Enter Note Done


Keywords: Genetic testing; Genotype-phenotype correlations; Intellectual and developmental disability; Genome sequencing; Microarrays

G. Méjico 1; I. Canonero 1,2; M.F. Gosso 1; B. Brun 1; C. Rohr 1; M.F. Madeira 1; A.L. Ruggieri 1; P. Cecatto 1; I. Sfaello 2; Z. Sfaello 2; E. Cuestas 2; A. Martínez 2

1) Rosario, Héritas, Rosario, Santa Fe, Argentina; 2) Córdoba, Cetes, Córdoba, Córdoba, Argentina

Objective: To determine the detection rate and diagnostic/clinical advantages of implementing Array (aCGH) followed by Focused Clinical Exome Sequencing (CES) in individuals with unexplained developmental delay/intellectual disability (DD/ID).
Methods: Retrospective case series of individuals evaluated from 2016 until May 2019 by the Genetics and Neurology areas of our laboratory, in which diagnostic yield was performed after aCGH testing and followed by Focused CES in those who were negative. All of them have been proven negative by conventional cytogenetical analyses. Inclusion criteria: Studies that used aCGH and Focused CES to identify genetic abnormalities or pathogenic variants in patients with DD/ID and dysmorphia/congenital anomalies, in whom conventional cytogenetic analysis proved negative. Exclusion criteria: patients in whom genetic diagnostic had been carried out by other molecular studies.
Results: One hundred and ninety-five patients with DD/ID and dysmorphia were included. All of them were evaluated by karyotyping, aCGH and Focused CES on genes associated to DD/ID. Conventional cytogenetic analysis detected seven structural chromosomal rearrangements, of which only one was a balanced translocation. In forty-seven cases (24,10%) a pathogenic copy number variant was detected by aCGH and only eleven (5,60%) patients resulted in a variant of uncertain significance (VOUS). Otherwise, Focused CES on DD/ID genes yielded forty-eight cases (24,61%) with a pathogenic variant and eleven cases (5,60%) with a VOUS variant.
Conclusion: The combined diagnostic yield of causal genetic anomalies detected by aCGH or Focused CES on DD/ID genes in our case series was 60%. In order to improve this result, we are considering switching to clinical Whole Genome Sequencing with which, in addition to detecting CNVs and variants in coding sequences, could also identify intronic genetic variants and/or regulatory elements that we are not currently targeting due to both the intrinsic limitations of the techniques used and the enormous complexity implied in genetic counseling for WGS.