Copy number variants calling from WES data through eXome hidden Markov model (XHMM) identifies additional 2.5% pathogenic genomic imbalances smaller than 30 kb undetected by array‐CGH

Abstract

It has been estimated that Copy Number Variants (CNVs) account for 10%–20% of patients affected by Developmental Disorder (DD)/Intellectual Disability (ID). Although array comparative genomic hybridization (array‐CGH) represents the gold‐standard for the detection of genomic imbalances, common Agilent array‐CGH 4 × 180 kb arrays fail to detect CNVs smaller than 30 kb. Whole Exome sequencing (WES) is becoming the reference application for the detection of gene variants and makes it possible also to infer genomic imbalances at single exon resolution. However, the contribution of small CNVs in DD/ID is still underinvestigated. We made use of the eXome Hidden Markov Model (XHMM) software, a tool utilized by the ExAC consortium, to detect CNVs from whole exome sequencing data, in a cohort of 200 unsolved DD/DI patients after array‐CGH and WES‐based single nucleotide/indel variant analyses. In five out of 200 patients (2.5%), we identified pathogenic CNV(s) smaller than 30 kb, ranging from one to six exons. They included two heterozygous deletions in TCF4 and STXBP1 and three homozygous deletions in PPT1, CLCN2, and PIGN. After reverse phenotyping, all variants were reported as causative. This study shows the interest in applying sequencing‐based CNV detection, from available WES data, to reduce the diagnostic odyssey of additional patients unsolved DD/DI patients and compare the CNV‐detection yield of Agilent array‐CGH 4 × 180kb versus whole exome sequencing.

Germline CNV Detection through Whole-Exome Sequencing (WES) Data Analysis Enhances Resolution of Rare Genetic Diseases

“…In terms of diagnoses restricted to ExomeDepth findings, this reached 8.8% (40/454 of patients), with CNVs being most commonly detected in neurodevelopmental disorders, metabolic abnormalities, and neuromuscular disorders (Table 1). Around 10-20% of the intellectual development disorders are attributed to CNVs, so far traditionally detected by array-CGH [34][35][36][37]. However, recognition of small (<30 Kb) CNVs depends on the resolution of each platform and may be missed, indicating that ancillary analysis of WES data for the detection of both known and novel SNVs and CNVs may be appropriate when investigating patients with neurodevelopmental disorders.…”

A novel 268 kb deletion combined with a splicing variant in IL7R causes of severe combined immunodeficiency in a Chinese family: a case report

“…Currently, the combination of pathogenic variant screening and CNV calling has been increasingly used in WES, which largely improves the detection efficiency for the diagnosis of inherited diseases [ 30 , 31 ]. Recent technological advances have enabled CNV calling from WES data using accurate and highly sensitive bioinformatics tools [ 32 , 33 ]. Here, we identified a novel 268 kb deletion in the IL7R gene combined with a splicing variant, (c.221 + 1G > A), as the cause of the SCID phenotype in a female patient.…”

Identification of the first homozygous intragenic deletion in the YY1AP1 gene in a consanguineous family: New insights into the phenotypic variability associated with Grange syndrome

“…CNVs were detected using XHMM (Fromer et al, 2012), which uses principal component analysis (PCA) normalization and a hidden Markov model to genotype CNVs from normalized read-depth information, as previously described (Tisserant et al, 2022).…”