Laterality and Sidedness in Orofacial Clefts: Definitions and a Framework for Future Research

Introduction

Directional asymmetry in unilateral cleft lip with or without cleft palate (UCL ± P) has been consistently reported across populations yet has largely been treated as a descriptive epidemiological feature rather than examined as a potentially informative aspect of craniofacial development. ¹ In developmental biology, some anatomical structures are arranged asymmetrically; by contrast, the human face develops relatively symmetrically from 5 facial prominences. ² Left-right patterning during embryogenesis is driven by a complex cascade of molecular pathways, and persistent nonstochastic asymmetry therefore typically prompts consideration of underlying morphogenetic processes.^3–7

Such asymmetry is unlikely to represent random developmental variation alone. Alternatively, it may reflect differing susceptibility to environmental factors or gene interactions within the pathways governing craniofacial morphogenesis, and as such may be informative about how the craniofacial field is developmentally organized.

Recent interest in cleft laterality has emerged across multiple disciplines; however, findings have been heterogeneous and at times appear conflicting.^8,9 Moreover, the terms sidedness and laterality are frequently used interchangeably within the literature, often without distinction between anatomical description and biological interpretation.

Discussion of cleft laterality was recently revisited at the 15th International Congress on Cleft Lip/Palate and Related Craniofacial Anomalies in Kyoto, Japan, prompting this position paper. Our aim is not to determine whether cleft laterality carries etiological or clinical significance, but to clarify definitions, identify recurring methodological challenges, and propose a reporting framework to support future investigations that are methodologically transparent and capable of cumulative interpretation.

Definitions

The notation UCL ± P is used throughout in preference to UCL/P to avoid ambiguity. Unlike UCL/P, in which the forward slash leaves it unclear whether palatal involvement is present or absent, UCL ± P explicitly denotes a phenotypic spectrum in which the palate may or may not be involved. This distinction is consistent with the paper's broader aim of precision in terminology.

Within the cleft literature, the terms sidedness and laterality have been used interchangeably, despite referring to distinct concepts. We propose to assign each term to a specific meaning to reduce ambiguity.

Side (anatomical location): the location of a cleft relative to the midline, described from the patient's perspective. This is individual-level and purely spatial (eg, “The cleft is on the patient's left side”).

Sidedness (distribution of side involvement): the anatomical descriptor of which side a cleft occurs on at the group or population level. At the population level it captures directional patterns (eg, “There is a predominance of left-sidedness in unilateral cleft lip.”).

Laterality (embryological process of left-right patterning): the process that gives rise to the designation of sidedness in UCL ± P, and may also underlie downstream morphological, developmental, and functional differences observed between left- and right-sided clefts (eg, “Genetic and environmental factors influencing cleft laterality are being investigated.”).

Subphenotyping

Importantly, the impact of cleft side may not be uniform across UCL ± P subphenotypes. Analyses that group cleft lip only, cleft lip with alveolus, and cleft lip with palate into a single unilateral cleft category assume phenotypic equivalence across developmental expressions that differ in tissue deficiency, palatal involvement, and associated anomalies.

Evidence that additional congenital anomalies are more prevalent in right-sided compared to left-sided clefts has been demonstrated within unilateral cleft lip and palate (UCLP), but not consistently across UCL ± alveolus (UCL ± A), suggesting that sidedness-related differences may be subphenotype-specific. ¹⁰ Subphenotyping, where feasible, may help distinguish true developmental variation which may not be apparent when biologically distinct cleft phenotypes are analyzed together.

Congenital Anomalies and the Definition of Syndromic Clefting

In studies examining cleft sidedness, patients born with syndromic clefts are frequently excluded in an effort to examine outcomes within a more defined population. However, the criteria by which syndromic status is determined are often poorly specified within published reports. ¹¹

Historically, syndromic clefts were defined by a recognizable pattern of anomalies consistent with a named genetic condition. In contemporary registries, however, syndromic classification is recorded by a variety of healthcare professionals rather than formal genetic assessment and may reflect the assumption that additional congenital anomalies alone constitute a syndromic designation. Exclusion on this basis may remove individuals whose clefts are not truly syndromic, introducing variability across centers.

The presence of additional congenital anomalies represents a separate but related consideration. Across multiple independent cohorts, additional congenital anomalies have been consistently reported to be more prevalent in right-sided compared to left-sided UCLP.^10,12,13 Given this, exclusion on the basis of congenital anomalies is not an analytically neutral decision but may systematically alter cohort composition in a side-specific manner, and thereby influence observed associations between sidedness and downstream outcomes.

