other and that it is very

difficult to discriminate among them. Never-

theless, the multifactorial threshold (MF-T)

model as an explanation of the etiology of

cleft lip and palate has received wide support

and acclaim. In 1969, Carter identified three

of the predictions in Table 1 (No.'s 2,3,4)

which he felt that any trait meeting the re-

quirements of the MF-T model should satisfy.

The analysis of data which will now be dis-

cussed represents an attempt to satisfy these

three predictions of the multifactorial-thresh-

old model (Table 2) using Danish population

data (Melnick and Shields, 1976; Melnick et

al., 1977).

Prediction number 1 (Table 2) states that,

the less frequently affected sex has the greatest

risk for transmitting the trait. In the case of

CL(P), the more frequently affected sex is

male; therefore, mothers should be at greater

risk for transmitting the trait to their off-

spring. In the case of CP, females are more

often affected; therefore, males should be at

a higher risk for transmitting the trait. The

data in Table 3 show the incidence of clefting

TABLE 1. Predictions of the Multifactorial-Threshold

Model 1) The more affecteds in the family, the greater the risk

for additional affecteds2) The more severe the phenotype the greater the risk to

offspring3) The sex with the lower prevalence has a greater risk

to transmit the phenotype to offspring4) Consanguinity rates are increased5) As population incidence increases, so does the risk to

be affected6) The frequency of affected relatives of a proband de-

creases logarithmically with decreasing degree of re-lationship

TABLE 2. Carter Predictions of the MF-T model

1) The less frequently affected sex has the greatest risk

for transmitting the trait

2) The most severely affected individual has the greatest -

risk for transmitting the trait to offspring

3) Consanguinity rate is increased in affected families

13Bixler, GENETICS AND CLEFTING

TABLE 3. Incidence of Clefting in the Offspring of Affected Parents According to Parental Sex*

pNQ Chilfdien/ Affected Normal Total Incidencearents Parent Offspring (%)

CL(P)Fathers 141 1.9 68 200 268 25.4Mothers 105 2.6 66 206 272 24.3

CPFathers 24 1.9 4 43 47 8.9Mothers 64 1.9 14 113 127 11.0 * Only affecteds with children were counted.

TABLE 4. Incidence of CL(P) by Severity of Defect inParent Affected %Cleft Lip

Fathers (79) 31/134 23.1Mothers (57) 32/148 21.6

63/282 22.3Cleft Lip + Palate

Fathers (62) 37/134 27.6Mothers (48) 34/124 27.4

71/258 27.5 X= 1.16

in the offspring of CL(P) mothers and fathers.One hundred forty-one affected fathers had68 affected children from a total of 268 live-born offspring for an incidence of 25.4%. Formothers, this rate was 24.3%. Considering CP,the comparable rates were 8.9% for fathersand 11.0% for mothers. Collectively, theseresults show that there is not an increased rateof clefting in the offspring of the less fre-quently affected sex for either CL(P) or CP.These sex-combined incidence rates appearelevated over previously published data, butit must be remembered that they representincidence in a highly selected series since onlyaffected individuals who reproduced wereused in the analysis. Our data suggest that ahigh percentage of Danish cleft persons donot reproduce.The second prediction in Table 2 states

that the most severely affected cleft individualhas the greatest risk for transmitting the cleft-ing trait to offspring. If one considers thatcleft lip with cleft palate is a more severedefect than cleft lip alone, the data in Table4 show no significant difference in the inci-dence of affected offspring acording to the

severity of defect in the parent. The chi-squarefor this comparison is 1.16. Thus, the mostseverely affected individual did not appear tohave the greatest risk for transmitting the traitto offspring. A breakdown of the severity phe-notype into a system of unilateral and bilat-eral clefts of the lip and palate is shown inTable 5. It can be seen that a parent of achild with any degree of severity is equallylikely to have an affected offspring with anyother cleft type. A 4 X 4 contingency chi-square shows no interaction among these var-i0us cleft types. This supports the concept ofseverity as a consequence of variable geneexpression and not an expression of segregat-ing entities.

