Complex segregation analysis of nonsyndromic cleft lip/palate in a Chilean population

Abstract

A população urbana Chilena contemporânea deriva da mistura de ameríndios nativos com espanhóis, apresentando uma incidência média de fissura labial não sindrômica associada ou não a fissura palatina (NSCLP) de 1,8 por 1000 nascimentos vivos. A análise de segregação complexa usando o programa de computador POINTER foi feita em 249 pedigrees estendidos, distribuídos em 202 famílias simplex e 47 famílias multiplex obtidas de probands de NSCLP afetados (157 homens e 92 mulheres). Esses pedigrees deram origem a 326 indivíduos afetados e mais de 1454 parentes. Oito modelos hipotéticos foram examinados e comparados pelo teste <FONT FACE="Symbol">c</font> 2 log2 razão de máxima verossimilhança. Os modelos que postulam que NSCLP não era transmitida nestas famílias foram rejeitados, assim como os modelos que postulam apenas um componente multifatorial (P < 0,0001). O modelo que postula não haver componente poligênico para a transmissão não pôde ser rejeitado mas o modelo de não transmissão do efeito mais importante foi rejeitado (P < 0,0001). Entre os modelos do locus mais importante apenas o modelo recessivo de transmissão foi rejeitado, enquanto que as heranças codominante e dominante sem um componente multifatorial não puderam ser excluídas. O modelo não restrito sugere que a freqüência do alelo de suscetibilidade a NSCLP no locus mais importante é 0,0037 e sua penetrância é de 92%.

Complex segregation analysis of nonsyndromic cleft lip/palate in a Chilean population

Rafael Blanco¹, Mauricio Arcos-Burgos¹, Mónica Paredes ², Hernán Palomino¹, Lilian Jara¹, Hernán Carreño¹, Victor Obreque¹ and M.A. Muñoz ³

¹ Department of Cell Biology and Genetics, Medical School, University of Chile. Av. Independencia, 1027, Casilla 70061, Correo 7, Santiago, Chile. Phone: [phone], Fax: [phone], E.mail: [e-mail]. Send correspondence to R.B.

² School of Biological Sciences, University of San Marcos, Lima, Perú.

³ Cleft Lip/Palate Clinic, School of Dentistry, University of Chile.

ABSTRACT

The contemporary urban mixed Chilean population stems from the admixture of the native Amerindians with the Spaniards, showing an average incidence rate of nonsyndromic cleft lip with or without cleft palate (NSCLP) of 1.8 per 1000 live births. Complex segregation analysis using the computer program POINTER was conducted in two hundred and forty-nine (249) extended pedigrees distributed in 202 simplex families and 47 multiplex families ascertained from affected NSCLP probands (157 males and 92 females). These pedigrees yielded 326 affected individuals and over 1454 family members. Eight hypothetical models were examined and compared by -2 log-likelihood ratio c ² test. Models postulating that NSCLP was not transmitted in these families were rejected as well as model postulating only a multifactorial component (P < 0.0001). Model postulating no polygenic component to transmission could not be rejected but the model of no transmission of the major effect was rejected (P < 0.0001). Among the major locus models only the recessive model of transmission was rejected whereas codominant and dominant inheritance without a multifactorial component could not be excluded. The unrestricted model suggests that the frequency of the NSCLP susceptibility allele at the major locus is 0.0037, and its penetrance is 92%.

