Considering specific clinical features as evidence of pathogenic copy number variants

Abstract

Since the introduction of high-resolution microarray technologies, it has become apparent that structural chromosomal rearrangements can lead to a wide variety of clinical manifestations, including developmental delay/intellectual disability (DD/ID). It has been shown previously that the diagnostic yield of genome-wide array-based identification of submicroscopic alterations in patients with ID varies widely and depends on the patient selection criteria. More attempts have recently been made to define the phenotypic clues of pathogenic copy number variants (CNVs). The aim of this study was to investigate a well-phenotyped cohort of patients with DD/ID and determine whether certain clinical features may serve as indicators for pathogenic CNVs. A retrospective analysis was conducted for patients with DD/ID (n = 211) who were tested using genome-wide chromosomal microarray technologies and a review of the clinical data was performed. Pathogenic CNVs were detected in 29 patients. In comparison with individuals who had normal molecular karyotyping results (n = 182), malformations of the musculoskeletal system; congenital malformations of the CNS (particularly hydrocephalus and congenital malformations of the corpus callosum); minor anomalies of the eye, face, and neck subgroup (particularly downward-slanting palpebral fissures, minor anomalies of the ear, and micrognathia); brachydactyly; and umbilical hernia were more common in patients with chromosomal alterations. A multivariate logistic regression analysis allowed the identification of three independent pathogenic CNV predictors: congenital malformations of the corpus callosum, minor anomalies of the ear, and brachydactyly. Insights into the chromosomal phenotype may help to increase the diagnostic yield of microarray technologies and sharpen the distinction between chromosomal alterations and other conditions.

Phenotype comparison among individuals with developmental delay/intellectual disability with or without genomic imbalances

“…Eight previous studies, with different selection criteria, described specific clinical features that could favour the hypothesis of a GI in individuals with DD/ID (Shoukier et al 2013;Preiksaitiene et al 2014;Roselló et al 2014;Caramaschi et al 2014;D'Arrigo et al 2016;Cappuccio et al 2016;Caballero Pérez et al 2017;Maini et al 2018). However, the findings of these studies are heterogeneous.…”

Craniofacial abnormalities and developmental delay in two families with overlapping 22q12.1 microdeletions involving the MN1 gene

“…Our studies show the importance of high‐resolution microarray analysis in patients with orofacial clefts in determining pathogenic CNVs and recognizing cancer risk before its clinical presentation. Genomic alterations are a well‐established cause of orofacial clefts [Preiksaitiene et al, ; Younkin at al., 2014]. Cleft lip and cleft palate are defects commonly recognized at birth, while additional clinical presentations, such as intellectual disability or developmental delay are identified later in life.…”

Single gene microdeletions and microduplication of 3p26.3 in three unrelated families: CNTN6 as a new candidate gene for intellectual disability

“…These features were described only in patients with CNTN6 duplications; therefore, they may be considered unique to this chromosomal aberration, in contrast with the deletion of CNTN6 , according to the Golzio and Katsanis classification [ 17 ]. According to Preiksaitiene et al [ 18 ], hydrocephalus (p = 0.023), downslanting palpebral fissures (p = 0.008), minor anomalies of the ear (p = 0.002), and micrognathia (p = 0.004) are significantly associated with pathogenic CNVs. Additionally, minor anomalies of the ear have been demonstrated to be predictors of pathogenic CNVs, increasing the risk by 3.5-fold.…”