Multilocus Disease-Causing Genomic Variations for Genetic Disorders: Single Tertiary Centre Experience From Türkiye.

Abstract

Multilocus genomic variations (MGVs), defined as pathogenic variants in two or more independent loci, are increasingly recognised in individuals with complex clinical phenotypes, particularly in highly consanguineous populations. Recent advancements in technologies, including exome and whole-genome sequencing, have revolutionised the diagnostic landscape, facilitating the identification of MGVs. This retrospective study analysed the genetic data of 80 patients referred to our centre in Türkiye, each with at least two molecularly confirmed genetic diagnoses. Tests included standard karyotyping, chromosomal microarrays, targeted panels, and exome sequencing, with pathogenicity classified according to American College of Medical Genetics (ACMG) criteria. The cohort included diverse phenotypes, with a significant proportion arising from consanguineous unions (48.7%). Copy number variations were identified in 16% of cases, and 21% harboured variants in genes associated with actionable secondary findings. Patients exhibited distinct (82.5%) or overlapping (17.5%) phenotypes, supported by semantic similarity scores and protein-protein interaction analyses. This largest Turkish cohort on MGVs highlights the impact of consanguinity on rare disease genetics and underscores the value of comprehensive genomic testing. Accurate interpretation is vital for effective counselling and patient care.