Despite rising awareness, congenital heart disease (CHD) is still a major cause of significant morbidity and mortality. It is clinically defined as a group of structural malformations present at birth and characterized by abnormal development of the heart and may be induced by environmental influence, altered gene function, or stochastic factors ^[1][2][1,2]. It is the most frequently diagnosed congenital disease affecting about 0.8–1.2% of live births worldwide [3]. Incidence and mortality from CHD vary globally. In the recent years, patterns, prevalence, and risk factors for CHD among newborns in Saudi Arabia have been studied. Interestingly, Kurdi et al. found in a three-year cohort case-control study that the prevalence rate for CHD was as high as 14.8 per 1000 births [4]. A plausible explanation for this comparable rate is consanguineous mating (inbreeding), a prominent phenomenon of the Arab countries that is widely accepted and practiced, particularly among first cousins. From a genetic standpoint, inbreeding has significant genetic implications for the offspring of inbred populations as it renders the genomes of the offspring autozygous due to identical chromosomal segments inherited from both parents. It is known form previous research that children born to closely related parents are at higher risk, approximately 2.0–2.5 times, of congenital malformations than the offspring of unrelated parents [5]. First-cousin marriage has been found to aggravate the estimation of malformation risk to 5–8% [6]. In Saudi Arabia, epidemiological reports have estimated that first-cousin marriages among families of children with CHD (41.6%) were significantly higher than the general population (28.4%) [7]. Therefore, the incidence of autosomal recessive congenital anomalies is expected to be higher in such highly inbred populations. Moreover, it has been shown that consanguinity increases the frequency of homozygosity for autosomal dominant traits, such as familial hypercholesterolemia, and possibly increases the prevalence of complex multifactorial conditions such as CHD [8].

Owing to the fact that Saudi Arabia has one of the highest consanguinity rates among Arab countries (>50%) besides its high fertility rate, it represents fertile ground for exploring the relevance of consanguinity to basic human genetics and applied clinical genetics [9]. Tracing back the biparental inherited recessive mutations of the same ancestral haplotype on which they reside has provided one of the most potent tools in interrogating the role of consanguinity in autosomal recessive disorders. Alkuraya has discussed a combination of techniques for mapping novel recessive disease genes.

