A genotype-first approach for the molecular and clinical characterization of uncommon de novo microdeletion of 20q13.33

Abstract

Background: Subtelomeric deletions of the long arm of chromosome 20 are rare, with only 11 described in the literature. Clinical features of individuals with these microdeletions include severe limb malformations, skeletal abnormalities, growth retardation, developmental and speech delay, mental retardation, seizures and mild, non-specific dysmorphic features.

Methodology/principal findings: We characterized microdeletions at 20q13.33 in six individuals referred for genetic evaluation of developmental delay, mental retardation, and/or congenital anomalies. A comparison to previously reported cases of 20q13.33 microdeletion shows phenotypic overlap, with clinical features that include mental retardation, developmental delay, speech and language deficits, seizures, and behavior problems such as autistic spectrum disorder. There does not appear to be a clinically recognizable constellation of dysmorphic features among individuals with subtelomeric 20q microdeletions.

Conclusions/significance: Based on genotype-phenotype correlation among individuals in this and previous studies, we discuss several possible candidate genes for specific clinical features, including ARFGAP1, CHRNA4 and KCNQ2 and neurodevelopmental deficits. Deletion of this region may play an important role in cognitive development.

Figure 1. Microarray-based characterization of microdeletions at 20q13.33.

(A–F) Microarray results for study subjects 1–6, respectively. Study subject 1 was analyzed using a SNP microarray; study subjects 2–6 were analyzed using an oligonucleotide CGH-based array. For study subject 1, Copy Number Analyser for GeneChip (CNAG) version 3.0 was used for the analysis. For study subjects 2–6, results were visualized using custom aCGH analysis software (Genoglyphix; Signature Genomic Laboratories). Study subject 5 had a concurrent duplication at 20q13.33 (E). Probes are arranged with the most proximal 20q13.31 probes on the left and the most distal 20q13.33 probes on the right. (G) Schematic representation of deletions in study subjects 1–6 and in previously reported study subjects. Blue boxes represent genes of interest within the region.

Figure 2. Dysmorphic features in individuals with microdeletions at 20q13.33.

(A,B) Study subject 1 at age 8 years. No dysmorphic facial features were noted. (C) Study subject 2 at age 4 years. Note bitemporal narrowing, bulbous nose, and upslanting palpebral fissures. (D) Study subject 3 at age 3 years 3 months. Note bifrontal prominence, prominent forehead, triangular shape, mild hypertelorism, epicanthal folds, and ptosis. (E) Hand of study subject 2.