Let us consider now the incidence of cleftpalate in offspring as related to severity ofdefect in the parent. Again, an assumption ismade that a cleft of the hard and soft palatesis a more severe defect thanjust a soft palatecleft. If one does this, the data in Table 6show that, of 31 parents with a mild defect,63 children were born, four ofwhom had cleftpalates for an incidence of 6.3%. Comparisonof parents with the severe defect gave a rateof 12.8%. The chi-square value for their com-parison was 1.17. Thus, the incidence of off-spring is not significantly different when theparents were either severely or mildly affected.

Finally, considering consanguinity rates forCL(P) and CP probands (Prediction No. 3,Table 2), it has been estimated that the rateof first-cousin marriages in the Danish popu-lation is approximately 1%. From the CL(P)and CP pedigrees obtained on the Danishprobands, the consanguinity rate is estimatedat about .4%. This is probably an underesti-mate of the true values for both cleft types,but at least the directional difference indicates

14 Cleft Palate Journal, January 1981, Vol. 18 No. 1

TABLE 5. Cleft Type of Offspring According to Parental Cleft Type

Parent

UCL BICL UCLP BICLP TOTAL

UCL 13 3 22 16 54BICL 5 0 1 3 9

Offspring UCLP 9 1 24 7 41BICLP 6 1 14 9 30TOTAL 33 5 61 35 134

4 X 4 Contingency X* = 3.59 (N.S.)

TABLE 6. Incidence of CP in Offspring by Severity ofDefect in Parent

- Affecteds %

Mild CP (S)

Fathers (10) 0/18 -Mothers (21) 4/45 8.9

4/63 6.3Severe CP (H+S)

Fathers (14) 4/29 13.8Mothers(43) 10/80 12.5

14/109 12.8 X"-2 X 4 contingency (interaction) = 1.39

2 X 2 contingency (severe vs. mild) = 1.17

no increased consanguinity rate for parents of

cleft children. In summary, of the three pre-

dictions listed by Carter (1969). as evidence

for an MF-T trait, none is confirmatory for

either CL(P) or CP.

Obviously, these data do not reject the MF-

T model. They simply show that CL(P) and

CP data do not conform to what has been

offered as predictors of such MF-T traits. A

logical explanation for this result is that gar-

den variety CL(P) and CP are both etiologi-

cally heterogeneous. Therefore, no single eti-

ologic model should ever prove satisfactory.

Accordingly, we began a search for heteroge-

neity in our owndata. It should be pointed

out that this ideafor CL(P) and CP is not

original with us even though it is supported

by the Danish data. Etiological heterogeneity

of clefts in the inbred mouse has been repeat-

edly demonstrated by F.C. Fraser and his co-

workers.

Before turmng to the problem of establish-ing etiological heterogeneity in these traits,we must first examine data coming from stan-dard genetic analysis madeon the Danishcleft population.

In Table 7 are data from the cleft twin

population of Denmark (Shields et al, 1979).Twin studies tell us nothing about geneticmode of inheritance, but they do provide cluesabout proportionate etiological contributions.For example, of 11 CL(P) pairs of genotypedMZ twins, only 36% were concordant. How-ever, a mere 1.5% of DZ pairs were concord-ant, which emphasizes a strong genetic con-tribution even though 36% is not a high con-cordance rate for a heritable trait and is notcompatible with a simply inherited trait. CPshowed a similar modest MZ concordance of33%. Such low MZ concordance rates havebeen offered as evidence to support designa-tions such as MF-T traits, but another possibleexplanation is etiological heterogeneity. If thetwin pairs were actually a mixture of cleftswith different etiologies (genetic and environ-mental), the same result could be obtained.