2. Consanguinity and CHD

The most detrimental consequences of consanguinity are frequent occurrences of autosomal recessive diseases in the offspring, leading to increased morbidity and mortality rates ^[10][11][13,14]. Encounters between people with two or more of these abnormal genes are frequently causing the presence of combination of pathogenic variant genes influencing the clinical presentation. Monies et al. reported the clinical exome sequencing (CES) on >2200 previously unpublished Saudi families as a first-tier test, highlighting 155 genes to be recessive, disease-related candidates in the Saudi population [9]. Autosomal-recessive variants account for 77.2% variants, 98.4% homozygous, and 41.3% founder variants [9]. The percentage of the genome rendered homozygous by consanguinity seems to be directly proportional to the degree of consanguinity ^[12][15]. In a population with a high consanguinity rate, the homozygous gene pool will inevitably include defective alleles. On the other hand, a similar mutation rate in consanguineous populations leads to increased allelic and even locus heterogeneity incidences. This is exemplified by Kamal et al. with a report of four novel mutations in the ALMS1 gene among Saudi patients with very rare autosomal recessive Alstrom disease presenting allelic heterogeneity in this inbred population ^[13][16]. Chehab et al. performed one of the largest cohort studies to date (>1500 patients) to assess the connection between consanguinity and CHD incidence. This cohort was represented by 19% of first-degree cousins, 5.9% of second-degree cousins, and 2.1% of other parental consanguinity. Comparatively, the consanguineous contributions in the control group without CHD were: 14% (first degree cousins), 5.9% (second degree cousins), and 3.6% (other parental consanguinity), showing a significant difference between the two groups. However, consanguinity rates vary greatly between different types of CHD. The highest incidences of atrial septum defect (ASD), tetralogy of Fallot (TOF), and valvular aortic stenosis (AS) were among the defects with consanguineous parents, supporting the theory that these defects may be caused by recessive genes ^[14][17]. The prevalence of consanguinity among patients with CHD is also evidenced in many other studies ^[7][15][16][7,18,19]. Monies et al. ^[15][18] have undertaken the most extensive study on the spectrum of mutational genetic diseases in the Saudi population in the diagnostic setting. The random selection of tested families representing all regions of the Kingdom aided the inference of essential patterns of genetic diseases in a highly consanguineous Saudi population relevant to the broader community of diagnostic NGS labs worldwide. The first 1013 Saudi families’ first report was tested with seven gene panels and whole-exome sequencing (WES). A breakdown of the diagnostic yield by indication shows marked variability, with the highest yield being multiple congenital malformations in the prenatal setting followed by skeletal dysplasia. The duo testing of couples with deceased children was associated with a high diagnostic yield, reaching 83% when novel candidate genes are counted. Autosomal recessive pathogenic and likely pathogenic mutations accounted for 71% cases and 97% homozygous cases, consistent with the high rate of consanguinity (78% of 482 families that provided the consanguinity information) in this cohort. Of the recessive positive cases, 33% were due to founder mutations ^[15][18]. This report has highlighted the role of consanguinity in identifying important patterns of genetic diseases in the Saudi population that are relevant to the international community. The study has also highlighted the need for in-depth research to understand the Saudi population’s gene pool using NGS technologies. Parental consanguinity has been well proven to play a significant role in the prevalence of congenital heart disease in the Saudi population ^[16][17][19,20]. A study on a group of 1028 consecutive CHD patients identified through the Congenital Heart Disease Registry at King Faisal Specialist Hospital in the central region of Saudi Arabia, Riyadh, indicated that the proportion of first-cousin mating among CHD patients is significantly higher than that of first-cousin intermarriages reported in the general population. This study suggested that first-cousin consanguinity was significantly associated with ventricular septal defect (VSD), ASD, atrioventricular septa l defect (AVSD), pulmonary stenosis (PS), and pulmonary atresia (PA). Therefore, in a population with a high degree of inbreeding, consanguinity may exacerbate underlying genetic risk factors with prevalence of recessive component as causation of some cardiac defects [7]. Most recent cross-sectional studies found the prevalence of CHD in SA ranging between 2.1 and 10.7 per 1000 persons with VSD ranging from 29.5 to 39.5% followed by ASD (8.9% to 18.1%) and PS (6% to 12.4%). It was also stated that CHD occurrence in Saudi Arabia was significantly associated with Down’s syndrome, consanguinity, and maternal diabetes ^[17][20]. Comprehensive data on cohort studies conducted over the span of 25 years to identify the prevalence of CHD in the Saudi population indicated the significance of consanguinity as a risk factor, as summarized in Table 1. Abbreviations: CHD, Congenital heart disease; VSD, ventricle septum defect; ASD, atrial septum defect; PS, pulmonary stenosis; PDA, patent ductus arteriosus; PA, pulmonary atresia; TOF, tetralogy of Fallot; AVSD, atrioventricular septum defect; COA, coarctation of the aorta; TA, tricuspid atresia; AS, aortic stenosis; TGA, transposition of the great arteritis; CA, congenital anomaly.3. The Genetic Landscape of Non-Syndromic CHD. Evidences of a genetic component in CHDs are familial recurrence and their association with inherited microdeletion syndromes [1]. Numerous CHD cases are known to be chromosomally abnormal, particularly those exhibiting syndromic characteristics such as multiple malformations of the organs, developmental delays, and growth abnormalities. Chromosomal aneuploidies are the first recognized genetic causes of CHD ^[30][33]. The condition affects nearly half of children born with trisomy 21 (one of 600) ^[31][34], 20–50% of babies born with Turner syndrome (one of 2500 female births) ^[32][35], and nearly all of those born with trisomy 13 and trisomy 18 ^[33][36].