The use of array-CGH analyses for investigation of children with mental retardation has led to the identification of a growing number of new microdeletion and microduplication syndromes, some of which have been clinically well characterised while some other await further delineation.
The proximal short arm of chromosome 17 is particularly prone to cryptic rearrangements for the presence of a high density of low copy repeats. The Miller-Dieker syndrome (MDS) is localized in the more distal region 17p13.3 containing the PAFAH1B1 (encoding LIS1) and YWHAE genes. Recently, novel co-locating microdeletions and microduplications in chromosome 17p13.3 were identified by array-CGH describing new genomic disorders in the MDS locus. Most of these rearrangements are non-recurring and vary in size, from one hundred kilobases to about three megabases. The clinical characterization of both microdeletions and microduplications has been dissected according to the extension and the genes involved in such rearrangements. The main characteristics of 17p13.3 microdeletion are significant postnatal growth retardation, mild to moderate mental retardation, and facial anomalies.
Our patient and his mother have an interstitial microduplication of about 329.5 Kbs containing only seven genes. Many other patients with microduplications of varying size have been reported with different breakpoints and gene content
]. Bruno et al.
] reported on two cases (cases 9 and 11) in which duplicated regions overlapped the one reported here, containing CRK
genes. Only the duplication described by Bi et al.,
] (subject 2) is superimposable on that described here, while the duplicated region of subject 1 spans 240 Kb and contains only four genes: TUSC5
, and MYO1C
). Among the genes comprised in the duplicated region, particular interest has been paid to YWHAE
is a gene encoding 14-3-3epsilon, which is highly conserved across species, from bacteria to humans, and binds to phosphoserine/phosphothreonine motifs in a sequence-specific manner. The individuals with duplications including YWHAE are characterized by a milder neurocognitive and pervasive developmental disorder phenotype, and share some minor craniofacial abnormalities
]. The main phenotypic features of the patients include autistic manifestations, behavioral symptoms, developmental delay, varying degree of mental retardation, speech delay, several common facial features, and subtle hand/foot malformations. Three families were reported
] with split-hand/foot malformation and long bone deficiency (SHFLD); the same authors suggested that a locus responsible for this condition is located within a duplicated segment on 17p13.3 band containing ABR
genes. In another study, seventeen patients with 17p13.3 duplication, among 56 families with SHFLD syndrome, showed a minimal critical region encompassing the BHLHA9
]. Therefore, the authors concluded that the 17p duplication could be considered as a susceptibility locus for SHFLD, which is necessary but not sufficient for the development of these malformations. The high degree of non-penetrance could be dependent on other modifiers not identified yet.
Figure 4 Schematic representation of five 17p13.3 duplications in relation to gene content. Enlargement of band p13.3 of chromosome 17. For each individual, the solid lines (grey shading) below the map represent duplicated regions and nucleotide positions are (more ...)
Bruno et al.
] suggested that there are two classes of co-locating microduplications on 17p13.3. Class I duplications involve YWHAE
, but not PAFAH1B1
and the patients show autistic manifestation and behavioral problems, speech and motor delay, mild dysmorphic facial features, subtle hand and foot anomalies, and tendency to overgrowth. Class II microduplications always involve PAFAH1B1
and may extend to CRK
and have been associated to hypotonia, mild developmental, and psychomotor delay. Some dysmorphic features as prominent forehead and pointed chin, sometimes associated with microcephaly and growth restriction, are the most common characteristics
]. Our patient is tall with mild facial anomalies like upslanting eyes, squared nasal tip, normal chin, large and low-set ears, short hands with low-set thumbs, while the feet had laterally set fifth toes. Moderate mental retardation was associated with a pervasive developmental disorder not otherwise specified (PDD-NOS) with social interactions and communication impairment, motor stereotypes, perseveration behaviours, and attention deficit. Brain MRI identified the presence of non-progressive neuroradiological features characterized by posterior corpus callosum hypoplasia and mild cerebellar hypoplasia. According to the identified duplication involving YWHAE
, but not PAFAH1B1
, our patient could fit as having a class I duplication. Furthermore, his clinical phenotype seems to overlap the features previously identified in such patients, as showed in Table
Phenotypic features of patient with 17p13.3. class I microduplication
However, in the patient’s family history we have to consider that his mother presented antisocial behaviour, bipolar disorder, and alcoholism, but unfortunately she was not available for clinical evaluation or MRI tests. Furthermore, his father was drug addicted and his grandmother was affected by depression. Several environmental problems, intertwining with genetic factors, affect this family. Although genetic and environmental influences may work independently, research is beginning to acknowledge that these factors work in concert to influence the behavioral phenotype, as depression and anxiety
]. We should therefore consider the 17p13.3 duplication in terms of genetic contribution to a phenotype that, especially in his mother, seems to be due to different components.