Whole Exome Sequencing in 16p13.11 Microdeletion Patients Reveals New Variants Through Deductive and Systems Medicine Approaches

Abstract

The 16p13.11 microdeletion, whose prevalence in the general population is about 0.04%, is known in literature as a predisposition factor to neurodevelopmental disorders, being found in about 0.13% of patients with schizophrenia, in 0.5–0.6% of patient with epilepsy, cognitive impairment, autism spectrum disorder (ASD) and aggressiveness. The goal of this study was to identify a specific gene set pattern unique for the affected patients in comparison with other familial components. Due to the incomplete penetrance of this copy number variant (CNV), we studied by whole exome sequencing (WES), with particular regard of 850 SFARI genes, three families with an affected member carrier of inherited 16p13.11 and 16p13.11p12.3 microdeletion and one family with an affected member with a de novo 16p13.11 microdeletion. By combining a deductive approach together with personalized network models, we identified gene signatures potentially capable of explaining the clinical phenotype. Candidate variants in genes of interest were identified as possibly involved in determining the neurological phenotype of the four patients, such as compound heterozygosity in CECR2, variants in MTOR and RICTOR genes, compound heterozygous single nucleotide variants in the LRRK2 gene. Moreover, genes present in the microdeletion region were partially present as central nodes, with a focus on NDE1. No additional pathogenetic or uncertain CNVs were found in all four patients. No significant variants were detected in genes included in the microdeletion in patients 1, 2 and 3, excluding the finding of unmasked recessive variants. In conclusion, WES is a fundamental tool in the genetic investigation of patients having a predisposing variant, which is not sufficient to define the clinical phenotype. Moreover, the analysis of WES data using Systems medicine tools, such as personalized network models, led to the prioritization of genes on a high throughput scale and to discover variants in genes that were not prioritized at first.

A de novo PAK1 likely pathogenic variant and a de novo terminal 1q microdeletion in a Chinese girl with global developmental delay, severe intellectual disability, and seizures

“…In the clinical practice, CMA technology manifests a great advantage in copy number variants (CNVs) detection, as well as uniparental diploid and triploid, and it has been recommended as a first-line detection tool in etiological diagnosis of patients with multiple congenital anomalies [ 26 , 27 ]. In addition, WES technology has been recommended as a fundamental tool to investigate additional sequence variants in patient with normal CMA result or unexplained CNVs [ 28 , 29 ]. In the present study, we present a Chinese pediatric patient with global developmental delay, speech delay, severe intellectual disability, and seizures and had a de novo PAK1 gene variant associated with a de novo terminal 1q44 microdeletion, without covering the reported three distinct SRO in 1q43q44 microdeletion region.…”

Severe Unilateral Microtia with Aural Atresia, Hair White Patch, Stereotypes in a Young Boy with De novo 16p13.11 Deletion: Reasons for a New Genotype–Phenotype Correlation

“…According to recent findings, however, some genes are suspected to be involved in the disease process. 26 27 28 Microtia often leads to hearing impairment or complete deafness in the affected ear due to the structural abnormalities of the ear canal and middle ear. Surgical procedures, such as ear reconstruction or the use of hearing aids, are commonly employed to address the functional and cosmetic aspects of microtia.…”

“…Large deletions (> 100 Kb) at 16p13.11 were observed in 23 patients, whereas in the control group, no deletions more than 16 Kb were found. Recently, Granata et al 27 reported on three distinct families in which two individuals were affected by inherited deletion in 16p13.11 and 16p13.11p12.3, respectively, and another third had a de novo 16p13.11 microdeletion. All four patients showed variable degrees of ID; two of them were also affected by language delay and dysmorphism, while in a single case was observed cryptorchidism and in another one stereotypes.…”

“…The 16p13.11 locus, deleted in our patient, is a genomic hotspot particularly rich in low-copy repeats (LCRs), highly homologous DNA sequences that increase the likelihood of copy number mutation through nonallelic homologous recombination. 27 The 16p13.11 region has been subdivided into three single-copy sequence intervals called interval I, II, and III, each flanked by LCRs. Typical 16p13.11 microdeletions have wide variable size (from 0.8 to 3.3 Mb) and encompass one or more of the three intervals.…”

Case Report: Prenatal Whole-Exome Sequencing Identified a Novel Nonsense Mutation of the KCNH2 Gene in a Fetus With Familial 2q14.2 Duplication

“…Additional mutations besides the structural variants were identified by WES detection in patients with familial 1q21.1 microduplication/microdeletion, duplication of Xp22.31, and 16p11.2 duplication who exhibited phenotypical variability ( Dastan et al, 2016 ; Qiao et al, 2017 ; Qiao et al, 2019 ). In addition, a recent study conducted by Granata et al (2022 ) identified variants in CECR2 , MTOR , RICTOR, and LRRK2 genes by WES detection in the affected patients who also had a 16p13.11 microdeletion and proposed that WES technology could be used as a fundamental tool to identify additional mutations in patients with a predisposing variant. In this study, the WES technology was employed to further investigate the genetic etiology in a fetus with familial 2q14.2 duplication who had more severe phenotypes.…”