Research Techniques Made Simple: Genome-Wide Homozygosity/Autozygosity Mapping Is a Powerful Tool for Identifying Candidate Genes in Autosomal Recessive Genetic Diseases

Abstract

Homozygosity mapping (HM), also known as autozygosity mapping, was originally used to map genes underlying homozygous autosomal recessive Mendelian diseases in patients from closely genetically related populations, followed by Sanger sequencing. With the increase in use of next-generation sequencing approaches, such as whole-exome sequencing and whole-genome sequencing, together with advanced bioinformatics filtering approaches, HM is again emerging as a powerful method for the identification of genes involved in disease etiology. In addition to its usefulness for research, HM is effective in clinical genetic services, increasing the efficiency of molecular diagnostics. For autosomal recessive Mendelian disorders with extensive genetic heterogeneity, HM can reduce both cost and turnaround time of mutation detection in the context of next-generation sequencing and can obviate expensive screening, such as biochemical testing in the setting of metabolic genodermatoses or antigen mapping for epidermolysis bullosa. It is therefore important for dermatology clinicians and researchers to understand the processes, principal uses, and advantages and limitations of HM when ordering or performing genetic tests for patients affected by heritable skin disorders.

Mutational spectrum of autosomal recessive limb-girdle muscular dystrophies in a cohort of 112 Iranian patients and reporting of a possible founder effect

“…The purpose of this method is to search for regions with homozygosity, which can vary from a few to several megabases in the patient's DNA. This way will be followed by identifying the region that carries a mutated gene involved in rare recessive traits [13]. Autozygosity Mapping is a powerful approach for gene tracking of autosomal recessive diseases in consanguineous families like Iran [14], and it can be the right choice for gene mapping in heterogeneous diseases such as LGMDs.…”

Autosomal recessive congenital ichthyosis: Genomic landscape and phenotypic spectrum in a cohort of 125 consanguineous families

“…The complexity of WES procedures may explain, at least in part, the observations that in a recent extensive study, only ∼25% of putative mutations in heritable diseases could be disclosed, the number being somewhat higher, ∼35%, in autosomal recessive disorders (Lee et al., ). Nevertheless, advanced genome‐wide tools, such as homozygosity mapping (HM) and whole transcriptome sequencing (RNA‐Seq), have been recently introduced for further identification and verification of pathogenicity of mutations (Cummings et al., ; Vahidnezhad, Youssefian, Saeidian, Mahmoudi, et al., ; Vahidnezhad, Youssefian, Saeidian, Touati, et al., ; Vahidnezhad, Youssefian, Jazayeri, & Uitto, ).…”

Phenotypic and genotypic characterization of families with complex intellectual disability identified pathogenic genetic variations in known and novel disease genes

“…Taking into consideration the complexity of the genetic architecture and the phenotypic heterogeneity of the NDDs 22 , we used a combination of HM and WGS approaches to establish the disease-causing genetic variations in the affected pedigrees. My group and others have repeatedly demonstrated how powerful the combination of these two techniques is in identifying disease-associated genetic variations and genes [23][24][25][26][27][28][29][30] . All families were found to carry pathogenic genetic variations in different disease genes, with six families having genetic variations (4 known and 2 novel) in known genes, while one family carried a pathogenic genetic variation in a novel gene ( Table 1).…”

“…The GenomeStudio program (GS; Illumina) was used to undertake quality assessments and generate PLINK input reports for HM 45 . Homozygous segments across all family members in each pedigree were determined as previously described, and only those shared by affected family members but not by healthy subjects were considered as disease-associated loci 24,27,29 . HM analyses were not carried out in Family ID-Fam04, in which direct WGS to identify the gene defects was performed in the only affected family member.…”