Adjacent 1 segregation of the translocation t(3;17) in the mother led to two different chromosome imbalances in the children. The first type adjacent 1 gave rise to a derivative 3 chromosome (der3) in patient 1 that resulted in partial monosomy 3p and a partial trisomy 17p. While the second adjacent 1 type led to a derivative 17 (der17) in patient 2 that resulted in partial monosomy 17p and a partial trisomy 3p. 17p13.3 deletion encompassed PAFAH1B and YWHAE genes.
While deletions of 17p13.3 are associated with well-known phenotype ranging from Miller Dieker syndrome  to partial callosal and milder phenotype , duplications of the same chromosomal region still need further clinical and molecular characterization.
So far, to the best of our knowledge, only 13 patients having large 17p13.3 duplications, including the entire MDS comprising both PAFAH1B1 and YWHAE genes have been reported [10–11–2–12–13–14–15–16] (FIG. 6). Interestingly, all submicroscopic 17p13.3 duplications reported to date, including the present case did not share any recurrent breakpoints and have varying sizes. It has also been reported that these duplications might be the result of parental translocations involving chromosome 19 , chromosome 10  and chromosome 5  but it has never involved the 3p26 region. The proximal short arm of chromosome 17 is distinctly prone to cryptic rearrangements due to the presence of extensive repetitive sequences . Furthermore, this MDS telomeric critical region is estimated to at least 400kb including eight genes in addition to PAFAH1B1gene .
Due to the variability of the involved genes, 17p13.3 duplications have been divided into two classes with distinct phenotypic features . While, Class I duplications involve only YWHAE gene including autistic manifestations, speech, motor delay and dysmorphic facial features, Class II duplications include necessary PAFAH1B1gene and may contain also YWHAE and CRK genes . The phenotypic features in these cases show moderate to mild developmental and psychomotor delay . Nevertheless, when all the three genes, YWHAE, CRK and PAFAH1B1 are duplicated, the phenotype seems to be more severe .
Here, our proband shared clinical and dysmorphic features described in patients with duplication of the complete MDS region such as abnormal behavior (Table 1).
We reviewed an exhaustive list for the selection of thirteen cases of 17p13.3 trisomic (Table 1) who showed common dysmorphic features including a high forehead, a small mouth, and a triangular chin. Some of these features were absent in our patient. In addition, our patient presented arachnodactyly, which is rarely described in patients with partial trisomy of 17p13.3 [10–2–12–17]. By means of complementary cytogenetic techniques, the chromosomal rearrangements were estimated to at least 3,6 Kb on chromosome 3p26.2 and 2,9 Mb on chromosome 17p13.3. The most frequent phenotypic features associated with partial trisomy 17p13.3 were correlated with duplication of the PAFAH1B1 and YWAHE genes that were located in the MDS region. It was hypothesized that the duplication of YWHAE might have an effect on neuronal network development and maturation, and was related to mild development delay and facial dysmorphisms while the duplication ofPAFAH1B1 that lead to its overexpression, was associated with moderate to severe development delay and structural brain abnormalities [10–2]. Brain-imaging analysis was performed in seven of the eleven reported patients and only four showed structural brain abnormalities (Table 1). Corpus Callosum hypoplasia or agenesis represented the main brain abnormality being frequently described [10–14–11–15]. Likewise, our patient presented corpus callosum hypoplasia. Curiously, patients having the smallest and the largest duplications of the entire MDS region reported so far have presented normal Magnetic Resonance Imaging (MRI) (P1/; P1/). This suggests that this heterogeneity depends on the size of the duplication and the involved genes as well as on the involvement of other gene interactions and modifier genes. Indeed, it has been proven that transgenic mice with increased lis1 expression in the developing brain revealed abnormalities in the neuroepithelium such as the thinning of the ventricular zone, and the ectopic positioning of mitotic cells . Furthermore, lis1 overexpression affected both radial and tangential migration. In fact, in this condition, migration delay in both trajectories was observed: radial migration at E13.5 and tangential migration at E12.5 rather than E14.5 . However, subtelomeric neuronal migration defects are not expected to be detected by MRI scans . Consequently, we can postulate that the overexpression of LIS1 gene could explain the phenotype of our patient particularly corpus callosum hypoplasia.
