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

Area of Science:

• Genetics
• Genomic Medicine
• Rare Diseases

Background:

• Multilocus genomic variations (MGVs), defined as pathogenic variants in two or more independent loci, are increasingly recognized in complex clinical phenotypes.
• Consanguineous populations exhibit a higher prevalence of MGVs, complicating genetic diagnosis.
• Advancements in next-generation sequencing technologies have improved the identification of MGVs.

Purpose of the Study:

• To analyze the genetic data of 80 patients with at least two molecularly confirmed genetic diagnoses in Türkiye.
• To investigate the role of consanguinity in the occurrence of MGVs.
• To evaluate the utility of comprehensive genomic testing in diagnosing complex phenotypes.

Main Methods:

• Retrospective analysis of genetic data from 80 patients.
• Utilized standard karyotyping, chromosomal microarrays, targeted panels, and exome sequencing.
• Classified variant pathogenicity using American College of Medical Genetics (ACMG) criteria.

Main Results:

• 48.7% of the cohort originated from consanguineous unions.
• Copy number variations were found in 16% of cases.
• 21% of patients had variants linked to actionable secondary findings.

Conclusions:

• This study represents the largest Turkish cohort investigating MGVs.
• Consanguinity significantly impacts rare disease genetics in this population.
• Comprehensive genomic testing is essential for accurate diagnosis, genetic counseling, and patient management.