Heritability and Prevalence of Mandibular Prognathism In Pakistan

 INTRODUCTION

Mandibular prognathism (MP) is a dentofacial anomaly characterized by a concave facial profile, a protrusive mandible, and a Class III skeletal and dental relationship.¹ It has significant functional and esthetic implications, making it both a clinical and genetic concern. The etiology of MP is multifactorial, but substantial evidence supports a strong hereditary component in its development.^2,3 Previous studies have suggested that MP is transmitted through an autosomal dominant inheritance pattern with incomplete penetrance, although environmental influences and gene-environment interactions may also contribute.^4-7

Cephalometric analysis remains the cornerstone of diagnosing and quantifying skeletal discrepancies associated with MP. It provides objective measurements to distinguish true mandibular prognathism from other forms of Class III malocclusion and aids in family-based inheritance studies.^8,9

Globally, several studies have investigated the heritability of MP, reporting variations in prevalence, inheritance patterns, and gender distribution across populations.^10-13 Zhou and Genno demonstrated autosomal dominant transmission in the majority of studied families^14,15 while Han emphasized incomplete penetrance and variable expression. Population based differences have also been observed, highlighting the importance of studying MP in diverse ethnic groups.⁹

Despite this, limited data exist regarding the genetic patterns of MP in South Asian populations, particularly in Pakistan, where high rates of consanguinity may influence expression of hereditary craniofacial anomalies. This study, therefore, aimed to evaluate the inheritance pattern, gender distribution, and heritability of MP in a Pakistani cohort, using cephalometric analysis to confirm skeletal involvement among affected family members.

 Family and pedigree-based studies remain a cornerstone in understanding the inheritance of MP. Reports from Japanese, Mediterranean, and Middle Eastern populations have consistently demonstrated strong familial aggregation of the trait, with higher concordance observed among first degree relatives.^10,12 However, data from South Asian populations remain scarce despite the high burden of untreated skeletal malocclusions and their significant psychosocial and functional impact.¹³

Understanding the heritability of MP in specific populations is clinically relevant, as it aids in early diagnosis, treatment planning, and genetic counseling. It also provides a basis for future genome-wide association studies aimed at identifying causal variants in diverse ethnic groups. The present study was therefore designed to evaluate the heritability and prevalence of mandibular prognathism within Pakistani families, using cephalometric, clinical, and pedigree analyses.

 METHODOLOGY

The presented study conducted in the orthodontic department of Punjab dental hospital, Lahore. The duration of study was one year. The minimum required sample size was calculated using the standard formula for proportion based studies, assuming an expected prevalence of mandibular prognathism of 5%, a confidence level of 95%, and a precision of 5%. The resulting estimate was approximately 73 individuals. To improve statistical power, accommodate pedigree complexity, and ensure reliable heritability estimates under an autosomal dominant inheritance model, the sample size was increased. After taking Institutional Ethical Board approval and informed consent to subjects, 150 persons of with MP were identified from fifty families by using nonprobability purposive sampling. The age varied from 15 to 54 years (28,6±9.45). The complete history of probands (index case) and their family members who were showing clinical signs of MP were taken and the written consent form was signed by the subjects. The inclusion criteria were: Class III molar relationship, Class III cuspid relationship, Anterior cross bite /edge to edge bite, skeletal class III, either gender, patients willing to participate in study whereas patient represented with Maxillary hypoplasia as a primary cause, Severe congenital disorders, any syndrome related with MP, Pseudo class III were excluded.

