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 (der3) in patient II-2 that resulted in partial monosomy 3p and partial trisomy 17p. On the other hand, the second adjacent 1 type led to a derivative 17 (der17) in patient II-7 that resulted in partial monosomy 17p and partial trisomy 3p. While deletions of 17p13.3 are associated with a well-known phenotype ranging from Miller Dieker syndrome [3] to partial agenesis of corpus callosum and milder phenotype [8], duplications of the same chromosomal region still need further clinical and molecular characterization. According to the involved genes, 17p13.3 duplications have been divided into either class I or class II leading to different clinical features [2].
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 [9-10-2-11-12-13-14-15] (FIG. 6) with varying sizes and different breakpoints. It has also been reported that these duplications might be the result of parental translocations. They never involved the 3p26 region.
The genomic distances (in base pairs from the 17p telomere) shown at the top of the figure were measured according to ensembl genome browser 59 (hg18). For each patient, a normal copy number is illustrated as a blue line and the duplicated segment as a pink line.
Here, our proband showed a loss of nearly 3,6 Kb on 3p26.2 and a gain of nearly 2,9 Mb on 17p13.3 and shared clinical and dysmorphic features including a high forehead and a triangular chin described in thirteen selected patients with duplication of the MDS region (Table 1). Our patient did not share some of these features whereas he presented arachnodactyly, which is rarely described in patients with partial trisomy of 17p13.3 [9-2-11-16]. The most frequent phenotypic features associated with partial trisomy of 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 of PAFAH1B1 that lead to its overexpression, was associated with moderate to severe development delay and structural brain abnormalities [9-2]. Brain-imaging analysis was performed in seven of the eleven reported patients and only four showed structural brain abnormalities (Table 1), of which Corpus Callosum hypoplasia or agenesis represented the main brain abnormality [9-13-10-14]. Likewise, our patient presented corpus callosum hypoplasia. Curiously, patients having the smallest and the largest duplications of the MDS region reported so far have presented normal Magnetic Resonance Imaging (MRI) (P1/[10]; P1/[15]). 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 [9]. Furthermore, lis1 overexpression affected both radial and tangential migration with a migration delay in radial migration at E13.5 and tangential migration at E12.5 rather than E14.5 [10]. However, subtelomeric neuronal migration defects are not expected to be detected by MRI scans [9]. Consequently, we can postulate that the overexpression of LIS1 gene could explain the phenotype of our patient particularly corpus callosum hypoplasia.
Table 1 Comparison of the phenotypic features of the proband with patients showing duplication of Miller-Dieker region
Paper
|
[12]
|
[ 15]
|
[ 11]
|
[ 10 ]
|
[9]
|
[ 14]
|
[ 13 ]
|
[ 16 ]
|
[ 10 ]
|
[ 14 ]
|
[ 14 ]
|
[ 2 ]
|
[ 10 ]
|
Present Study
|
Patient reference
|
Patient 1
|
Patient 1
|
Patient 1
|
Patient 3
|
Patient 7
|
Patient 12
|
Patient 1
|
Patient 1
|
Patient 2
|
Patient 13
|
Patient 15
|
Patient 10
|
Patient 1
|
Patient 1
|
Size of duplication,Mb
|
10,7
|
5,77
|
4,2
|
4
|
3,6
|
3,4
|
3,22
|
3,1
|
3
|
2,78
|
2,16
|
2
|
1,8
|
2,9
|
Inheritance
|
maternal
|
De novo
|
?