INTRODUCTION

The etiology of nonsyndromic cleft lip with or without cleft palate (CL(P)) remains unresolved. The most widely accepted model for CL(P) in the 70’s and early 80’s was that of a multifactorial inheritance (Carter, 1969; Fraser, 1970; Carter et al., 1982; Hu et al., 1982). Nowadays powerful computer programs of complex segregation analysis have been developed as in POINTER (Lalouel and Morton, 1981; Lalouel et al., 1983). The application of this program to pedigree data has raised evidence for the existence of a major locus. Marazita et al. (1986) reexamined the data of Carter et al. (1982) and found that the multifactorial threshold (MFT) model could be rejected in favor of a mixed model (single major locus plus multifactorial components). A similar result had been previously reported by Demenais et al. (1984) in France. Melnick et al. (1986) reanalyzed the Chinese families studied by Hu et al. (1982) and also found that an MFT model could be rejected in favor of a single recessive major locus. Chung et al. (1986) reported that the Danish data (Bixler et al., 1971; Melnick et al., 1980) could be explained by a combination of major gene action (autosomal recessive) and multifactorial inheritance, while the Japanese data (Koguchi, 1975) fitted a multifactorial inheritance. The study of Marazita et al. (1992) in families from Shangai, China concluded that the best fitting model was autosomal recessive, while Hecht et al. (1991) proposed an autosomal dominant model for a US population. This same model was postulated by Nemana et al. (1992) in Madras, India and by Ray et al. (1993) in West Bengal, India. Therefore, results obtained by different authors in populations with different ethnic origin and with different admixture rates show divergence, with some reports postulating a dominant major locus, others a recessive major locus and some a multifactorial threshold model (Chung et al., 1986; Marazita et al., 1986; De Paepe, 1989; Temple et al., 1989; Hecht, 1990; Hecht et al., 1991; Farral and Holder, 1992; Marazita et al., 1992; Mitchell and Risch, 1992; Ray et al., 1993; Clementi et al., 1995).

In accordance with the hypothesis of a major gene, several studies have been carried out, where various candidate genes have been analyzed in different populations either through association or linkage studies (Ardinger et al., 1989; Hecht et al., 1991; Chenevix-Trench et al., 1991, 1992; Holder et al., 1992; Stoll et al., 1992; Vintiner et al., 1992, 1993; Sassani et al., 1993; Hecht et al., 1993; Davies et al., 1995; Carinci et al., 1995; Stein et al., 1995; Mitchell et al., 1995; Jara et al. 1995). These studies have been carried out in Caucasian populations with the exception of the report by Jara et al. (1995) performed in an admixed Caucasoid- Amerindian population. The results of these investigations have also shown heterogeneous results which seem to reflect genetic heterogeneity and ethnic background, suggesting that more than one susceptibility loci is involved in some cases of nonsyndromic CL(P) showing at the same time great interpopulation variability.

Comparative studies among racial groups with different admixture rates are of great interest and potential importance since they could permit a discrimination of whether the incidence differences reflect underlying heterogeneity or differences in gene frequency.

The contemporary Chilean population stems from the admixture of the native Amerindians with the Spaniards (Rothhammer et al., 1968). The incidence rates of CL(P) in the urban mixed Chilean population (1.8 per 1000 live births, males: 2.4 x 1000 and females: 1.2 x 1000) show on the average intermediate values compared with those reported for Asians or Caucasians (Blanco and Rosales, 1988). The relationship between ethnicity, Amerindian admixture, genetic markers, and socioeconomic strata in public and private health care systems in Chile has been extensively studied (Valenzuela and Harb, 1977; Valenzuela et al., 1987; Valenzuela, 1988; Palomino et al., 1990). These reports have demonstrated that the degree of Amerindian admixture can be determined by the frequencies of the alleles of the ABO and Rh loci. The Chilean socioeconomic strata presents a gradient of Amerindian admixture, with the highest values in lower socioeconomic strata. Moreover, a strong correlation between Amerindian admixture and the incidence of CL(P) has been reported in Santiago, Chile (Palomino et al., 1990). In the present study, cases and controls belong to middle-low and low socioeconomic strata.

The present study was undertaken to examine the pattern of inheritance of CL(P) in the Chilean population. We present evidence that a major locus contributing to CL(P) is detectable by complex segregation analysis in a sample of Chilean extended pedigrees.

MATERIAL AND METHODS

The sample consisted of 249 multigenerational extended pedigrees ascertained through a fixed sampling method during the period 1992-1995. We have chosen this sampling method following the operational characteristics of segregation analysis proposed by MacLean et al. (1975). This sampling strategy chooses arbitrarily a sample size at the beginning of the ascertainment procedure without making further changes in its size regardless the tested hypothesis is rejected or not. The data was obtained from affected CL(P) probands (157 males and 92 females) attending the Cleft Lip/Palate Clinic of the School of Dentistry of the University of Chile at Santiago, the Dr. Alfredo Gantz Mann Foundation, a private clinic for the rehabilitation of the cleft patient, also located in Santiago and from the "Centro de Amigos del Niño Fisurado" CEAMFI, Talca, also a private foundation in the city of Talca, located approximately 400 km south from Santiago, which helps both in the rehabilitation of the cleft patient as well as in giving psychological support to their parents and relatives. The 249 pedigrees were distributed in 202 simplex families (one affected in the extended pedigree) and 46 multiplex families (more than one affected in the extended pedigree) which yielded 326 affected individuals (probands and affected relatives included) and over 1454 family members. The status of affected family members was verified by field workers.