Socio-demographic data (name, age, family history, sex, address) were collected. The clinical examination was done and Class III molar and canine relationship confirmed the selection of proband. The cast analysis was done on the cast to analysis the occlusal records. The lateral view of the individual in which the subject's head was parallel to the  floor was taken. Lateral cephalograms of 150 subjects were taken and Composite Cephalometric analysis was done. The facial and cranial structures were outlined and SNA, SNB and ANB angles were measured. Three generation pedigree was drawn. Pedigree analysis was done to estimate genetic model, gender distribution, penetrance and incidence amongst siblings and parents. For each proband, a three-generation pedigree was constructed. First-degree relatives (parents, siblings, children) were prioritized for inclusion in the study. If first-degree relatives were not available or were unaffected, second-degree relatives (grandparents, aunts/uncles, nieces/nephews) were considered. Third-degree relatives (cousins, great-grandparents) were only included in families where sufficient data from first- and second-degree relatives was not available, in order to maintain the integrity of inheritance pattern analysis. The degree of relation and inclusion decision was based on the availability of clinical evidence and the proband's family structure. For each proband, a three-generation pedigree was constructed. First-degree relatives (parents, siblings, children) were prioritized for inclusion in the study. If first-degree relatives were not available or were unaffected, second-degree relatives (grandparents, aunts/uncles, nieces/nephews) were considered. Third-degree relatives (cousins, great-grandparents) were only included in families where sufficient data from first and second-degree relatives was not available, in order to maintain the integrity of inheritance pattern analysis. Clinical examination was carried out in all cases, and cephalometric radiographs were obtained only for individuals who demonstrated clinical signs of mandibular prognathism to confirm skeletal discrepancies and support pedigree analysis. Asymptomatic relatives were not subjected to radiographic exposure. All imaging was performed using standardized digital cephalometric equipment with low-dose settings and appropriate shielding, in line with institutional radiological safety protocols and the ALARA (As Low As Reasonably Achievable) principle. Informed consent was obtained from all participants.

 A-point (A). B-point (B). Sella(S). Nasion (N). Orbitale (Or). Pogonion (Pog). Gnathion (Gn). Menton (Me).Anterior Nasal Spine (ANS).Posterior Nasal Spine (PNS). Gonion (Go). Articulare (Ar). Porion (Po). Sella-Nasion (S-N)-a line connecting S to N.

 Frankfort Horizontal (FH)-a line connecting Po to Or. Angles measured on each Cephalogram as given in Fig 2.

SNA angle: This angle shows the horizontal position of the maxilla in relation to the cranial base. >85° - protrusive or prognathic maxilla, <79° - deficient or retrognathic maxilla

SNB angle: This angle states the horizontal position of the mandible compared with the cranial base. >82° - prognathic mandible, <76° - retrognathic mandible. ANB: A point Nasion-B point. The ANB angle measures the relative position of the maxilla to mandible. A positive ANB angle shows that the maxilla is positioned anteriorly relative to the mandible (Class I or Class II malocclusion cases) while the negative ANB angle shows that the maxilla is positioned posteriorly relative to the mandible (Class III malocclusion cases).

 To identify the variability and degree of severity of MP based on -4.

STATISTICAL ANALYSIS

Data were compiled and analyzed using SPSS version 25.0. Descriptive statistics including mean, standard deviation, and frequency distributions were calculated for demographic and clinical variables. To assess the genetic contribution of mandibular prognathism, heritability (h²) was estimated using the following standard formula:

 h2=VG/VP

Where VG is Genetic variance and VP is for Phenotypic variance. The genetic variance was estimated based on familial correlations observed in first-degree relatives using pedigree analysis, and phenotypic variance was determined from the total sample. Inheritance patterns were evaluated through pedigree chart analysis to detect autosomal dominant trends with incomplete penetrance. The gender-wise distribution of affected individuals was tested using the Chi square test. A p-value of < 0.05 was considered statistically significant.

RESULTS

50 probands with extended family were taken from different areas and casts of Punjab (Fig 3, 4). The males were present in greater percentage in all the three categories i.e. probands, parents and children as mentioned in Table 1. Over all, the entire trend was more towards mild form of mandibular prognathism in the collected sample. Majority of the inheritance observed presented a trend of father to son mode of inheritance. Inheritance pattern from mother to son and mother to daughter was nearly equal which was about 23% (Fig 6). The first-degree relatives affected ratio was highest as compared to second and third degree. Among the first-degree relatives, the father and mother showed equal ratio. Third degree relatives were showing minimum number of affected individuals. A detailed analysis of degree of severity based on the gender showed that the greatest number of affected falls in mild form. But males were slightly more on the moderate side than the females. The calculated heritability of MP in the population of the present study was 0.806 (h²).