The clinical findings in this case are certainly due to the cumulative effect of two imbalances as the result of adjacent–1 malsegregation in the maternal balanced translocation. Numerous features might be attributed to genes that are lost in chromosome 3p in addition to 17p13.3 duplication. In fact, it has been shown that terminal 3p deletions cause a wide range of phenotypes and are responsible for a rare contiguous gene disorder (OMIM# 613792). This syndrome is characterized by a recognizable phenotype including postaxial polydactyly, renal abnormalities, moderate bilateral sensorineural hearing loss, bilateral macular hypoplasia, respiratory difficulties, hypoplastic corpus callosum, congenital heart defect and gastrointestinal abnormalities [19–20]. The severity of the phenotype depends on the size of the deletion as well as on the gene content and disrupted genes involved in the breakpoints .
The proposed pathogenic mechanism for this syndrome is the haploinsufficiency of three important genes (CNTN4, CNTN6 and CRBN) (FIG. 7) leading to developmental delay or mental retardation [21–22–23]. It has been demonstrated that both CNTN4 and CNTN6 genes encode a neural adhesion molecule that is part of the immunoglobulin superfamily [24–25]. In fact, the CNTN6 gene plays a crucial role in the development, maintenance, and plasticity of functional neuronal networks in the central nervous system. It has been shown that Cntn6 deficiency in mice causes profoundmotor coordination abnormalities and learning difficulties . Owing to its function, we suggest that CNTN6 gene could be responsible for the observed psychomotor development retardation in the current case. On the other hand, CNTN4, an important gene for brain development, is known to be involved in axon growth, guidance, and fasciculation [27–28–29–30]. In addition, it probably contributes to the behavioral abnormalities in our patient showing aggressiveness, anger and agitation. In fact, knockout mice of homologous neuronal adhesion molecules showed morphological, neurological and behavioral abnormalities .
The deletion included also CRBN gene encoding a protein of the ubiquitin proteasome pathway, which seemed to play a crucial role in brain development  (FIG. 7). In fact, CRBN protein is part of DCX protein ligase complex involved in the regulation of the surface expression of certain types of ion channels in neuronal memory synapses. Furthermore, the 3p26 deletion disrupted a more distal gene: CHL1 (FIG. 7).The latter encodes a protein member of the L1 family of neural cell adhesion molecules  and plays a crucial role in development of cortex by regulation of neuronal differentiation and axon guidance [34–35] and is involved in the maturation of nervous system by regulation of synaptic activity and plasticity [36–37]. Previous studies suggested CHL1 as a dosage-sensitive gene with a main role in intellectual disabilities [21–38–39–40]. Interestingly, Frints hypothesized that reduction equal to 50% of chl1 in the developing brain marks cognitive deficit .
Haploinsufficiency of CNTN4, CNTN6 and CRBN and disruption of CHL1 within the breakpoints could then be responsible for the observed neurodevelopmental phenotype in the proband.
We reviewed six previously reported cases having 3p deletion, compared them to the present case report, and noted that the most frequent features are microcephaly, corpus callosum hypoplasia and facial dysmorphia (Table 2). Conversely, some studies reported cases with 3p deletion and normal phenotypes [45–46–20]. In other studies, the authors have even hypothesized that the distal 3p deletion is probably associated with normal intelligence and normal physical features [47–41].
Interestingly, both 3p deletion and17p duplication could share the same network in neuronal migration since both anomalies lead to corpus callosum hypoplasia and pachygyria. So far, both genes duplicated in 17p especially PAFAH1B1 and genes deleted in 3p especially CNTN6 and CRBN affected the process of cortical development by alteration of the stabilization of microtubules, the axon growth and the axon guidance [48–26–49].
Neuronal migration is a complex process that involves several actors and factors [50–51]. The most critical step responsible for a normal brain development is the cell migration from the ventricular zone into the cortical plate .
Mutations and chromosomal aberrations can alter the chromosome 3D organization. This alteration could play a more important role than we believe it does in chromosomal interactions and transcriptional regulation of genes. In fact, it has been shown that the chromatin 3D modification could disturb the topologically associating domains (TADs) and consequently the regulation of gene expression [53–54–55]. Such alteration could explain the phenotypic variability in human disease ranging from milder phenotype to microdeletion/microduplication syndrome.