2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-The Occurrence of Noncoding Variants, Copy Number Variants and Variants in Difficult-to-Sequence Genes in Over 10,000 Whole Exome Sequencing Tests

Pdf Summary

This study analyzed over 10,000 whole exome sequencing tests to assess the occurrence of noncoding variants, copy number variants (CNVs), mosaic variants, and variants in technically challenging genes. The results showed that WES assays optimized for the detection of these variants have clinical utility across different age groups. The positive rate was higher when testing included family members compared to testing only the proband. This is because including family members allowed for easier identification of de novo variants and the ability to phase variants in autosomal recessive genes. Patients tested between 0 to 2 years had the highest positive rate, indicating a higher likelihood of a genetic etiology for their symptoms. However, even older adults had a positive rate, demonstrating the clinical utility of WES throughout the lifespan.<br /><br />Positive results included variants in over 1,000 genes, with a third of these genes reported only once, highlighting the value of WES when the differential diagnosis is broad. The study also found that WES assays optimized to detect technically challenging variants may not completely overcome the limitations of short read next-generation sequencing (NGS). Nonetheless, more than 1 in 20 patients who received a positive result had a diagnostic noncoding variant, small CNV, mosaic variant, or variant in a technically challenging gene, confirming the value of using such assays.<br /><br />The study reported the specific genes that accounted for a significant proportion of positive results, including ANKRD11, MECPS, PTPN11, ARID1B, TTN, SCN1A, KMT2A, PRRT2, PTEN, and FLG. The occurrence of these variants was further analyzed, with variants in noncoding regions responsible for 1.1% of positive results, CNVs contributing to 15.3% (including small CNVs <1,000 bp in size), variants in genes with sequence homology accounting for 12.4% of positive results, and variants in technically challenging genes responsible for 2% of positive results. Additionally, mosaic variants were reported in 1% of positive results.<br /><br />Overall, this study highlights the positive rate and diagnostic utility of WES assays in detecting various types of variants, including those in noncoding regions, CNVs, mosaic variants, and technically challenging genes.

Asset Subtitle

Presenting Author - Kim Gall, MSc; Co-Author - Julie Hathaway, MSc., CGC, CCGC; Co-Author - Victoria Howell, MS, CGC; Co-Author - Alicia Scocchia, MS, CGC; Co-Author - Allison Sluyters, MSc, CGC, CCGC; Co-Author - Inka Saarinen, MSc.; Co-Author - Tiia Kangas-Kontio, PhD; Co-Author - Milja Kaare, PhD; Co-Author - Kirsty Wells, PhD; Co-Author - Maria Calvo del Castillo, PhD; Co-Author - Mikko Muona, PhD; Co-Author - Tuuli Pietila, PhD; Co-Author - Matias Rantanen, MSc.; Co-Author - Massimiliano Gentile, PhD; Co-Author - Pertelli Salmenpera, PhD; Co-Author - Jussi Paananen, PhD; Co-Author - Samuel Myllykangas, PhD; Co-Author - Juha W. Koskenvuo, MD, PhD;

Meta Tag

Exome sequencing

Genetic Testing

NextGen Sequencing

Sequencing

Co-Author Julie Hathaway, MSc., CGC, CCGC

Co-Author Victoria Howell, MS, CGC

Co-Author Alicia Scocchia, MS, CGC

Co-Author Allison Sluyters, MSc, CGC, CCGC

Co-Author Inka Saarinen, MSc.

Co-Author Tiia Kangas-Kontio, PhD

Co-Author Milja Kaare, PhD

Co-Author Kirsty Wells, PhD

Co-Author Maria Calvo del Castillo, PhD

Co-Author Mikko Muona, PhD

Co-Author Tuuli Pietila, PhD

Co-Author Matias Rantanen, MSc.

Co-Author Massimiliano Gentile, PhD

Co-Author Pertelli Salmenpera, PhD

Co-Author Jussi Paananen, PhD

Co-Author Samuel Myllykangas, PhD

Co-Author Juha W. Koskenvuo, MD, PhD

Presenting Author Kim Gall, MSc

Keywords

whole exome sequencing

noncoding variants

copy number variants

mosaic variants

technically challenging genes

positive rate

differential diagnosis

short read next-generation sequencing

diagnostic noncoding variant

specific genes