DISCUSSION

Mandibular prognathism (MP) serves as an ideal model for studying inherited facial traits due to its distinct clinical and skeletal features. Phenotypically, MP is marked by a concave facial profile, protrusive mandible, and a characteristic Class III molar and cuspid relationship. These features form the core diagnostic criteria and are reliably assessed through clinical examination and radiographic evaluation. Lateral cephalometry continues to be a valuable and non-invasive tool for identifying craniofacial anomalies and quantifying both skeletal and dental deviations, making it essential in both diagnosis and phenotypic classification.¹³

This study revealed that MP in the Pakistani population predominantly follows an autosomal dominant pattern of inheritance with incomplete penetrance, which mirrors findings from other regional and international studies. For example, Zhou et al. reported that approximately 89% of families affected by MP displayed an autosomal dominant inheritance pattern, underscoring the likelihood of a major gene effect in the expression of this trait.¹⁴ Similarly, Genno et al. demonstrated comparable inheritance patterns in Eastern Mediterranean families, reinforcing the universality of this genetic trend across diverse populations.¹⁵ These findings validate our own pedigree analyses, in which multiple generations exhibited the trait, albeit with variability in expression,a hallmark of incomplete penetrance.

The phenomenon of incomplete penetrance, observed in this study, is consistent with studies conducted by Milosevic et al. (2022) and Han (2021), who also reported notable intra-familial variability in MP expression.^10,16 Such variability suggests that while a dominant gene may be responsible for  the trait, its expression is likely influenced by additional genetic modifiers and possibly environmental interactions. This multifactorial nature complicates predictions of trait transmission but also opens avenues for investigating contributing epigenetic or developmental factors. An important observation in this study was the gender disparity, with males accounting for 58% of affected individuals compared to 42% females. This aligns with the theory that males have a lower genetic threshold for expressing MP, requiring fewer contributory alleles or modifiers for the phenotype to manifest.¹⁵ A similar trend was reported in a Japanese study, where males were found to be 1.5 times more likely to develop MP compared to females.¹⁷ This consistent gender-based difference in expression may hint at hormonal, developmental, or genetic factors that interact with the underlying inheritance mechanism.

In examining inheritance trends, we observed that father to-son transmission (44%) occurred more frequently than mother-to-offspring transmission (23%). This skewed pattern is noteworthy, especially in light of prior studies suggesting that paternal transmission may be more predictive of MP expression. Although this does not imply a Y-linked inheritance (as autosomal genes are involved), it does highlight potential differences in parental genetic contribution or expression penetrance across genders. The distribution of affected individuals across relatives further emphasizes the genetic basis of MP. In our data, first-degree relatives had the highest proportion of affected individuals (35%), followed by second-degree (13%) and third-degree relatives (4%). This gradient in prevalence reinforces the dominant inheritance model, as close genetic relationships predict a higher likelihood of trait manifestation.

Finally, the heritability estimate of 0.806 calculated in this study strongly supports a major genetic contribution to MP. This value is notably higher than heritability estimates reported in some earlier studies, which could be attributed to differences in sample size, population diversity, or environmental influence. The relatively controlled familial sample in our study may have minimized environmental variance, thus inflating the genetic estimate. Nonetheless, comparable trends have been reported by Sharath et al. and Genno et al., both of whom noted strong correlations between affected parents and their offspring, reinforcing the heritable nature of the condition.^15,18 An important consideration in this study is the ethical and methodological limitation associated with radiographic assessment. In line with ALARA principles, cephalometric radiographs were restricted to family members who exhibited clinical signs of mandibular prognathism, while asymptomatic relatives were excluded from imaging. This approach minimized unnecessary radiation exposure and adhered to institutional ethical standards.

 However, it may also have introduced a degree of selection bias, as subclinical carriers or individuals with mild skeletal discrepancies could have been missed. Consequently, the calculated prevalence and heritability values should be interpreted with this limitation in mind. Future research could address this issue by employing non-radiographic diagnostic alternatives, such as 3D facial scans, photographic morphometric analysis, or molecular genetic testing, to identify subclinical cases without exposing participants to additional radiation. Such approaches would not only strengthen the validity of heritability estimates but also enhance the ethical soundness of large-scale family-based investigations in craniofacial genetics.

CONCLUSION

The findings suggest that MP is a hereditary condition with an autosomal dominant inheritance pattern and incomplete penetrance. The phenotypic expression of MP in the Pakistani population predominantly falls within the mild range, with males being slightly more affected than females. Future studies should explore genome-wide associations to identify specific genes or loci responsible for MP in local populations.

CONFLICT OF INTEREST

None to declare

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