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

Abstract

Background The chromosomal microarray analysis (CMA) is recommended as a first‐tier test for individuals with developmental delay (DD)/intellectual disability (ID) and/or multiple congenital anomalies. However, owing to high costs, this technique is not widely performed for diagnostic purposes in several countries. The aim of this study was to identify clinical features that could favour the hypothesis of genomic imbalances (GIs) in individuals with DD/ID. Methods The sample consisted of 63 individuals, and all of them underwent a detailed evaluation by a clinical geneticist and were investigated by the CMA. They were divided into two groups. Group A composed of 20 individuals with pathogenic copy number variants (CNVs); and group B composed of 43 individuals with normal CMA results or variants of uncertain clinical significance (VUS). Results Pathogenic GIs were found in 20 cases (32%), including 11 individuals with an abnormal karyotype, VUS was found in five individuals (8%) and the results were normal in 38 individuals (60%). Major anomalies were found in 15/20 (75%) individuals in group A against 35/43 (81%) in group B. Dysmorphisms (≥5) were found in 17/20 (85%) in group A and 41/43 (95%) in group B. The most frequent major anomalies detected in group A were congenital heart disease, epilepsy and renal malformation; and in group B, they were malformations of central nervous system, congenital heart disease, microcephaly, epilepsy and hearing impairment. There was no significant statistical difference among the frequencies in groups A and B. Conclusions Evidences point that every individual with DD/ID, with no specific clinical suspicion, should have screening for GIs as a first‐tier test, regardless of the presence or absence of additional major anomalies or dysmorphisms. Future studies with a similar design would be helpful, especially in countries where the access to new technologies is still limited.

Genomic imbalances in craniofacial microsomia

“…Among the 17 individuals in our study, pathogenic CNVs were found in four (23.5%), including the three previous imbalances found by MLPA at the 22q11.2 region, and CNVs classified as VOUS in other four (23.5%) individuals. These percentages are similar to those found in CMA studies of individuals with multiple congenital anomalies (de Souza et al, 2019).…”

Identification of genomic imbalances in oral clefts

“…The interpretation of the chromosomal imbalances was based on international recommendations, according to the protocol developed by the FCM/UnicampCytogenetics and Cytogenomics Laboratory. 23 , 24 All CNVs were compared with data derived from the international databases: the Database of Genomic Variants (DGV), Affymetrix Database of Genomic Variants (aDGV), Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER), Clinical Genome Resource (ClinGen), and Online Mendelian Inheritance in Man (OMIM). Cases with pathogenic and possibly pathogenic CNVs were classified as abnormal CMA, and those with normal CMA that included CNVs were classified as benign, possibly benign, or as a variation of unknown significance (VOUS).…”

Dual Molecular Diagnoses of Recessive Disorders in a Child from Consanguineous Parents: Case Report and Literature Review

“…The data were analyzed using the Affymetrix ® Chromosome Analysis Suite (ChAS) version 4.0 (Thermo Fisher Scientific Inc.—Life Technologies, Carlsbad, CA, USA). The interpretation and classification of copy number variants (CNVs) and regions of homozygosity (ROH) were performed as previously described [ 13 , 14 ] following recommendations from the American College of Medical Genetics and Genomics(ACMG) [ 15 ] and the European guidelines for constitutional cytogenomic analysis [ 16 ]. The percentage of homozygosity in the patient’s autosomal genome was calculated by the sum of all homozygous regions detected (excluding the sex chromosomes), divided by total autosomal length, and multiplied by 100 [ 17 ] after using fixed detection settings.…”