This is illustrated by analyses of neurodevelopmental outcomes, where associations between cleft side and academic performance have been shown to differ depending on whether patients with additional anomalies are included or excluded. In studies from the same research group, one analysis excluding such patients reported poorer academic outcomes in left-sided clefts, but a subsequent analysis including all affected individuals reported the opposite.^13,14 The authors attributed this reversal in part to the differential exclusion of patients with additional anomalies.

Future studies examining the clinical implications of cleft sidedness should clearly define the criteria used for syndromic classification and specify whether cases with additional congenital anomalies were included or excluded. Such transparency may assist in clarifying whether differences or null findings observed between left- and right-sided clefts reflect underlying developmental variation or the influence of cohort selection.

Weight of Evidence in Laterality Research

Interpretation of associations between cleft sidedness and clinical outcomes is further complicated by heterogeneity in study design. Contradictory results may reflect bias, confounding, and selection effects rather than true differences in outcomes between left- and right-sided clefts.

The potential for bias is illustrated across multiple outcome measures, including dentoalveolar development. In studies examining dental anomalies, smaller case series have frequently reported increased prevalence of anomalies on the cleft side in unilateral clefts.^15–17 Separately, larger cohort analyses have identified side-specific patterns of dental development according to cleft sidedness. In a Brazilian case-control study including 250 individuals with unilateral cleft lip and palate, a higher prevalence of bilateral dental agenesis in individuals with right-sided unilateral clefts was reported, ¹⁸ a finding supported by subsequent studies reporting greater contralateral incisor agenesis in right UCL ± P.^19,20

These findings demonstrate that observed associations between cleft sidedness and downstream outcomes may be sensitive to sample size and analytic methodology. Future comparisons should therefore consider the influence of study size and statistical approach when interpreting laterality-related conclusions and clearly report analytic strategies to facilitate comparison across studies.

Genetic Considerations in Cleft Laterality

Left-right patterning during embryogenesis is governed by conserved genetic pathways that establish asymmetric signaling across the embryonic axis prior to organogenesis. Craniofacial morphogenesis is likewise regulated through coordinated genetic programs controlling neural crest migration, tissue growth, and fusion of the facial processes. In this context, the consistent predominance of left-sided clefts raises a fundamental developmental question: why does directional asymmetry in UCL ± P occur consistently in favor of the left side, rather than reflecting the random failure of an apparent symmetric developmental process?

It should be acknowledged that deformational or disruptive mechanisms may also contribute to clefting in some contexts, including potential spatial interactions between the developing face and heart during early embryogenesis, which may partly account for the association between orofacial clefts and congenital cardiac anomalies.

Emerging genetic evidence suggests that left- and right-sided clefts may have partially distinct genetic architectures. Variants in genes involved in craniofacial morphogenesis, including TP63 and NTN1, have demonstrated side-specific associations with cleft lip in Han Chinese populations, while FAT4, which is involved in left-right differentiation, has been identified as a potential modifier of orofacial cleft laterality.^21–24 Although the implications of these findings remain uncertain, and replication in larger and more diverse cohorts is needed, they raise the possibility that cleft sidedness reflects genetic variation within biological pathways governing craniofacial morphogenesis.

The observation that right-sided UCLP tends to demonstrate greater morphological severity and higher rates of associated congenital anomalies is consistent with a multifactorial model of inheritance, in which right-sided clefts require a higher threshold of combined genetic and environmental influence to manifest.^9,10,25,26 If sidedness reflects differential susceptibility during craniofacial morphogenesis, systematic comparison of left- and right-sided clefts may provide insight into the genetically regulated mechanisms that contribute to directional asymmetry in UCL ± P.

Sex as a Confounder

Cleft subtypes are known to demonstrate sex-specific distribution, with UCL ± P occurring more frequently in males than females. ²⁷ However, sex is not consistently accounted for in studies examining associations between cleft side and downstream clinical outcomes.

Given the recognized influence of sex on craniofacial growth, cleft subtype, dental development, and neurodevelopmental trajectories, observed associations between cleft laterality and outcome may be modified by sex. Future investigations should therefore report sex distribution within study populations and, where feasible, consider whether stratified analyses are warranted to evaluate whether associations between cleft side and outcome differ between males and females.

Recommendations for Future Research and Reporting

We recommend that future studies:

Clearly distinguish between anatomical side, population-level sidedness, and embryologic laterality.