Abstract
Multilocus disease-causing genomic variations (MGVs) and multiple genetic diagnoses (MGDs) are increasingly being recognised in individuals and families with Mendelian disorders. This can be mainly attributed to the widespread use of genomic tests for the evaluation of these disorders. We conducted a retrospective study of families evaluated over the last 6 years at our centre to identify families with MGVs and MGDs. MGVs were observed in fourteen families. We observed five different consequences: (i) individuals with MGVs presenting as blended phenotypes (ii) individuals with MGVs presenting with distinct phenotypes (iii) individuals with MGVs with age-dependent penetrance (iv) individuals with MGVs with one phenotype obscured by another more predominant phenotype (v) two distinct phenotypes in different individuals in families with MGVs. Consanguinity was present in eight (8/14, 57.1%) of them. Thirteen families had two Mendelian disorders and one had three Mendelian disorders. The risk of recurrence of one or more conditions in these families ranged from 25% to 75%. Our findings underline the importance of the role of a clinical geneticist in systematic phenotyping, challenges in genetic counselling and risk estimation in families with MGVs and MGDs, especially in highly inbred populations.
Highlights
Next-generation sequencing techniques (NGS) like whole-exome sequencing (WES) and whole-genome sequencing (WGS) have become affordable and accessible for the diagnosis of Mendelian disorders
We describe how the input of clinical information and systematic phenotyping aided in the dissection of phenotypes, challenges faced in genetic counselling and how multilocus disease-causing genomic variations (MGVs) re-defined the risk of recurrence in these families
The study highlights the impact of systematic phenotyping through inputs of medical geneticists on the analysis and recognition of MGVs in the genomic data
Summary
Next-generation sequencing techniques (NGS) like whole-exome sequencing (WES) and whole-genome sequencing (WGS) have become affordable and accessible for the diagnosis of Mendelian disorders. The unbiased approach of these techniques has led to significant insights into novel and complex diseasecausing molecular mechanisms. Molecular and bioinformatics knowledge have become a necessity for contemporary geneticists in order to aid comprehensive elucidation of the phenotypes and their underlying genetic mechanisms [1, 2]. Though the analysis and prioritisation of variants in broadspectrum tests especially WES is challenging, it provides a unique opportunity to decipher the underlying cause of complex genetic disorders. The use of WES has led to the identification of multilocus disease-causing genomic variations (MGVs) in individuals with multiple genetic diagnoses (MGDs) i.e., more than one genetic diagnosis due to genomic variations at more than one genetic loci, segregating independently [3, 4]. We describe how the input of clinical information and systematic phenotyping aided in the dissection of phenotypes, challenges faced in genetic counselling and how MGVs re-defined the risk of recurrence in these families
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