Another approach to the study of inherit-ance of traits is to perform a segregationanalysis. This involves the enumeration ofphenotypes in first-degree relatives to see ifthey conform to predicted patterns of singlegene locus segregation. A segregation analysiswas performed on the total, non-syndromicpopulation of both CL(P) and CP with inter-esting results. For CL(P), the segregationvalue was .17 with a penetrance of 34%. Thisis very low for a dominant trait and lowerthan would be expected even for a recessivetrait. Regarding the latter possibility, pedi-grees of multiply affected CL(P) Danish fam-ilies clearly do not support recessive inherit-ance. For CP, the segregation frequency was16, very similar to that observed for CL(P),

and the estimate for the proportion of spo-radic cases in this group was a very high 80%.These segregation analyses clearly do not sup-port simple Mendelian inheritance and pro-vide additional impetus to consider that non-

TABLE 7. Danish Cleft Twin Pairs (1933-1972)

Bixler, GENETICS AND CLEFTING 15

MZ DZ

Concordant Discordant Rate Concordant Discordant Rate

CL(P) 4 7 36% 1 67 1.5%CP 1 2 33% 0 13 0%

TABLE 8. Birth Order of CL(P) Probands

Birth Order

Group 1 2 3 4 5+ Total

Isolated 156 84 46 20 51 357Familial 40 24 23 16 24 127

* Group type was dependent upon birth order. (X* =13.6, P < 0.01)

syndromic CL(P) and CP may not be single

etiological entities.

Returning now to how we began our study

of etiological heterogeneity in this population,

a simple division of both CL(P) and CP into

familial and isolated cases was initially ac-

complished. The working hypothesis behind

this division was that familial cases represent

simple genetic ones, while isolated cases rep-

resent a mixture of cases with different etiol-

ogies. This assumption is too simplistic but it

provided a point of departure for further stud-

ies. Given this subdivision, an attempt was

made to discern dichotomies in any of several

epidemiological parameters which would es-

tablish that familial and isolated cases were,

in fact, different kinds of clefts. A number of

parameters for both CL(P) and CP were ex-

amined including sex and cleft severity inter-

actions, parental age, birth order, seasonal

and annual incidences, malformation rates in

relatives, and several others. Only those which

indicated a likelihood of distinguishing be-

tween the two groups (familial vs. isolated)

will be mentioned here. Tables eight through

10 summarize data on factors which might

discriminate between familial and isolated

CL(P). Birth order (Table 8) was found to be

significantly different between the two

groups. Multiple regression analysis holding

maternal and paternal age constant estab-

lished that it was parity which was signifi-

cantly lower in the isolated cases. Specifically

noted was a clustering of clefts in the first and

second born children in families with isolated

ocurrence families.

Occupational status (Table 9) was different

in the two groups. Using the ranking scale of

occupational scores by the U.S. Bureau of the

Census, it was seen that isolated cases were

significantly associated with a higher occu-

pational or socio-economic status. Finally, a

very interesting finding was that the malfor-

mation rate for congenital defects in the sib-

lings of probands was five times higher in

those cases occurring as isolated cases than in

those in the familial groups (Table 10). These

were birth defects of any type other than

clefts, which suggests some dysmorphic fac-

tor(s) present in these families predisposing to

malformations. It is important to note that

this malformation frequency was not in-

creased in parents and other relatives. A sum-

mary of these factors for CL(P) appears in

Table 11.

Three factors were also identified that

might discriminate between familial and iso-

lated CP. Annual incidence was rather uni-

form throughout the first years of the study,

but during the period from 1956 through

1971, there was a significant increase in iso-

lated occurrences. This can be demonstrated

graphically in the next two figures which

show the cumulative sums of cases occurring

in these years. Figure 1 illustrates the occur-

ence of the familial cases, and for them the

pattern was no different from the pattern of

non-cleft births in the general population.

However, the isolated occurrences (figure 2)

showed a marked increase during the period

of 1956 through 1971. This was especially

noticeable in the period 1959 through 1964:

Two other population parameters, sex ratio

and sex ratio related to severity appeared to

discriminate partially between the familial

and isolated cases of CP. A summary of these

factors is given in Table 12.

