Beyond assumptions: Revisiting the link between consanguinity and pediatric neurodevelopmental disorders

Abstract

Parental consanguinity is associated with an increased risk of autosomal recessive disorders, some of which may present neurological and developmental impairment. In this issue, a retrospective cohort study from Jazan, Saudi Arabia, by Alhamoud et al, published in the World Journal of Clinical Pediatrics”, evaluated the relationship between consanguinity and neurodevelopmental outcomes in pediatric patients and found no statistically significant association despite minor differences in clinical patterns. This finding highlights the challenges of detecting genetic effects within heterogeneous clinical populations, particularly when neurodevelopmental conditions include both monogenic and multifactorial etiologies. This editorial contextualizes these results within current genetic and epidemiological understanding, emphasizing that cohort-level findings may not fully capture underlying biological risk. It also outlines key clinical and public health considerations, including targeted developmental screening and culturally appropriate genetic counseling, and underscores the need for well-designed prospective studies incorporating genomic data and precise phenotyping.

Key Words: Consanguinity; Neurodevelopmental disorders; Epilepsy; Genetic counseling; Autosomal recessive diseases; Pediatric neurology; Gene-environment interaction; Saudi Arabia; Middle East

Core Tip: This editorial interprets a recent cohort study reporting no clear association between consanguinity and neurodevelopmental disorders by highlighting the distinction between monogenic and multifactorial conditions and the impact of cohort heterogeneity on the detectability of risk. It emphasizes the importance of risk-stratified clinical approaches, including early developmental screening and culturally sensitive genetic counseling, and calls for prospective, genomically informed research to clarify disease-specific associations.

This editorial refers to "Association between consanguinity and neurological and developmental disorders in pediatric patients: A retrospective cohort study in Jazan, Saudi Arabia" by Alhamoud et al, 2026; https://doi.org/10.5409/wjcp.118721

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INTRODUCTION

Consanguineous marriage remains a common social practice across many parts of the Middle East, including Saudi Arabia, where it continues to shape population genetics and disease patterns[1]. From a biological perspective, consanguinity increases genomic homozygosity, thereby elevating the probability of expression of autosomal recessive variants implicated in a wide spectrum of pediatric disorders, including neurological and neurodevelopmental conditions[2]. This genetic architecture has long been associated with an increased burden of autosomal recessive disorders, many of which present with neurological manifestations such as epilepsy, global developmental delay, and intellectual disability[3] (Figure 1), which illustrates the mechanistic pathway linking consanguinity to neurodevelopmental outcomes. Clinical studies examining the relationship between consanguinity and neurodevelopmental outcomes, however, have yielded variable findings, reflecting differences in study design, population structure, and outcome definitions[4,5]. Against this backdrop, the current study from Jazan, Saudi Arabia, seeks to re-examine this association in a real-world pediatric cohort[6]. This editorial aims to contextualize these findings within established genetic and epidemiological frameworks, emphasizing how cohort characteristics may influence the detectability of associations.

Figure 1 Basic genetic pathway linking consanguinity to neurodevelopmental risk. This figure illustrates the fundamental mechanism by which consanguinity increases genomic autozygosity, thereby increasing the probability of autosomal recessive disease expression. A subset of these disorders manifests with neurological and neurodevelopmental impairment.

The retrospective cohort study from Jazan, Saudi Arabia, published in the World Journal of Clinical Pediatrics by Alhamoud et al[6], evaluated the relationship between parental consanguinity and a broad spectrum of neurological and developmental disorders in children, including both potentially monogenic and multifactorial phenotypes. Although modest differences in epilepsy subtypes and developmental conditions were observed between consanguineous and non-consanguineous groups, no statistically significant association was identified. As a real-world clinical cohort from a high-consanguinity region, the study provides useful context for examining how cohort characteristics may influence the detectability of associations.