The ascertainment probability (p) was estimated separately from the segregation analysis according to the equation åa (a-1)/år (r-1) where a, number of probands and r, total number of affecteds (Simpson, 1983).

In order to compare the fit of the family data to MFT, Mendelian major-locus (ML) and combined MFT-plus-ML models, the extended pedigrees were analyzed by complex segregation analysis using the unified mixed model (Lalouel and Morton, 1981; Lalouel et al., 1983) as implemented in the computer program POINTER (Morton et al., 1983).

The model partitions the total variation in the underlying liability to CL(P) into three independent components: a diallelic single major locus component, a polygenic background and a random environment component. Model parameters are: q, the frequency of the high-risk allele A; t, the displacement at the single major locus; d, degree of dominance at the major locus, such that d = 0 corresponds to a recessive gene, d = 1 corresponds to a dominant gene, 0 < d < 1 corresponds to some degree of additivity and d = 5 is referred to as codominant; H is the polygenic heritability in the offspring; Z, ratio of adult to childhood heritability, and t1, t2 and t3, the respective probabilities that genotypes AA, Aa, and aa transmit the allele A. For example, if the single major locus is Mendelian, then t1 = 1, t2 = 5, and t3 = 0, whereas the t’s are equal if there is no transmission of a major effect.

Pointer only accepts nuclear families as an input. Extended pedigrees were analyzed by dividing them into their component nuclear families. Those nuclear families not containing affected probands though containing affected relatives of the" pointer" (nominal probands) were codified in each sibship considering that the ascertainment probability value p = 1. Only nuclear families ascertained through pointers with at least one affected individual were included. This last approach was chosen because simulations and empirical results have shown similar results either including or not families with no affected members (Marazita et al., 1992). The extended pedigrees yielded a total number of 295 nuclear families. In addition, as nonsyndromic CL(P) is disorder with sex dependent liability, two classes were defined, males (2.4 per 1000 live births) and females (1.2 per 1000 live births). Conditional likelihood was used when maximizing the different models based on the sex incidences. Neither differential mortality nor marriage was taken into account.

RESULTS

Table I presents the results of complex segregation analysis of the data. Seven constrained hypothetical models were contrasted using likelihood ratio test (models 1 to 7) with the unconstrained model or mixed model (model 8). -2 log likelihood values for each comparison were examined using c ² test. Parameter estimates corresponding to maximum likelihood models under each set of constraints are shown for each examined model.

* =
P < 0.05; ** = P < 0.001.

Hypothesis	Parameters
	D	t	q	H	t1	t2	t3	Z	-2 ln (L) + c	d.f.	c 2	P
1. No transmission
(q = H = 0)	(0)	(0)	(0)	(0)	...	...	...	(1.0)	1102.20	5	297.6	< 0.0001
2. Multifactorial	(0)	(0)	(0)	0.99	...	...	...	(1.0)	895.22	4	90.68	< 0.0001
Major locus
3. Dominant	(1)	4.68	0.0036	(0)	(1.0)	(0.5)	(0)	(1.0)	805.09	3	0.55	> 0.05
4. Codominant	(0.5)	9.35	0.0037	(0)	(1.0)	(0.5)	(0)	(1.0)	805.14	3	0.60	> 0.05
5. Recessive	(0)	5.27	0.0725	(0)	(1.0)	(0.5)	(0)	(1.0)	894.90	3	90.36	< 0.0001
6. d-non-restricted	0.92	7.73	0.0037	(0)	(1.0)	(0.5)	(0)	(1.0)	805.06	2	0.52	> 0.05
7. t1 = t2 = t3	0.99	7.71	0.0048	0.30	(0.99)	(0.99)	(0.99)	(1.0)	943.84	1	130.3	< 0.0001
8. Mixed model	1.0	2.69	0.0043	0.45	(1.0)	0.41	(0)	(1.0)	804.54	0	...	...

Table I - Complex segregation analysis (POINTER) of nonsyndromic cleft lip/palate in a Chilean population.