As a general comment on the altered sex

prevalence for both CL(P) and CP, it has

been suggested that the developmental

thresholds for both primary and secondary

16 Cleft Palate Journal, January 1981, Vol. 18 No. 1

TABLE 9. Occupational scores for heads of households of CLL+P proband families

Familial head Isolated head

OC§;2agfnal 15080113"? of household of household

gory no. (%) no. (%)

Professional 9 2 (1.6) 18 (5.0)

Proprietors and managers 8 4 (3.1) 16 (4.5)

Clerical and sales 7 8 (6.3) 31 (8.7)

Craftsmen 6 14 (10.9) 45 (12.6)

Operatives 5 14 (10.9) 36 (10.0)

Domestic and service workers 3 21 (16.4) 56 (15.6)

Laborers (incl. farm) 2 65 (50.8) 155 (43.3)

None 1 0 (0.0) 1 (0.3)

Total - 128 (100.0) 358 (100.0)

t = 2.06, p < 0.05

TABLE 10. Congenital Anomalies in the Parents and 320;

Siblings of CL+P Probands -

aas Sibling 280}- Parents Siblings Rate |

Familial 0.016 (4/256) 0.007 (3/460) 0.65% 240 |-

Isolated 0.017 (12/718) 0.031 (24/783) 3.06% a

Sibling difference significant (X* = 6.84, p < 0.01) 200 -& .pS2 160}UD

. 8 -

TABLE 11. Factors Potentially Discriminating 120}

Between Familial and Isolated CL(P) |

1. Parity (birth order)-Increase in 1st and 2nd born iso- 80}

lated cases. Multiple regression analysis employing

maternal and paternal ages and parity showed that 40}

the lower parity was related to the isolated cases. |

2. Occupational status-Isolated cases significantly associ- BT aaa Fd bg d ded dd d bad dd dd dba

ated with the higher occupational (socio-economic) 1944 47 50 53 56 59 62 65 68 7

tatus.loll FIGURE 2.

3. Congenital malformations in siblings-five times higher in

isolated case families. Malformation frequencies in

parents and other relatives were not different in the 2

groups.

60

40

20

OCUSUMS

L 1 |_ _L i 1 1 1. 1 jod I_ _L 1 1 1 1 1 } 1 . i p00 d pl p cupj

1944 47 50 53 56 59 62 65 68 71

FIGURE 1.

palate formation are different for the two

sexes. Hence, differential timing of palatal

morphogenesis in the two sexes could account

for different incidences. Niswander (1972) and

co-workers have suggested another possibility

that differential fetal lethality is related to

different thresholds of development in the two

sexes. lTizuka (1973) and Nishimura (1970)

have reported an increased rate of clefting in

Japanese abortuses. Unfortunately, although

the fetal loss may be higher, the sex ratio of

these affecteds is unknown. This is another

indication, then, that the phenotype of CL(P)

and CP should be considered to be broader

than was originally thought, perhaps even:

encompassing lethality. Altered sex ratios in

living affecteds and sex ratio-severity interac-

tions as observed here could be used as sup-

portive evidence for this idea.

What has been attempted is the identifica-

tion of heterogeneity in the categories of non-

syndromic CL(P) and CP in an attempt to

explain why genetic analyses do not provide

answers that are readily interpreted. Based

upon the data presented and discussed here,

it appears that there are at least three groups

of CL(P) and CP: syndromic, familial, and

isolated (Table 13). About 1% of all CL(P)

cases represent syndromes whereas the figure

is much higher, 8%, for isolated cleft palate.

Familial cases comprised about 25% of all

CL(P) occurrences, and for isolated cleft pal-

ate they represented 12% of the total. There

was some evidence presented here to support

the validity of the division of clefts into fa-

milial and isolated cases, but, even with this

grouping, the familial cases may still be etio-

logically heterogeneous in composition. Fi-

nally, the isolated cases make up the largest

group of all-74% of CL(P) cases and 80% of

CP cases, and it seems certain that further

heterogeneity will be discerned for them.