To interpret these findings, it is important to distinguish between the observed results of this cohort and their broader biological and epidemiological context. A key consideration is the distinction between monogenic autosomal recessive disorders, which are directly influenced by consanguinity, and complex or polygenic neurodevelopmental conditions, in which genetic risk is distributed across multiple variants and environmental factors. However, many neurodevelopmental disorders-such as autism spectrum disorder and certain forms of developmental delay-are complex and polygenic, arising from interactions between multiple genetic variants and environmental factors, which may attenuate any direct or uniform association with consanguinity[1,7,8]. In addition, pediatric neurological presentations, including epilepsy, may arise from non-genetic mechanisms such as immune-mediated or acquired factors, further contributing to clinical heterogeneity and influencing observed associations[9]. Consanguinity increases genomic autozygosity. This, in turn, elevates the burden of autosomal recessive disorders, with neurodevelopmental outcomes varying according to gene penetrance, involvement of critical developmental pathways, and environmental modifiers[10].

Within this framework, the absence of a clear association in the present cohort can be understood in light of several methodological considerations. The study population comprises a heterogeneous group of neurodevelopmental phenotypesspanning both monogenic and multifactorial conditions, which may dilute condition-specific genetic signals. In addition, factors such as limited sample size, lack of genetic confirmation, absence of stratification by degree of consanguinity, and potential residual confounding may reduce the ability to detect modest or condition-specific associations. Taken together, these considerations suggest that the findings reflect limitations in detectability within a heterogeneous retrospective cohort. This distinction between monogenic and multifactorial neurodevelopmental disorders remains central to interpreting epidemiological findings in consanguineous populations (Figure 2).

Figure 2 Conceptual model explaining variability in neurodevelopmental outcomes associated with consanguinity. This figure expands on the basic genetic pathway by incorporating modifying factors, including gene penetrance, involvement of specific developmental pathways, degree of consanguinity, and environmental influences. It illustrates how these factors contribute to heterogeneous clinical outcomes and may affect the detectability of associations in clinical studies.

ROLE OF DEGREE OF CONSANGUINITY IN RISK STRATIFICATION

The degree of biological relatedness between parents is a key determinant of genetic risk and should be considered as a graded rather than binary exposure. Closer consanguineous unions are associated with higher genomic autozygosity, increasing the probability of inheriting identical pathogenic variants. This gradient is reflected in the coefficient of inbreeding, which is higher in first-cousin unions than in more distant relationships[1,11]. Consistent with this pattern, the risk of congenital anomalies shows a modest increase, from approximately 2%-3% in the general population to around 4%-6% in first-cousin offspring, while the effect is more pronounced for autosomal recessive disorders. In contrast, associations with neurodevelopmental disorders are less consistent, reflecting their heterogeneous and often multifactorial genetic architecture[12,13]. Failure to account for variation in the degree of consanguinity may obscure dose-response relationships and reduce the ability to detect associations in heterogeneous cohorts. Accordingly, treating consanguinity as a graded exposure is important for accurate epidemiological interpretation[14].

STRENGTHS AND LIMITATIONS OF THE STUDY

This study has several notable strengths, including its grounding in a real-world clinical cohort and its focus on Jazan, a region with a high prevalence of consanguinity, which provides valuable context-specific data from an understudied population. These features enhance the practical relevance of the findings and contribute to regional insight into the relationship between consanguinity and neurodevelopmental disorders. However, several limitations should be considered. The retrospective, single-center, hospital-based design introduces risks of selection, information, and referral bias and may limit generalizability. The inclusion of a broad range of neurological and developmental conditions results in substantial phenotypic heterogeneity, potentially diluting condition-specific associations. In addition, the lack of stratification by degree of consanguinity limits the assessment of potential dose-response relationships, while possible misclassification of exposures and outcomes may affect precision. The relatively small sample size and lack of longitudinal follow-up further limit the ability to detect modest associations and to evaluate developmental trajectories. Finally, the absence of genetic or molecular data limits the identification of underlying monogenic etiologies and precludes more precise differentiation between autosomal recessive disorders and complex, multifactorial neurodevelopmental conditions.

