In this study group of Romanian patients with GDD/ID we observed pathogenic CNVs or VOUS in 26% of patients. Pathogenic CNVs and uniparental disomy were seen in 17% of patients. The recurrent pathogenic CNVs were seen in 18/32 patients (56%) with pathogenic findings (CNVs or uniparental disomy).
A similar percentage of pathogenic CNVs was also seen in other studies (7, 8, 9). This high number of diagnosed cases using microarray analysis, sustain the great diagnosis performance given by this investigation, indicated as first tier test in GDD/ID (4). Also, a genomic approach for the patients with an unspecific phenotype such as GDD/ID associated or not with other signs is very useful, in our case, only in 2% of cases being suggested an etiologic diagnosis at physical evaluation.
The high percentage of recurrent CNVs, of 56% between pathogenic findings was also seen by other authors (10), these CNVs also having a potential recognisable phenotype, often partial, compared to the classical described in literature, and this could be an argument to continue giving an importance to phenotype evaluation, which could bring in some situation a diagnosis, more easily and cheaply confirmed by a targeted genetic testing, such as MLPA, qPCR or FISH technique. These recurrent CNVs seen in our study were: 15q11.2-q31.1 deletion (Prader-Willi syndrome), 4p16 deletion (Wolf-Hirschhorn syndrome), 22q11.21 deletion/duplication (Velo-cardio-facial syndrome), 7p11.23 deletion (Williams syndrome), 5q35 deletion (Sotos syndrome), 16p11.2 deletion/16p11.2 duplication, 18p11 duplication, 18p11 deletion, 1q21 deletion, 1p36 deletion, 17p11.2 duplication, these findings were also remarqued by other studies (10, 11). Chromosome 8 was often involved in pathogenic CNVs, 4 patients presenting large deletion/duplication: 18q21.2-23 duplication, two 18p11.32-11.21 duplication and the same 18p11.32-11.21 deletion.
Among the analysed cases, the patient 3, a 12 years old boy with isolated GDD/ID, presents a 7.4 Mb duplication of X chromosome, including more OMIM genes, SOX3 being a known morbid gene, coding for a transcription factor implicated in neurogenesis, which is associated with mental retardation, X-linked, with isolated growth hormone deficiency. The patient presented a GDD/ID, same as other cases described in literature, but not short stature and GH deficiency (12, 13, 14, 15). CNV was interpreted as pathogenic CNVs. The particularity for patient 3 is the presence of 22q11.2 duplication, associated to X chromosome duplication.
The patient 5, a girl with GDD/ID and dysmorphic signs, presented 29.4Mb duplication of 1q41-1q44 region, which included 43 morbid OMIM genes (including ZBTB18) and this phenotype was already described in association with this CNVs (16, 17, 18, 19). This CNVs is known as 1q41-q42 microdeletion syndrome.
In patient 6, a boy with GDD/ID, ASD and obesity was observed a 16p13.2-16p13.13 duplication (3.8Mb), including GRIN2A gene, known to be associated with epilepsy and GDD/ID, which partially superpose with our patient picture. This duplication also included the region 16p13.2, known to be associated with 16p13.2 deletion syndrome (USP7 gene), which is involves an autistic spectrum disorder and GDD/ID, also seen in our patient, as in other group of patients with same characteristics (11).
Another particular CNVs is 14q32.2 deletion, seen in patient 45, which included some genes involved in intellectual disability, as YY1 gene, responsible of Gabriela de Vries syndrome(20). Overlapping CNVs were described in Decipher patients (260834, 291402), with similar phenotypes as our patient, however the cases with this CNV are very rares.
6q15-q21 deletion of 20.3 Mb seen in patient 71 is another rare CNV also recorded by some authors in association with intellectual delay (21, 22, 23), including an important number of OMIM genes involved in neurogenesis.
In patient 153, the 7p15.3-p21.1 deletion was also described in association with intellectual disability (24), including TWIST1 gene, associated with Robinow-Sorauf syndrome and Sweeney-Cox syndrome.
The deletion in 4q22.2-q24 region in patient 166 is also a very rare CNVs, it was described in patients with intellectual disability, dysmorphic features and internal malformations (25, 26).