It should be mentioned now that even

though these analysis have not supported the

MF-T model, it is probable that the etiology

of CL(P) and CP is actually multifactorial-

more clearly stated, that more than one factor

is responsible for clefting, especially in isolated

TABLE 12. Factors Potentially DiscriminatingBetween Familial and Isolated CP 1. Annual incidence-Significant increase in isolated occur-

rences during 1956-71, especially noticeable 1959-64.2. Sex ratio in affected siblings-M/F sex ratio in sibships of

isolated cases (637/716) is significantly lower thanthat in familial sibships (121/118)

3. Sex ratio related to severity-Sex ratio related to severityof defect (females more severe) in familial cases only.

TABLE 13. Heterogeneous Groups of CL(P) and CP Syndromic-Includes such various etiologies as monogenic

(Van der Woude syndrome), chromosomal(Trisomy 13), environmental (Robin syn-drome). CL(P) = 1%; CP = 8%

Familial-Includes all kindreds with 2 or more affectedsin first, second or third degree relatives. CL(P)= 25%; CP = 12%. (Syndromes, multiple loci-alleles)

Isolated(Non-familial) -Includes all kindreds in which the

probands is the only affected in first, second andthird degree relatives. CL(P) = 74%; CP = 80%.(Isolated familial cases and syndromes)

Bixler, cEnETICS AND CLEFTING 17

cases for which there is some evidence of

environmental causation (i.e., increased an-

nual incidence, increased malformation rate

in siblings). Conceivably, several different en-

vironmental teratogens act on a single devel-

opmental morphogenetic mechanism which is

controlled by one or two genes, thereby pro-

viding the presumed gene-environment inter-

action. Is there any evidence for such a sup-

position? At the workshop on Etiology of Fa-

cial Clefting, Dr. Juriloff presented evidence

obtained with the inbred mouse that terato-

gen-induced CP appears to be influenced or

regulated by at least two and possibly three

gene loci with dominance or epistatic effects.

In regard to CL(P), the control of sponta-

neous CL(P) in the inbred mouse appears to

take place either by two major recessive loci

or by a single major locus with modifiers

(allelic or otherwise). The conclusions from

animal models are compatible with the hu-

man data and further support the probable

existence of etiological heterogeneity in the

familial cases of CL(P).

Melnick and Shields (1976) have proposed

an explanation of the observed differences in

human data and what might be expected for

a simple Mendelian trait by the concept of

allelic restriction. Basically, this idea applies the

genetic concept of lyonization to the autoso-

mal chromosomes. That is, the random inac-

tivation of autosomal loci in a given embry-

onic precursor pool of cells is the initiating

genetic event. Such inactivation at the appro-

priate developmental stage produces observ-

able phenotypic frequencies at low rates in

gene carriers which are comparable to those

clefting frequencies observed here. Note that

this allelic restriction hypothesis does not de-

tract from the basic interpretation of the cleft

data emphasized here, etiologic heterogeneity

within the clefting phenotypes CL(P) and CP.

In spite of our present lack of clear under-

standing of the etiology of clefting in man,

these data do accomplish one thing for genetic

counseling. No longer should we pool together

all the population cleft data on recurrence

risks in order to tell an affected parent that

he or she carries a 5% empiric risk for affected

offspring. If there are other affected near rel-

atives that risk is considerably higher, and our

segregation analysis says that it is at least 16%.

Assuming that there is heterogeneity within

the familial groups too, this risk may be even

18 Cleft Palate Journal, January 1981, Vol. 18 No. 1

higher. For isolated cases, a recurrence risk

much less than 1% can be given explaining to

the family our present inability to recognize

the small number of chance isolated familial

cases in this group.

The issue that these data make is that our

present phenotypic definition for facial cleft-

ing in man is too incomplete to permit accu-

rate genetic counseling. Withsuch incomplete

definition we will continue to provide evi-

dence of heterogeneity. The resolution of this

problem will come only when we begin to -

conduct careful genetic marker studies, look-

ing for biochemical traits of known genetic

control which are either linked to (located on

the same chromosome) or closely associated

with (such as having a common biochemical

pathway) either of these two dysmorphic en-

tities. For example, if a linkage relationship

could be established between cleft palateand

the major histocompatibility complex (HL-A)

for either familial or isolated cases, one would

have a very powerful tool for discriminating

sub-groups of CP not otherwise phenotypi-

cally distinguishable. Such studies are being

planned at several research institutions and at

some meeting in the near future I look forward

to the reporting of these most welcome results.

Reprints

Dr. David Bixler I :Indiana University School of Dentistry1121 W. Michigan St.Indianapolis, Ind. 46202

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