B-308 Multigenerational Consanguinity and Genomic Absence of Heterozygosity (AOH) Burden: A Case Report

Abstract

Among the various types of genomic variations described in the literature, absence of heterozygosity (AOH) events are among the most significant, affecting large regions of the genome. Commonly associated with clinical findings, particularly in carcinogenesis (where they are termed loss of heterozygosity, LOH), AOH regions may also contribute to the expression of autosomal recessive disorders and may indicate possible alterations in genomic imprinting. When multiple runs of homozygosity (ROH) are identified throughout the genome, these findings are generally interpreted as regions identical by descent (IBD). In this context, the aim of this study was to report a case of a third-degree consanguineous patient presenting a genomic AOH burden approaching that expected for first-degree consanguinity. A 12-year-old female patient diagnosed with autism spectrum disorder and intellectual disability, with a multigenerational family history of consanguinity, in which the parents are first cousins, as well as the maternal grandparents and maternal great-grandparents, was evaluated. The medical report described emotional dysregulation, impulsivity, aggressiveness, hyperactivity, and impairments in adaptive behavior and executive functioning, with difficulties in school adaptation and social interaction. Conventional karyotyping and molecular testing for Rett syndrome revealed no abnormalities. Comparative genomic hybridization microarray analysis (array-CGH) was requested and performed using the CytoScan™ 750K kit (Thermo Fisher Scientific) and Chromosome Analysis Suite software v4.4.0.63 (ChAS). Data analysis followed the guidelines of the American College of Medical Genetics and Genomics, using the GRCh37/hg19 reference genome. Only regions of homozygosity larger than 5 Mb and containing more than 50 probes were analyzed. Array-CGH analysis revealed regions of absence of heterozygosity (AOH) encompassing approximately 19.3% of the total genome, a pattern close to that expected for first-degree consanguinity (∼25%) and significantly higher than that expected for first-cousin unions (∼6.25%), according to the criteria established by Kearney et al. (2011). AOH and ROH are frequent genomic findings that affect large genomic regions, potentially influencing phenotypes, biological fitness, and pathological processes such as neoplastic progression. Although AOH regions may harbor homozygous recessive mutations, their isolated identification is not, per se, indicative of pathology and may represent a benign finding. The presence of multiple AOH regions throughout the genome is often interpreted as IBD, raising clinically relevant considerations, such as the possibility of recessive diseases and, in cases of excessive genomic homozygosity, reflecting underlying parental consanguinity. This finding reinforces the importance of detailed phenotypic evaluation and consideration of the multigenerational family context. The present case report highlights the influence of multigenerational consanguinity on increased constitutional homozygosity, with potential implications for the expression of autosomal recessive disorders and predisposition to neoplastic conditions. SNP-array analysis demonstrated a proportion of AOH comparable to that observed in individuals born from first-degree consanguinity, reinforcing the cumulative impact of inbreeding across generations. These findings emphasize the relevance of AOH burden quantification as a complementary tool in genomic assessment and genetic counseling, particularly in patients with complex, multigenerational consanguineous backgrounds.