The hypothesis of no familial transmission of nonsyndromic CL(P) in these families (cohort effect) (comparison between models 1 and 8) was strongly rejected (c ² (5 d.f. ) = 297.6, P < 0.0001). The hypothesis of a multifactorial component only (comparison between model 2 and model 8), was also rejected (c ² (4 d.f.) = 90.68, P < 0.0001).

Within the models postulating a major locus (dominant, codominant or recessive) only the recessive model could be rejected (comparison between model 5 and 8) (c ² (3 d.f.) = 90.36, P < 0.0001). On the contrary, codominant (comparison between model 5 and 8) and dominant models (comparison between models 3 and 8) could not be rejected (c ² (3 d.f.) = 0.60, P > 0.05 and c ² (3 d.f.) = 0.55, respectively).

Model postulating no polygenic component (comparison of models 6 and 8) could not be rejected (c ² (1 d.f.) = 0.52, P > 0.05), whereas the model of no transmission of the major effect was rejected (comparison of the models 7 and 8) (c ² (1 d.f.) = 130.3, P < 0.0001).

Therefore, the model that best fits the data is the major locus model without a multifactorial component. The unrestricted model (model 6) suggests that the frequency of the CL(P) susceptibility allele at the major locus is 0.0037, and its penetrance is 92%.

DISCUSSION

The results of complex segregation analysis of CL(P) of the present data are consistent with a dominant or codominant major locus model of inheritance, with no indication that the addition of a multifactorial or sporadic component to the major locus model would improve the fit of the data. These findings from CL(P) families living in Santiago, Chile are very similar to those reported by Hecht et al. (1991) in a US population, by Nemana et al. (1992) in Madras, India and by Ray et al. (1993) in West Bengal, India. These results have been obtained in ethnically different populations. In the same manner the hypothesis of an autosomal recessive locus has also been proposed by different authors in ethnically contrasting populations (Melnick et al. (1986) in a Chinese population and Chung et al. (1986) in the Danish population). It seems reasonable to speculate that these differences may be due to genetic heterogeneity in turn a reflection of a non-linear multi-loci genetic interaction. Moreover, the results thus far obtained with different candidate genes seem to point in the same direction. These latter studies have differed in the type of pedigree included in them. Linkage studies have only used multiplex pedigrees whereas association studies have included both multiplex and simplex pedigrees. The rationale of this approach is quite obvious. Linkage studies have tried to identify one major locus responsible for CL(P) and association studies have raised evidence that there is more than one locus involved.

It remains to be analyzed therefore if the results thus far obtained for complex segregation analysis are correlated with the type of pedigree included in such studies. At the same time they could be correlated with some of the susceptibility loci which have already been reported.

RESUMO

A população urbana Chilena contemporânea deriva da mistura de ameríndios nativos com espanhóis, apresentando uma incidência média de fissura labial não sindrômica associada ou não a fissura palatina (NSCLP) de 1,8 por 1000 nascimentos vivos.

A análise de segregação complexa usando o programa de computador POINTER foi feita em 249 pedigrees estendidos, distribuídos em 202 famílias simplex e 47 famílias multiplex obtidas de probands de NSCLP afetados (157 homens e 92 mulheres). Esses pedigrees deram origem a 326 indivíduos afetados e mais de 1454 parentes.

Oito modelos hipotéticos foram examinados e comparados pelo teste c ² log₂ razão de máxima verossimilhança.

Os modelos que postulam que NSCLP não era transmitida nestas famílias foram rejeitados, assim como os modelos que postulam apenas um componente multifatorial (P < 0,0001). O modelo que postula não haver componente poligênico para a transmissão não pôde ser rejeitado mas o modelo de não transmissão do efeito mais importante foi rejeitado (P < 0,0001). Entre os modelos do locus mais importante apenas o modelo recessivo de transmissão foi rejeitado, enquanto que as heranças codominante e dominante sem um componente multifatorial não puderam ser excluídas. O modelo não restrito sugere que a freqüência do alelo de suscetibilidade a NSCLP no locus mais importante é 0,0037 e sua penetrância é de 92%.

(Received August 19, 1996)

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Publication Dates

• Publication in this collection
  06 Jan 1999
• Date of issue
  Mar 1998

History

• Received
  19 Aug 1996