CLINICAL AND PUBLIC HEALTH IMPLICATIONS

The findings of this study should be interpreted within the established understanding that consanguinity primarily increases the risk of autosomal recessive Mendelian disorders, a subset of which may present with neurodevelopmental impairment, rather than uniformly elevating risk across all neurodevelopmental conditions. Accordingly, clinical practice should adopt a risk-stratified approach that considers the degree of consanguinity, relevant family history, and the child’s clinical phenotype. Early developmental screening remains essential in high-consanguinity settings, with priority given to children from closer consanguineous marriages, such as first cousins, those with a positive family history of inherited disorders, or those exhibiting early developmental or neurological concerns, to enable timely diagnosis and intervention. Targeted surveillance strategies should focus on individuals with a higher pre-existing genetic risk, even when cohort-level associations appear inconclusive. Integrating genetic counseling into routine care ensures accurate, personalized risk communication about autosomal recessive inheritance while respecting cultural values and avoiding stigma, thereby supporting informed reproductive decision-making without undermining sociocultural norms[15]. From a public health perspective, embedding genetic services and developmental screening within primary healthcare systems can enhance access to genetic services and the early detection of genetic conditions. Educational initiatives should promote risk differentiation, emphasizing that increased risk varies with genetic relatedness and family context rather than applying uniformly to all consanguineous families, thereby avoiding misinterpretation or unnecessary alarm[16]. Collectively, these measures support a targeted, evidence-based, and culturally appropriate framework for addressing neurodevelopmental health in populations with high rates of consanguinity.

FUTURE RESEARCH DIRECTIONS

Future research should prioritize well-designed, prospective multicenter studies to improve representativeness and reduce selection bias. Integration of genomic approaches, including whole-exome or whole-genome sequencing, will be essential for identifying underlying monogenic etiologies and clarifying the contribution of recessive variants. Standardized and precise phenotyping is equally important for reducing diagnostic heterogeneity and enabling condition-specific analyses[17]. Stratification by degree of consanguinity should be incorporated to assess potential dose–response relationships, while longitudinal follow-up is needed to evaluate neurodevelopmental trajectories and long-term outcomes. Further investigation of gene–environment interactions may also enhance understanding of how genetic susceptibility and environmental exposures jointly influence neurodevelopmental risk[18].

Key messages

Consanguinity increases the risk of autosomal recessive (monogenic) disorders, which may secondarily contribute to neurodevelopmental impairment, while its association with complex neurodevelopmental disorders remains variable and less direct.

Jazan’s study found no clear association, highlighting the complexity and heterogeneity of neurodevelopmental conditions rather than disproving risk.

Early developmental screening and targeted surveillance are essential in high-consanguinity populations to enable timely intervention.

Culturally sensitive genetic counseling and public health strategies are critical to address risk while respecting sociocultural contexts.

Clinical takeaway sentence: Routine developmental screening and culturally sensitive genetic counseling should remain standard practice in high-consanguinity populations, regardless of inconclusive cohort-level associations.

CONCLUSION

In conclusion, the findings from this cohort should be interpreted with caution, as the absence of a detectable association in a heterogeneous retrospective population does not rule out underlying genetic risk. Instead, it highlights the importance of considering disease-specific genetic architecture, particularly the distinction between monogenic autosomal recessive disorders and multifactorial neurodevelopmental conditions. In high-consanguinity settings, clinical practice should prioritize precise phenotyping, appropriate genomic evaluation when indicated, and early developmental screening to enable timely identification of at-risk children. These efforts should be complemented by culturally sensitive, non-stigmatizing genetic counseling that supports informed decision-making. Such an approach may improve early identification of high-risk children while supporting responsible interpretation of cohort-level findings in high-consanguinity populations.