|
De novo
|
De novo
|
De novo
|
paternal
|
maternal
|
De novo
|
paternal
|
De novo
|
De novo
|
De novo
|
maternal
|
Age at diagnosis, years
|
prenatal
|
4
|
13
|
1
|
10
|
28
|
0.5
|
6
|
1
|
13mo
|
14
|
6.5
|
14
|
2
|
Gender
|
F
|
F
|
F
|
M
|
F
|
F
|
F
|
F
|
F
|
M
|
F
|
M
|
M
|
F
|
Birth height, cm
|
NA
|
55
|
Normal
|
50
|
53
|
NA
|
51
|
NA
|
NA
|
NA
|
NA
|
Normal
|
53
|
52
|
Birth weight, g
|
NA
|
2680
|
Normal
|
3380
|
3060
|
NA
|
3000
|
NA
|
4200
|
NA
|
NA
|
Normal
|
3350
|
3500
|
Current height
|
NA
|
+1SD
|
+1SD
|
+1SD
|
+1SD
|
NA
|
50–75th percentile
|
111 cm (10–25th percentile
|
Normal
|
NA
|
NA
|
Normal
|
+3.5 SD
|
+1,05DS
|
Current weight
|
NA
|
+1SD
|
+1SD
|
+1SD
|
+2SD
|
NA
|
25th percentile
|
17 kg (10th percentile)
|
-2SD
|
NA
|
NA
|
Normal
|
+1SD
|
+0,6DS
|
Cranio-facial dysmorphism
Hypotonic face
|
NA
|
+
|
+
|
+
|
-
|
+
|
-
|
-
|
+
|
+
|
NA
|
NA
|
+
|
-
|
Broad midface
|
NA
|
NA
|
+
|
+
|
-
|
-
|
-
|
+
|
+
|
-
|
-
|
NA
|
-
|
-
|
High forehead
|
+
|
+
|
-
|
+
|
-
|
NA
|
-
|
+
|
+
|
+
|
NA
|
NA
|
+
|
+
|
Upward palpebral fissures
|
NA
|
+
|
-
|
-
|
+
|
NA
|
+
|
+
|
-
|
-
|
NA
|
-
|
-
|
+
|
Hypertelorism
|
NA
|
+
|
+
|
+
|
-
|
-
|
+
|
+
|
+
|
-
|
-
|
-
|
+
|
+
|
Epicanthus
|
NA
|
NA
|
NA
|
+
|
NA
|
NA
|
-
|
-
|
-
|
-
|
NA
|
NA
|
-
|
+
|
Strabismus
|
NA
|
NA
|
-
|
-
|
+
|
NA
|
+
|
-
|
-
|
-
|
NA
|
-
|
-
|
-
|
Broad nasal bridge
|
NA
|
+
|
+
|
+
|
-
|
NA
|
+
|
+
|
+
|
+
|
NA
|
-
|
+
|
+
|
Small mouth
|
NA
|
+
|
+
|
+
|
Normal
|
+
|
+
|
+
|
+
|
+
|
+
|
Prominent cupid bow
|
Normal
|
+
|
Low-set-ears
|
+
|
NA
|
-
|
-
|
-
|
NA
|
-
|
+
|
+
|
+
|
NA
|
NA
|
+
|
-
|
Triangular chin
|
NA
|
NA
|
+
|
+
|
NA
|
+
|
+
|
-
|
+
|
+
|
+
|
+
|
-
|
+
|
Neck appearance
|
NA
|
NA
|
Normal
|
Short
|
Normal
|
NA
|
Short
|
Normal
|
Short
|
NA
|
NA
|
Normal
|
Normal
|
Short
|
Limb abnormalities
|
NA
|
NA
|
+
|
-
|
-
|
-
|
Long fingers
|
Long fingers
|
+
|
-
|
-
|
-
|
-
|
Long fingers
|
Hip luxation
|
NA
|
NA
|
-
|
+
|
-
|
NA
|
-
|
-
|
-
|
NA
|
NA
|
-
|
-
|
-
|
Equinovalgus
|
NA
|
NA
|
-
|
Right
|
-
|
NA
|
+
|
-
|
-
|
NA
|
NA
|
-
|
-
|
-
|
Neurological features
Hypotonia
|
NA
|
+
|
+
|
+
|
-
|
NA
|
-
|
-
|
+
|
-
|
+
|
+
|
+
|
-
|
Delayed mental development
|
NA
|
+
|
+
|
+
|
+
|
LD
|
+
|
-
|
+
|
Mild LD
|
Mild LD
|
-
|
+
|
-
|
Delayed motor development
|
NA
|
+
|
+
|
+
|
+
|
+
|
+
|
+
|
+
|
NA
|
+
|
-
|
+
|
+
|
Abnormal behavior
|
NA
|
NA
|
+
|
+
|
+
|
+
|
+
|
+
|
+
|
-
|
-
|
Autism
|
+
|
+
|
Brain imaging results
|
NA
|
Normal
|
Normal
|
Dilated lateral ventricles/ Corpus Callosum Agenesis
|
Reduced brain size, Corpus Callosum Hypoplasia, Cerebellar Agenesis
|
NA
|
Cortical Atrophy and Hypoplasia of Corpus Callosum
|
NA
|
NA
|
Thin Corpus Callosum, Cerebellar vermis hypoplasia
|
NA
|
NA
|
Normal
|
Corpus Callosum Hypoplasia
|
|
+: present/-:absent/NA:not available
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Numerous features in this case might be attributed to genes that are lost in chromosome 3p in addition to 17p13.3 duplication as a result of adjacent-1 malsegregation of the maternal balanced translocation. In fact, it has been shown that terminal 3p deletions are responsible for a rare contiguous gene disorder (OMIM# 613792) [17]. Interestingly, 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 [22-23-17]. In other studies, the authors have even hypothesized that distal 3p deletion is probably associated with normal intelligence and normal physical features [24-18] and 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, essentially CNTN4, CNTN6 and CRBN [25-26]. 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 profound motor coordination abnormalities and learning difficulties [25]. 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 is known to be involved in axon growth, guidance, and fasciculation [25] and it probably contributes to the behavioral abnormalities in our patient showing aggressiveness, anger and agitation. In fact, cntn4 knockout mice showed morphological, neurological and behavioral abnormalities [25]. The deletion also included CRBN gene that plays a crucial role in brain development [26]. 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, 3p26 deletion disrupted a more distal gene: CHL1 that plays a crucial role in development of the cortex by regulating neuronal differentiation and axon guidance [27]. Previous studies suggested CHL1 as a dosage-sensitive gene with a main role in intellectual disabilities [28]. Interestingly, Frints hypothesized that reduction equal to 50% of chl1 in the developing brain marked cognitive deficit [29].
