In addition to pathogenic CNVs and UPDs, approximately 3.5% of children with intellectual and/or developmental disabilities in our study populations showed greater than 68 Mb of ROH, suggesting presence of parental consanguinity. Post-testing surveys confirmed the 1st cousin relationships for all the cases with an estimated F 1/16 and presence of consanguinity in 4 out of 5 cases with an estimated F1/32 although the information from medical records was incomplete or inconsistent with the suggested mating type. In our practice, we report results suggesting presence of parental consanguinity but not specify the biological relationship of the parents as recommended by the ACMG guidelines , because SNP array analysis is not designed to be a paternity test or to assign a specific relationship between the parents of the proband patient. Also, the observed size of ROH may not precisely predict the true biological relationship due to variables such as recombination during meiosis, multiple loops of consanguinity or multiple generations of breeding within a relatively closed community. For the patients showing an estimated F ¼ or 1/8, we have included the percentage of homozygosity in our clinical report and stated that the result may suggest a first- or second-degree parental relationship or incestuous mating.
Incestuous parental relationships identified by SNP-based microarrays have been reported previously. One was a 3-year-old boy with multiple medical conditions showing 668 Mb of genomic homozygosity which was consistent with the patient being conceived as the product of a mating between first-degree relatives . In a report on a SNP data, ROH of greater than 20% of the genome were identified in two of 5000 samples analyzed in a cytogenetics laboratory in Australia . Our study has shown that a level of ROH greater than 20% correlates with an estimated coefficient of inbreeding F1/4 which is suggestive of a first degree relationship such as parent–child or brother-sister mating, as exemplified in case 001. However, an incestuous relationship, which represents a complicated social and legal issue, may not be readily identified during a doctor’s visit or genetic counseling, as shown in our post-testing survey. Genetic counseling for consanguinity can be complicated particularly when incestuous mating is uncovered by use of microarrays.
The frequency of consanguineous mating may vary significantly in different geographic regions or in different ethnic populations [12, 15–17]. Our study patients were referred from hospitals in South Florida (mainly Miami-Dade and Broward counties) and Brazil. Hispanic or Latino Americans account for 65% of the population in Miami-Dade and 25% of the population in Broward (2010 census data). The Hispanic or Latino Americans in Florida originate mainly from Cuba (32%) and Puerto Rico (28%) and Mexico (9%). It was estimated in 2008 that over one million of Brazilians live in USA and about 300,000 of them live in Florida. First cousin marriage is legal in Florida. The rate of consanguineous marriage in Miami-Dade and Broward counties is unknown but is likely to be higher than the generally estimated average (<1%) in USA. The rate of consanguineous mating in Brazil was estimated as 1.6% with a heterogeneous geographic distribution and half of the consanguineous marriages have a coefficient of inbreeding F 1/16 or higher . There was a consensus that consanguineous marriages are associated with an increased risk of congenital malformations and autosomal recessive disease . The estimated excess risks of morbidity and precocious mortality for the children with F1/4, 1/8, 1/16 and 1/32 are about 40%, 20%, 10%, 5%, respectively [9, 10]. A recent review suggests that the risk for congenital heart disease is increased in consanguineous marriages .
Different from previous clinical studies on the families with a history of consanguineous mating, we detected parental consanguinity in about 3.5% of children referred for developmental problems. Most of these children were referred for congenital anomalies or multiple malformations, developmental delay or intellectual disability, dysmorphic features, failure to thrive/growth retardation or short stature. The finding of parental consanguinity in these cases is highly suggestive of an underlying recessive cause. For example, following the array study, case 012 was diagnosed with Schimke immune-osseous dysplasia, an autosomal-recessive pleiotropic disorder caused by loss of function mutations in SMARCAL1 leading to spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency [20, 21]. A diagnosis of autosomal recessive spinal muscular atrophy has been suspected in case 009. In case 001, the 6 year-old girl initially referred for mental problems had a history of proximal renal tubular acidosis (RTA) at 18 months of age, basal ganglia and corneal calcifications secondary to RTA. Further diagnostic work-up has revealed increased excretion of Krebs cycle intermediate and a tentative diagnosis of 2-ketoglutarate dehydrogenase deficiency, a very rare metabolic disorder [22–24]. Involvement of multiple recessive mutant genes or a complex genetic mechanism is possible in some patients, particularly in the children as products of incestuous mating. Consanguinity may not be noted in many cases without microarray studies and identification of the biological relationship of the parents in such cases is clinically important for additional diagnostic testing. Further studies of phenotype and possible correlating metabolic deficiency, as well as sequencing of the ROH regions would determine the genetic mechanisms of the developmental problems in these children.