Table 2 Comparison of the phenotypic features of the proband with patients showing 3p26 deletion
Paper
|
[ 4 ]
|
[ 18 ]
|
[ 19 ]
|
[ 20 ]
|
[ 21 ]
|
[ 17 ]
|
Present Study
|
Patient reference
|
Patient 1
|
Patient 1
|
Patient 2
|
Family F
|
Patient 1
|
Patient 1
|
Patient 1
|
Size of deletion,Mb
|
4,5
|
1,5
|
1,05
|
2,95
|
7,4
|
2,9
|
2,9
|
Inheritance
|
De novo
|
paternal
|
maternal
|
?
|
?
|
maternal
|
maternal
|
Age at diagnosis, years
|
16
|
9
|
24
|
14
|
prenatal
|
1 and 2 months
|
2
|
Gender
|
M
|
M
|
M
|
M
|
F
|
M
|
F
|
Birth height, cm
|
71
|
123
|
58
|
140
|
NA
|
48
|
52
|
Birth weight, g
|
2695
|
2600
|
5350
|
3400
|
295
|
3000
|
3500
|
Current height
|
NA
|
NA
|
-2SD
|
NA
|
NA
|
|
+1,05DS
|
Current weight
|
NA
|
NA
|
-2SD
|
NA
|
NA
|
|
+0,6DS
|
Cranio-facial dysmorphism
|
+
|
NA
|
+
|
+
|
+
|
+
|
+
|
Upward palpebral fissures
|
NA
|
NA
|
NA
|
+
|
NA
|
NA
|
+
|
Hypertelorism
|
+
|
NA
|
NA
|
NA
|
+
|
NA
|
+
|
Blepharophimosis
|
+
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
Eyelid
|
+
|
+
|
NA
|
NA
|
NA
|
NA
|
NA
|
Broad nasal bridge
|
+
|
NA
|
+
|
+
|
+
|
+
|
+
|
Micrognathia
|
+
|
NA
|
NA
|
NA
|
+
|
NA
|
|
Low-set-ears
|
+
|
NA
|
+
|
+
|
+
|
NA
|
-
|
Short philtrum
|
-
|
NA
|
+
|
+
|
+
|
NA
|
+
|
Limb abnormalities
|
-
|
-
|
-
|
bilateral clinodactyly of the fifth finger
|
NA
|
NA
|
+
|
Ptosis
|
+
|
+
|
NA
|
NA
|
+
|
NA
|
-
|
Microcephaly
|
+
|
+
|
+
|
+
|
brachycephaly
|
+
|
+
|
Neurological features
Hypotonia
|
+
|
+
|
+
|
|
NA
|
NA
|
-
|
Delayed mental development
|
+
|
+
|
+
|
+
|
NA
|
-
|
-
|
Delayed motor development
|
NA
|
NA
|
+
|
+
|
NA
|
NA
|
-
|
Abnormal behavior
|
NA
|
NA
|
NA
|
Hysterical and aggressive
|
NA
|
NA
|
+
|
Brain imaging results
|
NA
|
Centrotemporal spikes in the left hemisphere
|
Corpus callosum hypoplasia
|
NA
|
NA
|
Corpus callosum dysgenesis
|
Corpus Callosum Hypoplasia
|
|
+: present/-:absent/NA:not available
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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 PAFAH1B1genes duplicated in 17p and CNTN6 as well as CRBN genes deleted in 3p affected the process of cortical development by destabilization of microtubules and alteration of axon growth and axon guidance [30-25-31].
Neuronal migration is a complex process that involves several actors and factors in order to elaborate an appropriate cell migration from the ventricular zone into the cortical plate during normal brain development [32]. Mutations and chromosomal aberrations can alter chromosome 3D organization. This alteration could play a more important role than we believe it does in the chromosomal interactions and transcriptional regulation of genes. In fact, it has been shown that chromatin 3D modification could disturb the topologically associating domains (TADs) and consequently the regulation of gene expression [33]. Such alteration could explain the phenotypic variability in human disease ranging from milder phenotype to microdeletion/microduplication syndrome. Furthermore, this variability can be explained by the consanguinity in this family, which reduces the fitness of individuals by increasing the degree of homozygosity and promoting the development of deleterious recessive genes [34].